Prof. Dr. Gabriele Sadowski

Thermodynamics
TU Dortmund University

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  • Boosting the kinetic efficiency of formate dehydrogenase by combining the effects of temperature, high pressure and co-solvent mixtures
    Jaworek, M.W. and Gajardo-Parra, N.F. and Sadowski, G. and Winter, R. and Held, C.
    Colloids and Surfaces B: Biointerfaces 208 (2021)
    The application of co-solvents and high pressure has been shown to be an efficient means to modify the kinetics of enzyme-catalyzed reactions without compromising enzyme stability, which is often limited by temperature modulation. In this work, the high-pressure stopped-flow methodology was applied in conjunction with fast UV/Vis detection to investigate kinetic parameters of formate dehydrogenase reaction (FDH), which is used in biotechnology for cofactor recycling systems. Complementary FTIR spectroscopic and differential scanning fluorimetric studies were performed to reveal pressure and temperature effects on the structure and stability of the FDH. In neat buffer solution, the kinetic efficiency increases by one order of magnitude by increasing the temperature from 25° to 45 °C and the pressure from ambient up to the kbar range. The addition of particular co-solvents further doubled the kinetic efficiency of the reaction, in particular the compatible osmolyte trimethylamine-N-oxide and its mixtures with the macromolecular crowding agent dextran. The thermodynamic model PC-SAFT was successfully applied within a simplified activity-based Michaelis-Menten framework to predict the effects of co-solvents on the kinetic efficiency by accounting for interactions involving substrate, co-solvent, water, and FDH. Especially mixtures of the co-solvents at high concentrations were beneficial for the kinetic efficiency and for the unfolding temperature. © 2021 Elsevier B.V.
    view abstract10.1016/j.colsurfb.2021.112127
  • Co-Crystal Screening by Vapor Sorption of Organic Solvents
    Veith, H. and Luebbert, C. and Rodríguez-Hornedo, N. and Sadowski, G.
    Crystal Growth and Design (2021)
    The formulation of active pharmaceutical ingredients (APIs) as pharmaceutical co-crystals (CCs) is a promising way to overcome the poor aqueous solubility and therewith poor bioavailability of many APIs. Identifying suitable coformers (CFs) that form CCs with the API is a major challenge during CC development. In this work, we developed a material-sparing and simple approach to identify whether a certain API/CF combination can form CCs. This approach is based on the solvent vapor sorption of API/CF combinations in a dynamic vapor-sorption apparatus. CC formation is detected based on the solvent vapor uptake behavior of an API/CF crystal mixture. This screening approach was applied for carbamazepine (CBZ)/nicotinamide and CBZ/acetylsalicylic acid systems using ethanol and methanol as the volatile solvents. CC formation was observed for both systems with both solvents used. Additionally, the process and success of CC formation by vapor sorption is explained by predicted phase diagrams using the Perturbed-Chain Statistical Associating Fluid Theory. The developed approach is beneficial over co-grinding and other batch crystallization approaches in that it can be performed with only a few milligrams of the API, low solvent consumption, and a solvent sorption versus time behavior for identifying CC formation. © 2021 American Chemical Society.
    view abstract10.1021/acs.cgd.1c00355
  • Combining crystalline and polymeric excipients in API solid dispersions – Opportunity or risk?
    Veith, H. and Wiechert, F. and Luebbert, C. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 158 (2021)
    Amorphous solid dispersions (ASDs) are often metastable against crystallization of the active pharmaceutical ingredient (API) and thus might undergo unwanted changes during storage. The crystallization tendency of ASDs is influenced by the API crystallization driving force (CDF) and the mobility of the molecules in the ASD. Low molecular weight-excipients are known to stabilize amorphous APIs in so-called co-amorphous formulations. Due to their success in stabilizing co-amorphous APIs, low-molecular weight excipients might also enhance the stability of polymeric ASDs. In this work, we investigated the potential of combined low-molecular weight excipient/polymer formulations with in-silico tools and validated the predictions with long-term stability tests of the most promising excipient/polymer combinations. The considered critical quality attributes for the ASDs were the occurrence of amorphous phase separation, API CDF, and molecular mobility in the ASD. As an example, carbamazepine/polyvinylpyrrolidone ASDs were investigated combined with the excipients fructose, lactose, sucrose, trehalose, saccharin, tryptophan, and urea. Although all excipients had a negative impact on the ASD stability, saccharin still turned out to be the most promising one. Long-term stability studies with ASDs containing either saccharin or tryptophan verified -in agreement to the predictions- that API crystallization occurred faster than in the reference ASDs without additional excipient. This work showed that the addition of crystalline excipients to polymeric ASDs might not only offer opportunities but might also bear risks for the long-term stability of the ASD, even though the crystalline excipient stabilizes the polymer-free API. Consequently, excipients should be evaluated based on the thermodynamic phase behavior of the individual mixture of API/polymer/excipient, rather than based on pure-component properties of the excipient only. In-silico predictions proposed in this work remarkably decrease the number of screening tests for identifying suitable formulation excipients. © 2020 Elsevier B.V.
    view abstract10.1016/j.ejpb.2020.11.025
  • Determination of inherent dissolution performance of drug substances
    Sleziona, D. and Mattusch, A. and Schaldach, G. and Ely, D.R. and Sadowski, G. and Thommes, M.
    Pharmaceutics 13 (2021)
    The dissolution behavior of novel active pharmaceutical ingredients (API) is a crucial parameter in drug formulation since it frequently affects the drug release. Generally, a distinction is made between surface-reaction-and diffusion-controlled drug release. Therefore, dissolution studies such as the intrinsic dissolution test defined in the pharmacopeia have been performed for many years. In order to overcome the disadvantages of the common intrinsic dissolution test, a new experimental setup was developed within this study. Specifically, a flow channel was designed and tested for measuring the mass transfer from a flat, solid surface dissolving into a fluid flowing over the surface with well-defined flow conditions. A mathematical model was developed that distinguishes between surface-reaction-and diffusion-limited drug release based on experimental data. Three different drugs—benzocaine, theophylline and griseofulvin—were used to investigate the mass flux during dissolution due to surface reaction, diffusion and convection kinetics. This new technique shows potential to be a valuable tool for the identification of formulation strategies. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    view abstract10.3390/pharmaceutics13020146
  • Generalized Diffusion-Relaxation Model for Solvent Sorption in Polymers
    Borrmann, D. and Danzer, A. and Sadowski, G.
    Industrial and Engineering Chemistry Research (2021)
    Solvent sorption in polymers is of general interest for a wide variety of applications. It is well known that solvent sorption in polymers depends on both solvent diffusion and the slow rearrangement of the polymer, also known as polymer relaxation. This study provides a physically meaningful model approach for describing solvent diffusion in polymers, while considering relaxation in its most generalized form. A diffusion-relaxation model was created by combining the Stefan-Maxwell equations with multiple Maxwell elements. Parameter studies reveal the capability of the developed approach to describe anomalous solvent sorption behavior in polymers like sigmoidal, two-stage, pseudo-Fickian, case II, and super case II behavior. These parameter studies also provide detailed insights into the physical reasonings behind these phenomena. Moreover, to the best of our knowledge, this is the first time that first-principles modeling of multistage sorption curves is reported. ©
    view abstract10.1021/acs.iecr.1c02359
  • Historical Perspective of the Journal of Chemical & Engineering Data's Published Topics, 1956-2020
    Gardas, R.L. and Kofke, D.A. and Pini, R. and Sadowski, G. and Schwarz, C.E. and Siepmann, J.I. and Wu, J.
    Journal of Chemical and Engineering Data 66 (2021)
    view abstract10.1021/acs.jced.1c00193
  • Impact of deep eutectic solvents and their constituents on the aqueous solubility of phloroglucinol dihydrate
    Gajardo-Parra, N.F. and Do, H.T. and Yang, M. and Pérez-Correa, J.R. and Garrido, J.M. and Sadowski, G. and Held, C. and Canales, R.I.
    Journal of Molecular Liquids 344 (2021)
    Phlorotannins are highly bioactive phenolic compounds mainly found in brown algae. Phloroglucinol is the basic unit from which phlorotannins polymerize. Deep eutectic solvents (DES) are potentially beneficial for increasing phenolics solubility, therefore good solvent candidates for phlorotannins extraction processes. Solubility measurements were performed for phloroglucinol in pure water and aqueous mixtures of DES or their constituents, i.e., different hydrogen bond donors (HBD) and choline chloride (ChCl). The stable crystal form of the phenolic in equilibrium was phloroglucinol dihydrate within the studied temperature range (293.15–313.15 K) and water weight fractions (≥0.25). The water + ChCl + HBD mixtures yielded higher solubility for phloroglucinol dihydrate than the corresponding water + HBD or water + ChCl mixtures. Solubility predicted with PC-SAFT was in quantitative agreement with the experimental data. The solubility behavior of phloroglucinol dihydrate in the different mixtures was related to the hydrogen bonds formed using molecular dynamics and PC-SAFT. © 2021 Elsevier B.V.
    view abstract10.1016/j.molliq.2021.117932
  • Insights into influence mechanism of polymeric excipients on dissolution of drug formulations: A molecular interaction-based theoretical model analysis and prediction
    Ji, Y. and Hao, D. and Luebbert, C. and Sadowski, G.
    AIChE Journal 67 (2021)
    This study provides an analysis of the dissolution mechanism of poorly water-soluble drugs, indomethacin (IND) and naproxen (NAP), from polyvinyl acetate (PVAc) and polyvinylpyrrolidone/vinyl acetate 64 (PVPVA 64) formulations under the combination of the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and a chemical-potential-gradient model. Moreover, the dissolution kinetics of both drugs from these polymeric formulations were modeled in conformity with the in vitro experimental data obtained by means of a rotating disk system (USP II). The combination of the thermodynamic model PC-SAFT and a chemical-potential-gradient model was demonstrated to be an efficient approach to explain the drug dissolution mechanism from the drug/PVAc and PVPVA 64 formulations. These results have implications in reducing experimental time and resources for the sustained dissolution kinetics profile determination without compromising accuracy, in particular for the system of the drug/PVAc formulation when obtaining continuous drug dissolution in this work. © 2021 American Institute of Chemical Engineers.
    view abstract10.1002/aic.17372
  • Journal of Chemical & Engineering Data: An Update from the Editorial Team
    Siepmann, J.I. and Gardas, R.L. and Kofke, D.A. and Pini, R. and Sadowski, G. and Schwarz, C.E. and Wu, J.
    Journal of Chemical and Engineering Data 66 (2021)
    view abstract10.1021/acs.jced.0c01080
  • Journal of chemical & engineering data: Why change the cover page?
    Siepmann, J.I. and Gardas, R.L. and Kofke, D.A. and Pini, R. and Sadowski, G. and Schwarz, C.E. and Wu, J.
    Journal of Chemical and Engineering Data 66 (2021)
    view abstract10.1021/acs.jced.1c00048
  • Measurement and PC-SAFT Modeling of the Solubility of Gallic Acid in Aqueous Mixtures of Deep Eutectic Solvents
    Sepúlveda-Orellana, B. and Gajardo-Parra, N.F. and Do, H.T. and Pérez-Correa, J.R. and Held, C. and Sadowski, G. and Canales, R.I.
    Journal of Chemical and Engineering Data (2021)
    Deep eutectic solvents have appeared as potential solvents for improving the extraction of polyphenols from vegetable or fruit matrixes. Since gallic acid is abundant in these sources, it is considered as a typical standard for quantifying their total polyphenol content after extraction with solvents. However, there are no extensive studies on the solubility behavior of gallic acid in different solvents or deep eutectic solvents. Thus, in this work, the solubility of gallic acid is measured in pure water; aqueous solutions of different hydrogen bond donors such as ethylene glycol, levulinic acid, and glycerol; and aqueous mixtures of deep eutectic solvents using choline chloride as the hydrogen bond acceptor and ethylene glycol, levulinic acid, and glycerol as the hydrogen bond donors. All of the measurements were performed at 293.15, 303.15, and 313.15 K and at 101.3 kPa and were validated by comparing the solubility of gallic acid in water from the literature. Results suggest that a 50 wt % aqueous solution of deep eutectic solvent based on ethylene glycol or glycerol improves the gallic acid solubility compared with a 50 wt % aqueous solution of its corresponding hydrogen bond donor. The deep eutectic solvent containing levulinic acid acts as the best aqueous mixture for gallic acid dissolution. Nondissolved gallic acid was measured after equilibrium using powder X-ray diffraction, showing that its structure does not change upon mixing with all of the liquid mixtures. All of the solid-liquid equilibrium results were accurately modeled with perturbed-chain statistical associating fluid theory (PC-SAFT). © 2021 American Chemical Society.
    view abstract10.1021/acs.jced.0c00784
  • Methodology Based on the Theory of Information to Describe the Representation Ability of the DMC + Alkane Behavior
    Sosa, A. and Ortega, J. and Fernández, L. and Haarmann, N. and Sadowski, G.
    Industrial and Engineering Chemistry Research 60 (2021)
    An information theory-based methodology has been applied to the multiproperty modeling of solution properties. Under this framework, a practical application on a set of binary solutions formed by dimethyl carbonate and six even saturated hydrocarbons (from C6 to C16) is carried out. A dense experimental database is generated composed of volumetric and energetic properties (from mixing processes), and phase equilibria, in order to disambiguate some discrepancies showed by the literature data, mainly for the binary with dodecane. The experimental information is modeled with a semiempirical equation for gE, and with the PCP-SAFT equation of state, which presents a solid theoretical basis. The optimal parameterizations are sought using the precision-complexity binomial whose aim is to increase the validity range of the set of parameters obtained. The Akaike Information Criterion is used to search the best parameterizations, that is, the appropriate number of parameters (complexity) and their best values (precision). With regard to the suitability of the precision-complexity methodology on the models tested, the following is concluded: with PCP-SAFT, precise and reliable estimates are obtained; for the gE model, the proposed approach is essential to control the number of free parameters and to preserve the stable numerical behavior in a wide range of conditions. © 2021 American Chemical Society.
    view abstract10.1021/acs.iecr.0c05301
  • Pc-saft modeling of phase equilibria relevant for lipid-based drug delivery systems
    Sadowski, G. and Brinkmann, J. and Exner, L. and Verevkin, S.P. and Luebbert, C.
    Journal of Chemical and Engineering Data 66 (2021)
    In this work we investigated the solubilities of 10 active pharmaceutical ingredients (APIs), namely, fenofibrate, ibuprofen, cinnarizine, carbamazepine, indomethacin, naproxen, griseofulvin, glibenclamide, felodipine, and praziquantel in the pharmaceutically relevant excipients tricaprylin, Lauroglycol FCC, Capryol 90, Kolliphor TPGS, ethanol, and monolaurin. API solubilities were either determined gravimetrically, with high-performance liquid chromatography, or with differential scanning calorimetry. Mutual solubilities in the three possible mixtures out of Kolliphor TPGS, tricaprylin, and carbitol as well as the vapor sorption of ethanol in tricaprylin were determined experimentally. The Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) pure-component parameters for seven APIs were determined via fitting to vapor pressures and liquid densities or to solubilities in organic solvents. In total, 80 binary interaction parameters were fitted to the investigated binary mixtures. They can be used in the future to improve the accuracy of lipid-based drug delivery systems in-silico screenings with PC-SAFT. © 2021 American Chemical Society. All rights reserved.
    view abstract10.1021/acs.jced.0c00912
  • Phase behavior of ASDs based on hydroxypropyl cellulose
    Luebbert, C. and Stoyanov, E. and Sadowski, G.
    International Journal of Pharmaceutics: X 3 (2021)
    Novel polymeric carriers for amorphous solid dispersions (ASDs) are highly demanded in pharmaceutical industry to improve the bioavailability of poorly-soluble drug candidates. Besides established polymer candidates, hydroxypropyl celluloses (HPC) comes more and more into the focus of ASD production since they have the availability to stabilize drug molecules in aqueous media against crystallization. The thermodynamic long-term stability of HPC ASDs with itraconazole and fenofibrate was predicted in this work with PC-SAFT and compared to three-months enduring long-term stability studies. The glass-transition temperature is a crucial attribute of a polymer, but in case of HPC hardly detectable by differential scanning calorimetry. By investigating the glass transition of HPC blends with a miscible polymer, we were for the first time able to estimate the HPC glass transition. Although both, fenofibrate and itraconazole reveal a very low crystalline solubility in HPC regardless of the HPC molecular weight, we observed that low-molecular weight HPC grades such as HPC-UL prevent fenofibrate crystallization for a longer period than the higher molecular weight HPC grades. As predicted, the ASDs with higher drug load underwent amorphous phase separation according to the differential scanning calorimetry thermograms. This work thus showed that it is possible to predict critical drug loads above which amorphous phase separation and/or crystallization occurs in HPC ASDs. © 2020 The Authors
    view abstract10.1016/j.ijpx.2020.100070
  • Phase Equilibria for the Hydroaminomethylation of 1-Decene
    Huxoll, F. and Schlüter, S. and Budde, R. and Skiborowski, M. and Petzold, M. and Böhm, L. and Kraume, M. and Sadowski, G.
    Journal of Chemical and Engineering Data (2021)
    This work focuses on the measuring and modeling of phase equilibria of interest for the hydroaminomethylation of 1-decene with syngas (CO/H2) and diethylamine to N,N-diethylundecan-1-amine and water in a solvent system of methanol and n-dodecane. H2 solubilities were measured in undecanal and N,N-dimethyldodecan-1-amine at 343 and 363 K between 2 and 4 MPa via the isochoric saturation method. Vapor-Liquid equilibrium data were measured for the binary systems methanol/N,N-diethylundecan-1-amine, 1-decene/diethylamine, and 1-decene/N,N-diethylundecan-1-amine at temperatures between 299 and 372 K and at pressures of 0.005, 0.018, 0.025, or 0.030 MPa. Liquid-Liquid equilibria were measured in the ternary systems methanol/n-dodecane/diethylamine, methanol/n-dodecane/undecanal, and methanol/n-dodecane/N,N-diethylundecan-1-amine at 0.1 MPa and at temperatures ranging from 278.15 to 308.15 K. Measured and available phase-equilibrium data from literature were modeled using perturbed-chain polar statistical associating fluid theory. This then allowed for modeling the Henry's law constant for H2 and CO in the liquid components (methanol, n-dodecane, 1-decene, diethylamine, undecanal, N,N-diethylundecan-1-amine, and water) at 373.15 and 393.15 K. © 2021 The Authors. Published by American Chemical Society.
    view abstract10.1021/acs.jced.1c00561
  • Predicting deliquescence relative humidities of crystals and crystal mixtures
    Veith, H. and Luebbert, C. and Sadowski, G.
    Molecules 26 (2021)
    The presence of water in the form of relative humidity (RH) may lead to deliquescence of crystalline components above a certain RH, the deliquescence RH (DRH). Knowing the DRH values is essential, e.g., for the agrochemical industry, food industry, and pharmaceutical industry to identify stability windows for their crystalline products. This work applies the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) to purely predict the DRH of single components (organic acids, sugars, artificial sweeteners, and amides) and multicomponent crystal mixtures thereof only based on aqueous solubility data of the pure components. The predicted DRH values very well agree with the experimental ones. In addition, the temperature influence on the DRH value could be successfully predicted with PC-SAFT. The DRH prediction also differentiates between formation of hydrates and anhydrates. PC-SAFT-predicted phase diagrams of hydrate-forming components illustrate the influence of additional components on the hydrate formation as a function of RH. The DRH prediction via PC-SAFT allows for the determining of the stability of crystals and crystal mixtures without the need for time-consuming experiments. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    view abstract10.3390/molecules26113176
  • Predicting process design spaces for spray drying amorphous solid dispersions
    Dohrn, S. and Rawal, P. and Luebbert, C. and Lehmkemper, K. and Kyeremateng, S.O. and Degenhardt, M. and Sadowski, G.
    International Journal of Pharmaceutics: X 3 (2021)
    Amorphous solid dispersions (ASDs) are commonly manufactured using spray-drying processes. The product quality can be decisively influenced by the choice of process parameters. Following the quality-by-design approach, the identification of the spray-drying process design space is thus an integral task in drug product development. Aiming a solvent-free and homogeneous ASD, API crystallization and amorphous phase separation needs to be avoided during drying. This publication provides a predictive approach for determining spray-drying process conditions via considering thermodynamic driving forces for solvent drying as well as ASD-specific API/polymer/solvent interactions and glass transitions. The ternary API/polymer/solvent phase behavior was calculated using the Perturbed-Chain Statistical Associating Theory (PC-SAFT) and combined with mass and energy balances to find appropriate spray-drying conditions. A process design space was identified for the ASDs of ritonavir and naproxen with either poly(vinylpyrrolidone) or poly(vinylpyrrolidone-co-vinylacetate) spray dried from the solvents acetone, dichloromethane, or ethanol. © 2021 The Author(s)
    view abstract10.1016/j.ijpx.2021.100072
  • Predicting the API partitioning between lipid-based drug delivery systems and water
    Brinkmann, J. and Becker, I. and Kroll, P. and Luebbert, C. and Sadowski, G.
    International Journal of Pharmaceutics 595 (2021)
    Partitioning tests in water are early-stage standard experiments during the development of pharmaceutical formulations, e.g. of lipid-based drug delivery system (LBDDS). The partitioning behavior of the active pharmaceutical ingredient (API) between the fatty phase and the aqueous phase is a key property, which is supposed to be determined by those tests. In this work, we investigated the API partitioning between LBDDS and water by in-silico predictions applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and validated these predictions experimentally. The API partitioning was investigated for LBDDS comprising up to four components (cinnarizine or ibuprofen with tricaprylin, caprylic acid, and ethanol). The influence of LBDDS/water mixing ratios from 1/1 up to 1/200 (w/w) as well as the influence of excipients on the API partitioning was studied. Moreover, possible API crystallization upon mixing the LBDDS with water was predicted. This work showed that PC-SAFT is a strong tool for predicting the API partitioning behavior during in-vitro tests. Thus, it allows rapidly assessing whether or not a specific LBDDS might be a promising candidate for further in-vitro tests and identifying the API load up to which API crystallization can be avoided. © 2021 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2021.120266
  • Predicting vapor−liquid equilibria for sour-gas absorption in aqueous mixtures of chemical and physical solvents or ionic liquids with EPC-SAFT
    Bülow, M. and Ince, N.G. and Hirohama, S. and Sadowski, G. and Held, C.
    Industrial and Engineering Chemistry Research 60 (2021)
    Sour-gas absorption is the main unit operation used in refineries and petrochemical and natural gas processing plants for the effective reduction of climate-wrecking gases, mainly CO2 and H2S. Absorption is typically accomplished in an aqueous solvent mixture. The solvent mixture is vastly dependent on the application range; it might contain chemical solvents (amines), activators, and physical solvents. In this work, the vapor−liquid equilibria for absorption of the sour gases CO2 and H2S was investigated in systems containing the chemical solvent methyl diethanolamine (MDEA) and the physical solvents tetrahydrothiophene-1,1-dioxide (sulfolane) or the ionic liquid 1-butyl-3-methylimidazolium acetate. The solubilities of CO2 and H2S were predicted and validated using experimental literature data in a broad range of temperature (313−373 K), sour-gas loading (up to 2 moles gas per moles of MDEA), and pressure (up to 180 bar) at constant MDEA weight fraction (20.9 wt %) and sulfolane weight fraction (30.5 wt %). The equation-of-state electrolyte perturbed-chain statistical associating fluid theory (ePC-SAFT) was utilized in this work for the predictions combined with the Born term to physically correctly describe the Gibbs energy of solvation of ions in the aqueous mixture of chemical and physical solvents; this was introduced in a recent work [Bülow, M. et al. Fluid Phase Equilib. 2021, 535, 112967]. Using this approach allowed reducing the total number of binary interaction parameters in these systems of maximum 11 species to a minimum; these parameters were fitted exclusively to data of binary mixtures. The ePC-SAFT predictions of the gas solubility were most accurate at low sour-gas loadings and high temperatures. This work provides a thermodynamic framework for the solvent selection for sour-gas absorption in a broad range of conditions. This enables a realistic decrease in experimental effort for solvent selection in sour-gas absorption. © 2021 American Chemical Society
    view abstract10.1021/acs.iecr.1c00176
  • Production of polylactic acid aerogels via phase separation and supercritical CO2 drying: thermodynamic analysis of the gelation and drying process
    Bueno, A. and Luebbert, C. and Enders, S. and Sadowski, G. and Smirnova, I.
    Journal of Materials Science 56 (2021)
    The application range of aerogels, especially in the life-science sector, can be extended by utilizing biocompatible polymers such as polylactic acid (PLA). However, the low glass transition temperature (Tg) of PLA and the challenging gelation techniques limit the application of supercritical CO2 (scCO2) drying and thus the PLA-aerogel production. The aim of this work is to overcome this challenge and to provide a better understanding of the thermodynamics of the process. Therefore, the gelation of amorphous PLA (PDLLA) and semicrystalline PLA (PLLA) via thermal-induced phase separation (TIPS) was studied. To identify polymer/solvent/antisolvent ratios suitable for gelation, thermodynamic modeling (PC-SAFT) was used to describe the corresponding ternary phase diagrams. scCO2 drying was used to preserve the mesoporous gel structure formed during the gelation. Due to the decrease in the Tg of PLA in the presence of CO2, this could not be applied to all gels. It was found that the critical parameter to enable the scCO2 drying of low Tg polymers is the crystallinity degree (Xc) of the polymer. Based on these results, some guidelines for producing aerogels from polymers with low Tg are formulated. Graphical abstract: [Figure not available: see fulltext.] © 2021, The Author(s).
    view abstract10.1007/s10853-021-06501-0
  • Solubility of DNP-amino acids and their partitioning in biodegradable ATPS: Experimental and ePC-SAFT modeling
    Wysoczanska, K. and Nierhauve, B. and Sadowski, G. and Macedo, E.A. and Held, C.
    Fluid Phase Equilibria 527 (2021)
    Predicting the behavior of dinitrophenylated amino acids (DNP-AA) in aqueous solutions requires an understanding and accurate description of interactions that can occur in such systems. In this work, some properties of DNP-AA (DNP-glycine, DNP-alanine, DNP-valine, DNP-leucine) have been determined experimentally. These were liquid densities obtained at T=298.15 – 318.15 K, p=1 bar, and pH-dependent solubility data measured at T=298.15 K, p=1 bar. It was observed that the solubility order for DNP-AA does not follow the same sequence as for aliphatic amino acids. The thermodynamic model ePC-SAFT has been applied to predict the properties density and solubility, and additionally to estimate partition coefficients of DNP-AA in PEG (PEG 4000, PEG 6000, PEG 8000) - organic salt (sodium citrate, potassium citrate, potassium sodium tartrate) aqueous two-phase systems (ATPS). ePC-SAFT pure-component and binary interaction parameters for neutral DNP-AA were acquired using the joinzt joint-parameter method, namely by combining the parameters for dinitrobenzene with parameters for amino acids (glycine, L-alanine, L-valine, L-leucine) from literature. The pure-component parameters for charged DNP-AA- were inherited from their parent neutral DNP-AA. This work shows that ePC-SAFT allows predicting liquid densities and solubilities of neutral DNP-AA with good agreement to experimental results. Moreover, adjusting in sum six binary parameters between charged DNP-AA- and phase-forming species allowed modeling partition coefficients of four DNP-AA in nine different PEG – organic salt ATPS, each at four different ATPS compositions. This can be considered an excellent modeling result and proofs the suitability of ePC-SAFT for such systems. © 2020 Elsevier B.V.
    view abstract10.1016/j.fluid.2020.112830
  • Solvent influence on the phase behavior and glass transition of Amorphous Solid Dispersions
    Dohrn, S. and Luebbert, C. and Lehmkemper, K. and Kyeremateng, S.O. and Degenhardt, M. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 158 (2021)
    Understanding the long-term stability of amorphous solid dispersions (ASDs) is important for their successful approval for market. ASD stability does not only depend on the interplay between the active pharmaceutical ingredient (API) and the polymer in the final formulation but may already be disadvantageously influenced by process steps during the production (e.g. selection of inappropriate solvent for spray drying). Residual solvent can affect the API solubility in the polymer, molecular mobility (by influencing the glass-transition temperature) and induce liquid-liquid phase separation. Enhanced mobility in the ASD due to residual solvent can promote recrystallization in ASDs. The removal of residual solvent can be expensive, time-consuming, and usually requires secondary drying procedures to fulfil the regulatory requirements. The aim of this work is to predict the API solubility in polymer-solvent mixtures, solvent influence on the glass transition, and the occurrence of liquid-liquid phase separation of solvent-loaded ASDs using the thermodynamic model PC-SAFT and to experimentally validate these predictions. ASDs containing the APIs ritonavir or naproxen and the polymers poly (vinylpyrrolidone), poly (vinylpyrrolidone-co-vinyl acetate), or hydroxypropyl methylcellulose acetate succinate were spray-dried using the solvents acetone, ethanol, and dichloromethane. API solubility, sorption behavior, liquid-liquid phase separation and glass transition in the ternary API/polymer/solvent mixtures were predicted based on the binary phase behavior between API/solvent, API/polymer, and polymer/solvent and successfully validated experimentally using dynamic vapor sorption (DVS), and Raman spectroscopy. Thus, the presented methodology allows for an in-silico selection of appropriate solvent systems for solvent-based ASD preparation based on a limited amount of experimental data for binary systems only. © 2020 The Authors
    view abstract10.1016/j.ejpb.2020.11.002
  • Solvent mixtures in pharmaceutical development: Maximizing the API solubility and avoiding phase separation
    Dohrn, S. and Luebbert, C. and Lehmkemper, K. and Kyeremateng, S.O. and Degenhardt, M. and Sadowski, G.
    Fluid Phase Equilibria 548 (2021)
    Knowing the solubilities of active pharmaceutical ingredients (APIs) in pure solvents and solvent mixtures is essential for several manufacturing aspects of pharmaceutical product development. In this paper, we demonstrate that time-consuming and costly experiments can be reduced to a minimum using the thermodynamic model Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) that can simultaneously predict API solubilities in pure solvents and solvent mixtures as well as unwanted liquid-liquid phase separation (LLPS). We investigated the temperature-dependent solubility of naproxen, ritonavir, and indomethacin in the solvents acetone, dichloromethane, ethanol, ethyl acetate, methanol, 2-propanol, tetrahydrofuran, and water, and mixtures thereof. Solvent mixtures with predicted enhanced API solvation properties (cosolvency) were validated by experiments. Moreover, concentration regions in which LLPS was predicted to occur were also found to be in perfect agreement with the experimental data. © 2021 Elsevier B.V.
    view abstract10.1016/j.fluid.2021.113200
  • Solvent Selection in Homogeneous Catalysis - Optimization of Kinetics and Reaction Performance
    Huxoll, F. and Jameel, F. and Bianga, J. and Seidensticker, T. and Stein, M. and Sadowski, G. and Vogt, D.
    ACS Catalysis 11 (2021)
    Solvents have an enormous impact on yield and turnover of chemical reactions in complex media. There is, however, a lack of consistent model-based tools to a priori identify the appropriate solvent for homogeneously catalyzed reactions. Here, a thermodynamically consistent approach for a reductive amination reaction is presented. It combines solvent screening using a thermodynamic-activity model and quantum chemical calculations. The optimization of activity coefficient-based predicted kinetics gives a suitable list of candidate solvents. The results were confirmed by batch experiments in selected solvents. This approach allows reducing time and lab resources for solvent selection to a minimum. ©
    view abstract10.1021/acscatal.0c04431
  • Stability of pharmaceutical co-crystals at humid conditions can be predicted
    Veith, H. and Zaeh, M. and Luebbert, C. and Rodríguez-Hornedo, N. and Sadowski, G.
    Pharmaceutics 13 (2021)
    Knowledge of the stability of pharmaceutical formulations against relative humidity (RH) is essential if they are to become pharmaceutical products. The increasing interest in formulating active pharmaceutical ingredients as stable co-crystals (CCs) triggers the need for fast and reliable in-silico predictions of CC stability as a function of RH. CC storage at elevated RH can lead to deliquescence, which leads to CC dissolution and possible transformation to less soluble solid-state forms. In this work, the deliquescence RHs of the CCs succinic acid/nicotinamide, carbamazepine/nicotinamide, theophylline/citric acid, and urea/glutaric acid were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These deliquescence RH values together with predicted phase diagrams of CCs in water were used to determine critical storage conditions, that could lead to CC instability, that is, CC dissolution and precipitation of its components. The importance of CC phase purity on RH conditions for CC stability is demonstrated, where trace levels of a separate phase of active pharmaceutical ingredient or of coformer can significantly decrease the deliquescence RH. The use of additional excipients such as fructose or xylitol was predicted to decrease the deliquescence RH even further. All predictions were successfully validated by stability measurements at 58%, 76%, 86%, 93%, and 98% RH and 25 °C. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    view abstract10.3390/pharmaceutics13030433
  • Swelling and diffusion in polymerized ionic liquids-based hydrogels
    Jastram, A. and Lindner, T. and Luebbert, C. and Sadowski, G. and Kragl, U.
    Polymers 13 (2021)
    Hydrogels are one of the emerging classes of materials in current research. Besides their numerous applications in the medical sector as a drug delivery system or in tissue replacement, they are also suitable as irrigation components or as immobilization matrices in catalysis. For optimal application of these compounds, knowledge of the swelling properties and the diffusion mechanisms occurring in the gels is mandatory. This study is focused on hydrogels synthesized by radical polymerization of imidazolium-based ionic liquids. Both the swelling and diffusion behavior of these hydrogels were investigated via gravimetric swelling as well as sorption experiments implemented in water, ethanol, n-heptane, and tetrahydrofuran. In water and ethanol, strong swelling was observed while the transport mechanism deviated from Fickian-type behavior. By varying the counterion and the chain length of the cation, their influences on the processes were observed. The calculation of the diffusion coefficients delivered values in the range of 10−10 to 10−12 m2 s−1 . The gravimetric results were supported by apparent diffusion coefficients measured through diffusion-weighted magnetic resonance imaging. A visualization of the water diffusion front within the hydrogel should help to further elucidate the diffusion processes in the imidazolium-based hydrogels. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    view abstract10.3390/polym13111834
  • Thermodynamic Properties of Biogenic Amines and Their Solutions
    Huxoll, F. and Heyng, M. and Andreeva, I.V. and Verevkin, S.P. and Sadowski, G.
    Journal of Chemical and Engineering Data (2021)
    Vapor pressures of the biologically and industrially relevant amines 2-phenylethan-1-amine, 2-amino-1-phenylethanol, α-(methylaminomethyl)benzyl alcohol, 1-phenylmethanamine, and N,N-diethylundecan-1-amine were measured via the transpiration method. Pure-component parameters for the thermodynamic model PC-SAFT were fitted to these vapor pressures and to liquid densities. The pure-component parameters were validated with measured liquid densities of binary mixtures dimethylsulfoxid + 4-(2-aminoethyl)phenol, dimethylsulfoxid + 2-amino-1-phenylethanol, dimethylsulfoxid + α-(methylaminomethyl)benzyl alcohol, and dimethylsulfoxid + 1-phenylmethanamine at 0.102 MPa and temperatures from 298.15 to 343.15 K at different amine mass fractions. Solid-liquid equilibria at 0.1 MPa were measured in binary mixtures of α-(methylaminomethyl)benzyl alcohol + water and 4-(2-aminoethyl)phenol + water at 298.15 and 308.15 K. Finally, the presence of liquid-liquid phase separation for these systems was qualitatively predicted using PC-SAFT based on the solid-liquid equilibria only and validated for the system α-(methylaminomethyl)benzyl alcohol + water by experiments at 293.15 and 323 K at 0.1 MPa. © 2021 American Chemical Society.
    view abstract10.1021/acs.jced.1c00202
  • Application of PC-SAFT and DGT for the Prediction of Self-Assembly
    Reinhardt, A. and Haarmann, N. and Sadowski, G. and Enders, S.
    Journal of Chemical and Engineering Data 65 (2020)
    The self-assembly of a surfactant in water is a complex procedure. The classical thermodynamic model for aqueous solutions of a nonionic surfactant, originally developed by Nagarajan and Ruckenstein, includes four contributions for aqueous solutions of a nonionic surfactant. These contributions were calculated using correlations based on experimental data, which were available at that time. The most important contribution is the so-called transfer term for modeling the hydrophobic effect. In this work, we first suggest replacing the original term based on experimental vapor-liquid equilibrium data by the n-alkane activity coefficient at infinite dilution in water calculated with PC-SAFT. The second term in the original model describes the newly formed interface during the self-assembly. This contribution requires the interfacial tension of n-alkane + water mixtures, which was originally calculated using combining rules based on the surface tensions of pure water and pure n-alkane. The second new suggestion of this work is to replace this combining rule by the interfacial tension of n-alkane + water mixtures obtained from PC-SAFT combined with the density gradient theory. The impact of these modifications on the predicted physical properties of surfactant solutions is studied for aqueous solutions of n-octyl-β-d-glucopyranoside (C8G1) as a representative surfactant for the family of sugar surfactants. ©
    view abstract10.1021/acs.jced.0c00781
  • Correctly Measuring and Predicting Solubilities of Solvates, Hydrates, and Polymorphs
    Veith, H. and Luebbert, C. and Sadowski, G.
    Crystal Growth and Design 20 (2020)
    The formation of solvates, hydrates, or different polymorphs significantly alters the physicochemical properties of a target component (TC) (e.g., active pharmaceutical or agrochemical active ingredient), such as solubility and dissolution behavior. Thus, it is very important to know under which conditions a certain solvate, hydrate, or polymorph is formed. This information can be obtained from phase diagrams, which are usually based on solubility measurements. Possible pitfalls in measuring the solubility of TC hydrates or solvates in pure solvents and solvent mixtures are discussed, and strategies for obtaining reliable solubility data are proposed. To substantiate the proposed solubility-measurement strategies, a thermodynamic approach based on the Perturbed-Chain Statistical Associating Fluid Theory for modeling solvate/hydrate solubilities was developed. This approach allows identifying stability regions of solvates/hydrates and predicting solubilities of solvates/hydrates or of polymorphs in pure solvents and solvent mixtures. It was successfully verified for modeling the solubility of the indomethacin-methanol solvate in methanol and of the carbamazepine dihydrate in water. Furthermore, the solubility of carbamazepine dihydrate and theophylline monohydrate in water/ethanol mixtures was predicted in excellent agreement with experimental data. Copyright © 2020 American Chemical Society.
    view abstract10.1021/acs.cgd.9b01145
  • High-Pressure-Mediated Thiourea-Organocatalyzed Asymmetric Michael Addition to (Hetero)aromatic Nitroolefins: Prediction of Reaction Parameters by PCP-SAFT Modelling
    Weinbender, T. and Knierbein, M. and Bittorf, L. and Held, C. and Siewert, R. and Verevkin, S.P. and Sadowski, G. and Reiser, O.
    ChemPlusChem 85 (2020)
    Thiourea-organocatalyzed Michael additions of diethyl malonate to various heteroaromatic nitroolefins (13 examples) have been studied under high-pressure (up to 800 MPa) and ambient pressure conditions. High pressure was conducive to enhanced product yields by a factor of 2–12 at a given reaction time, high reaction rates (reaction times were decreased from 72–24 h down to 4–24 h) and high enantioselectivity. Elucidating the effects of solvents for maximizing reaction rates and yields has been carried out using the Perturbed-Chain Polar Statistical Associating Fluid Theory (PCP-SAFT), allowing for the first time a prediction of the kinetic profiles under high-hydrostatic-pressure conditions. © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
    view abstract10.1002/cplu.202000364
  • Hydrate formation in polymer-based pharmaceutical formulations
    Veith, H. and Turan, E. and Luebbert, C. and Sadowski, G.
    Fluid Phase Equilibria 521 (2020)
    Amorphous solid dispersions (ASD) are state-of-the art enabling formulations for poorly water-soluble active pharmaceutical ingredients (APIs). Depending on the relative humidity (RH), temperature, and API content, ASDs are often metastable against crystallization of the API or even against the formation of API hydrates in the ASD. Knowing the conditions at which API crystals or API hydrate formation may occur in ASDs therefore is an important prerequisite for developing a suitable formulation strategy for APIs. ASDs containing hydrate-forming APIs (carbamazepine/polyvinylpyrrolidone, carbamazepine/hydroxypropylmethylcellulose acetate succinate, and theophylline/polyvinylpyrrolidone) were investigated in this work. The influence of polymer type, RH, API content, and water sorption on the ASD stability was determined via phase diagrams predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These predictions were successfully validated by long-term stability tests at 295 K and 0%, 58%, 76%, 86%, and 93% RH. Hydrate crystals are formed above their critical RH. Thus, ASDs with carbamazepine (critical RH 65% at 295 K) as well as theophylline (critical RH 58% RH) showed hydrate crystals at 76%, 86% and 93% RH, no matter which polymer was used for preparing the ASD. © 2020 Elsevier B.V.
    view abstract10.1016/j.fluid.2020.112677
  • In-Silico Screening of Lipid-Based Drug Delivery Systems
    Brinkmann, J. and Exner, L. and Luebbert, C. and Sadowski, G.
    Pharmaceutical Research 37 (2020)
    Purpose: This work proposes an in-silico screening method for identifying promising formulation candidates in complex lipid-based drug delivery systems (LBDDS). Method: The approach is based on a minimum amount of experimental data for API solubilites in single excipients. Intermolecular interactions between APIs and excipients as well as between different excipients were accounted for by the Perturbed-Chain Statistical Associating Fluid Theory. The approach was applied to the in-silico screening of lipid-based formulations for ten model APIs (fenofibrate, ibuprofen, praziquantel, carbamazepine, cinnarizine, felodipine, naproxen, indomethacin, griseofulvin and glibenclamide) in mixtures of up to three out of nine excipients (tricaprylin, Capmul MCM, caprylic acid, Capryol™ 90, Lauroglycol™ FCC, Kolliphor TPGS, polyethylene glycol, carbitol and ethanol). Results: For eight out of the ten investigated model APIs, the solubilities in the final formulations could be enhanced by up to 100 times compared to the solubility in pure tricaprylin. Fenofibrate, ibuprofen, praziquantel, carbamazepine are recommended as type I formulations, whereas cinnarizine and felodipine showed a distinctive solubility gain in type II formulations. Increased solubility was found for naproxen and indomethacin in type IIIb and type IV formulations. The solubility of griseofulvin and glibenclamide could be slightly enhanced in type IIIb formulations. The experimental validation agreed very well with the screening results. Conclusion: The API solubility individually depends on the choice of excipients. The proposed in-silico-screening approach allows formulators to quickly determine most-appropriate types of lipid-based formulations for a given API with low experimental effort. Graphical abstract[Figure not available: see fulltext.]. © 2020, The Author(s).
    view abstract10.1007/s11095-020-02955-0
  • Influence of cytosolic conditions on the reaction equilibrium and the reaction enthalpy of the enolase reaction accessed by calorimetry and van ‘t HOFF
    Vogel, K. and Greinert, T. and Harms, H. and Sadowski, G. and Held, C. and Maskow, T.
    Biochimica et Biophysica Acta - General Subjects 1864 (2020)
    Background: Thermodynamic methods are finding more and more applications in systems biology, which attempts to understand cell functions mechanistically. Unfortunately, the state variables used (reaction enthalpy and Gibbs energy) do not take sufficient account of the conditions inside of cells, especially the crowding with macromolecules. Methods: For this reason, the influence of crowding agents and various other parameters such as salt concentrations, pH and temperature on equilibrium position and reaction enthalpy of the glycolytic example reaction 9 (2-Phospoglycerate - > Phosphoenolpyruvate + H2O) was investigated. The conditions were chosen to be as close as possible to the cytosolic conditions. Poly(ethylene glycol) MW = 20,000 g mol−1 (PEG 20,000) was used to analyze the influence of crowding with macromolecules. The equation of state electrolyte Perturbed-Chain Statistical Associating Fluid Theory (ePC-SAFT) was applied to consider the influence of crowding agents on the reaction equilibria. Results and conclusions: For the reaction enthalpies and for the equilibria, it was found that the influence of salts and temperature is not pronounced while that of pH and PEG 20,000 concentration is considerable. Furthermore, it could be shown that under identical measurement conditions there are no differences between the van ‘t Hoff and the calorimetrically determined reaction enthalpy. General significance: The results show how important it is to consider the special cytosolic conditions when applying thermodynamic data in systems biology. © 2020 Elsevier B.V.
    view abstract10.1016/j.bbagen.2020.129675
  • Modeling of Interfacial Tensions of Long-Chain Molecules and Related Mixtures Using Perturbed Chain-Statistical Associating Fluid Theory and the Density Gradient Theory
    Haarmann, N. and Reinhardt, A. and Danzer, A. and Sadowski, G. and Enders, S.
    Journal of Chemical and Engineering Data 65 (2020)
    Long-chain compounds such as fatty-acid methyl esters and fatty alcohols are often based on renewable sources and are widely used in soaps and as surfactants. Hence, the knowledge of their pure-component surface tensions and interfacial tensions against water is indispensable. As experimental data of these systems are scarce, a simultaneous and preferentially predictive thermodynamic modeling of phase equilibria and interfacial properties is desirable. In our previous works (Haarmann et al., Ind. Eng. Chem. Res. 2019, 58 (7), 2551-2574 and Haarmann et al., Ind. Eng. Chem. Res. 2019, 58 (11), 4625-4643), the focus was on the description of the phase equilibria of pure long-chain compounds and their binary mixtures with water using a homosegmental as well as a newly introduced heterosegmental approach of the Perturbed Chain Statistical Associating Fluid Theory. Here, both approaches were combined with the Density Gradient Theory in order to obtain interfacial properties. When the combined models were applied, the pure-component surface tensions of polar and self-associating long-chain compounds could be represented in very good agreement with the experimental data. Furthermore, the interfacial tensions of the binary mixtures long-chain compound (n-hexanol, methyl hexanoate, and n-hexanoic acid) + water were investigated. Copyright © 2019 American Chemical Society.
    view abstract10.1021/acs.jced.9b00339
  • Modeling the CO2Solubility in Aqueous Electrolyte Solutions Using ePC-SAFT
    Pabsch, D. and Held, C. and Sadowski, G.
    Journal of Chemical and Engineering Data 65 (2020)
    Carbon dioxide (CO2) solubility in aqueous electrolyte solutions is of special interest for carbon capture and storage and for biochemical processes, particularly at moderate to high temperatures, pressures, and electrolyte concentrations. Unfortunately, experimental determination at such conditions is rather laborious. Therefore, the ion-based model ePC-SAFT was used in this work to model the CO2solubility in such systems over a broad range of conditions. The mixtures under investigation were the basis system CO2+ water and higher systems containing either NaCl, KCl, MgCl2, CaCl2, NaNO3, KNO3, Mg(NO3)2, or NaHCO3. In the pH range considered in this work (pH < 7), CO2dissociation reactions were found to be negligible; thus, only physical interactions were considered. Assuming induced association for CO2, binary interaction parameters between CO2-water and CO2-ion species were determined by fitting to literature data. For this purpose, different literature data sets were compared, and only the most reliable data were used to estimate the binary parameters. ePC-SAFT was found to be able to accurately model the CO2solubility in water as well as in aqueous systems containing electrolytes over a broad range of temperatures, pressures, and salt concentrations. © 2020 American Chemical Society. All rights reserved.
    view abstract10.1021/acs.jced.0c00704
  • Partitioning of water-soluble vitamins in biodegradable aqueous two-phase systems: Electrolyte perturbed-chain statistical associating fluid theory predictions and experimental validation
    Wysoczanska, K. and Do, H.T. and Sadowski, G. and Macedo, E.A. and Held, C.
    AIChE Journal 66 (2020)
    Partition coefficients (K) of vitamins (riboflavin, nicotinic acid, nicotinamide, folic acid, cyanocobalamin) in aqueous two-phase systems (ATPS) composed by polyethylene glycol (PEG 4000, PEG 6000) and organic salt (sodium citrate and sodium tartrate) at T = 298.15 K and p = 1 bar have been studied. Data on liquid–liquid equilibria of the ATPS considered in this study have been taken from the literature (PEG-Na3Citrate) or measured in this work (PEG-Na2Tartrate) for PEG 4000 and PEG 6000 at T = 298.15 K and p = 1 bar. The experimental K values were validated by electrolyte perturbed-chain-statistical associating fluid theory predictions. The neutral cyanocobalamin has the highest K values among all studied vitamins at any ATPS studied in this work. This finding contrasted with expectations based on literature data which let assume that charged species have typically the highest K values in the considered ATPS. Thus, besides the typically strong charge–charge interactions especially specific forces (e.g., hydrogen bonding) explains the strong PEG-cyanocobalamin interaction resulting in the high K values. © 2020 The Authors. AIChE Journal published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.
    view abstract10.1002/aic.16984
  • Phase behavior of pharmaceutically relevant polymer/solvent mixtures
    Dohrn, S. and Luebbert, C. and Lehmkemper, K. and Kyeremateng, S.O. and Degenhardt, M. and Sadowski, G.
    International Journal of Pharmaceutics 577 (2020)
    In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called “amorphous solid dispersions” (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort. © 2020 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2020.119065
  • Solubility of Pharmaceutical Ingredients in Natural Edible Oils
    Brinkmann, J. and Rest, F. and Luebbert, C. and Sadowski, G.
    Molecular Pharmaceutics 17 (2020)
    Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico. Copyright © 2020 American Chemical Society.
    view abstract10.1021/acs.molpharmaceut.0c00215
  • Special Issue Celebrating 30 Years of SAFT
    Sadowski, G.
    Journal of Chemical and Engineering Data 65 (2020)
    view abstract10.1021/acs.jced.0c00970
  • Special Issue Honoring Hans Hasse
    Sadowski, G. and Vrabec, J.
    Journal of Chemical and Engineering Data 65 (2020)
    view abstract10.1021/acs.jced.0c00170
  • Standard Gibbs energy of metabolic reactions: IV. Triosephosphate isomerase reaction
    Greinert, T. and Baumhove, K. and Sadowski, G. and Held, C.
    Biophysical Chemistry 258 (2020)
    The glycolytic pathway is present in most organisms and represents a central part of the energy production mechanism in a cell. For a general understanding of glycolysis, the investigation from a thermodynamic point of view is essential and allows realising thermodynamic feasibility analyses under in vivo conditions. However, available literature standard Gibbs energies of reaction, ΔRg′0, are calculated using equilibrium-molality ratios Km′, which might lead to a misinterpretation of the glycolytic pathway. It was the aim of this work to thermodynamically investigate the triosephosphate isomerase (TPI) reaction to provide new activity-based reaction data. In vitro equilibrium experiments were performed, and activity coefficients were predicted with the equation of state electrolyte PC-SAFT (ePC-SAFT). The combination of experimental concentrations and predicted activity coefficients yielded the thermodynamic equilibrium constant Ka and a new value for ΔRg′0(298.15 K, pH 7) = 7.1 ± 0.3 kJ mol‑1. The availability of the new ΔRg′0 value allowed predicting influences of the reaction medium on the reaction equilibrium of the TPI reaction. In this work, influences of the initial substrate concentration, pH and Mg2+ concentration on the reaction equilibrium were investigated and a method is presented to predict these influences. The higher the substrate concentration and the higher the temperature, the stronger the reaction equilibrium is shifted on the product side. While the pH did not have a significant influence on the reaction equilibrium, Mg2+ yielded a shift of the reaction equilibrium to the substrate side. All these effects were predicted correctly with ePC-SAFT. Based on the ePC-SAFT predictions we concluded that a charge-reduction of the product by complexation of the product with Mg2+ was responsible for the strong influence of Mg2+ on the reaction equilibrium. Finally, the standard enthalpy of reaction of ΔRh′0(pH 7) = 18 ± 7 kJ mol‑1 was determined with the equilibrium constants Ka at 298.15 K, 304.15 K and 310.15 K using the van ‘t Hoff equation. © 2020 Elsevier B.V.
    view abstract10.1016/j.bpc.2020.106330
  • Standard Gibbs energy of metabolic reactions: V. Enolase reaction
    Greinert, T. and Vogel, K. and Seifert, A.I. and Siewert, R. and Andreeva, I.V. and Verevkin, S.P. and Maskow, T. and Sadowski, G. and Held, C.
    Biochimica et Biophysica Acta - Proteins and Proteomics 1868 (2020)
    The glycolytic pathway is one of the most important pathways for living organisms, due to its role in energy production and as supplier of precursors for biosynthesis in living cells. This work focuses on determination of the standard Gibbs energy of reaction ΔRg′0 of the enolase reaction, the ninth reaction in the glycolysis pathway. Exact ΔRg′0 values are required to predict the thermodynamic feasibility of single metabolic reactions or even of metabolic reaction sequences under cytosolic conditions. So-called “apparent” standard data from literature are only valid at specific conditions. Nevertheless, such data are often used in pathway analyses, which might lead to misinterpretation of the results. In this work, equilibrium measurements were combined with activity coefficients in order to obtain new standard values ΔRg′0 for the enolase reaction that are independent of the cytosolic conditions. Reaction equilibria were measured at different initial substrate concentrations and temperatures of 298.15 K, 305.15 K and 310.15 K at pH 7. The activity coefficients were predicted using the equation of state electrolyte Perturbed-Chain Statistical Associating Fluid Theory (ePC-SAFT). The ePC-SAFT parameters were taken from literature or fitted to new experimentally determined osmotic coefficients and densities. At 298.15 K and pH 7, a ΔRg′0(298.15 K, pH 7) value of −2.8 ± 0.2 kJ mol− 1 was obtained. This value differs by up to 5 kJ mol− 1 from literature data. Reasons are the poorly defined “standard” conditions and partly undefined reaction conditions of literature works. Finally, using temperature-dependent equilibrium constants and the van ‘t Hoff equation, the standard enthalpy of reaction of ΔRh′0(298.15 K, pH 7) = 27 ± 10 kJ mol− 1 was determined, and a similar value was found by quantum-chemistry calculations. © 2020 Elsevier B.V.
    view abstract10.1016/j.bbapap.2020.140365
  • Standard Gibbs energy of metabolic reactions: VI. Glyceraldehyde 3-phosphate dehydrogenase reaction
    Greinert, T. and Vogel, K. and Mühlenweg, J.-K. and Sadowski, G. and Maskow, T. and Held, C.
    Fluid Phase Equilibria 517 (2020)
    Glycolysis is a very central metabolic pathway for many organisms because it represents a key component in their energy production. For this reason, it has always been an extensively studied pathway. The glyceraldehyde 3-phosphate dehydrogenase (GDH) reaction is an important reaction of glycolysis yielding nicotinamide adenine dinucleotide (NADH). The aim of this work is to investigate the thermodynamics of the GDH reaction and determine the standard Gibbs energy of reaction ΔRg'0 and standard enthalpy of reaction ΔRh'0. Currently, so-called ‘standard’ data exist in the literature that depend on the conditions they were measured at. In this work, ΔRg'0 and ΔRh'0 values were determined that are independent from reaction conditions by accounting for the activity coefficients of the reacting substances. Therefore, the equation of state electrolyte Perturbed-Chain Statistical Associating Fluid Theory (ePC-SAFT) was used. The required ePC-SAFT parameters were taken from literature or fitted to new experimental osmotic coefficients. A value of ΔRg'0 = 51.5 ± 0.4 kJ mol−1 was determined at 298.15 K. This value deviates by up to 10 kJ mol−1 from existing literature values, caused by activity coefficients in the reaction medium. It can be used to determine the Gibbs energy of reaction ΔRg', which will allow statements concerning the feasibility of the GDH reaction. Further, a method is presented to predict influences of pH, initial substrate concentration and Mg2+ concentration on the reaction equilibrium. Finally, we measured the standard reaction enthalpy for the GDH reaction ΔRh'0 by titration calorimetric measurements (ΔRh'0 = 4.6 ± 0.1 kJ mol−1). This value was within van ’t Hoff evaluated ΔRh'0 (9 ± 16 kJ mol−1) using temperature-dependent equilibrium constants from equilibrium measurements corrected by ePC-SAFT predicted activity coefficients. © 2020 Elsevier B.V.
    view abstract10.1016/j.fluid.2020.112597
  • The influence of polymeric excipients on desupersaturation profiles of active pharmaceutical ingredients. 1: Polyethylene glycol
    Schneider, R. and Taspinar, L. and Ji, Y. and Sadowski, G.
    International Journal of Pharmaceutics 582 (2020)
    Polymeric excipients have proven to be beneficial in stabilizing supersaturated solutions of poorly soluble active pharmaceutical ingredients (APIs). They are therefore considered an important tool in improving oral bioavailability of such APIs. To better understand this effect, desupersaturation of two model APIs – naproxen and indomethacin– were investigated with up to 1 wt% of polyethylene glycol (PEG) in aqueous solution. A crystal-growth model is proposed that allows simultaneous differentiation between thermodynamic and kinetic effects. It could be revealed that PEG, independent of molecular weight and concentration, acts as a solubilizer, thus increasing the equilibrium solubility of the API and thereby reducing the thermodynamic driving force for crystal growth from supersaturated solutions. In contrast, PEG does not change the kinetic crystal-growth parameters. This theoretical approach allowed predicting the API crystal-growth-dominated desupersaturation profiles in the presence of PEG at different concentrations only using the kinetic crystal-growth parameters determined for polymer-free systems and API solubilities measured in the presence of PEG. © 2020 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2020.119317
  • The interplay of dissolution, solution crystallization and solid-state transformation of amorphous indomethacin in aqueous solution
    Schneider, R. and Kerkhoff, J. and Danzer, A. and Mattusch, A. and Ohmann, A. and Thommes, M. and Sadowski, G.
    International Journal of Pharmaceutics: X 2 (2020)
    Supersaturation profiles of amorphous indomethacin in aqueous solution containing 0.4 wt% and 4 wt% of isopropanol were predicted by combining separately-determined kinetics for dissolution, solution crystallization, and solid-state transformation. The kinetics of solid-state transformation were measured and compared to various data from the literature. The proposed kinetic model accounts for dissolution, solution crystallization and amorphous-to-crystalline solid-state transformation. It was validated for different initial amounts of amorphous and crystalline material and systems with different isopropanol contents. Furthermore, the influence of polyethylene glycol on the supersaturation behavior was investigated. The results clearly show the robustness of the model and give insight into the interplay of dissolution, solution crystallization, and solid-state transformation of. In particular, the influence of solid-state transformation on the overall supersaturation profile was elucidated in a quantitative manner. An amorphicity function φ(t) is proposed to account for the kinetics of the solid-state transformation. Its general form could be derived consistently from different sets of experimental data and seems to be independent of the particle size of the amorphous material and hydrodynamic conditions. This work is among the first of its kind to successfully integrate dissolution, crystallization from solution and solid-state transformation in a model that shows good predictability. © 2020 The Author(s)
    view abstract10.1016/j.ijpx.2020.100063
  • The role of molecular interactions on Michaelis constants of α-chymotrypsin catalyzed peptide hydrolyses
    Knierbein, M. and Held, C. and Sadowski, G.
    Journal of Chemical Thermodynamics 148 (2020)
    In this work, the effects of co-solvent and pressure on Michaelis constants at ambient temperature were analyzed for the enzymatic peptide hydrolyses of L-phenylalanine-p-nitroanilide (HPNA) and of N-succinyl-L-phenylalanine-p-nitroanilide (SPNA). These two substrates resemble each other in their molecular structure. That is, at the position of SPNA's succinyl-group (S), HPNA possesses a hydrogen atom (H). Two co-solvents were considered: trimethylamine N-oxide and dimethyl sulfoxide. The thermodynamic model Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) was used to predict the activity of HPNA and SPNA under different reaction conditions regarding solvent composition and pressure. The PC-SAFT parameters (pure-component parameters and one binary parameter between substrate and solvent) were fitted to solubility data of HPNA in different solvents (water, ethanol, ethyl acetate, dimethyl sulfoxide), which were measured in this work at 30 °C and 1 bar. The resulting PC-SAFT predicted Michaelis constants were validated by experimental literature data. Results show that pressure decreased the Michaelis constants of both reactions, HPNA hydrolysis and SPNA hydrolysis. In spite of that, co-solvent effects on the Michaelis constants were predicted to be contrary for the two hydrolysis reactions. For the hydrolysis of HPNA, the co-solvents under investigation decreased the Michaelis constant while the co-solvents increased the Michaelis constant for the hydrolysis of SPNA. These PC-SAFT predictions were in qualitative agreement with the experimental literature data. This shows that molecular interactions are the key to understand the effects of co-solvents on Michaelis constants for the considered reactions. Applying the thermodynamic model PC-SAFT allowed predicting the observed combined effects of co-solvent and pressure on enzymatic reaction kinetics, which opens the door for solvent design of enzymatic reactions in the future. © 2020 Elsevier Ltd
    view abstract10.1016/j.jct.2020.106142
  • Thermodynamic Modeling of Solvent-Impact on Phase Separation in Amorphous Solid Dispersions during Drying
    Dohrn, S. and Reimer, P. and Luebbert, C. and Lehmkemper, K. and Kyeremateng, S.O. and Degenhardt, M. and Sadowski, G.
    Molecular Pharmaceutics 17 (2020)
    Understanding and prevention of unwanted changes of a pharmaceutical formulation during the production process is part of the critical requirements for the successful approval of a new drug product. Polymer-based formulations, so-called amorphous solid dispersions (ASDs), are often produced via solvent-based processes. In such processes, active pharmaceutical ingredients (APIs) and polymers are first dissolved in a solvent or solvent mixture, then the solvent is evaporated, for example, via spray drying or rotary evaporation. During the drying step, unwanted liquid-liquid phase separation may occur, leading to polymer-rich and API-rich regions with crystallization potential, and thus, heterogeneities and a two-phasic system in the final ASD. Phase separation in ASDs may impact their bioperformance because of the locally higher degree of API supersaturation. Although it is known that the choice of the solvent plays an important role in the formation of heterogeneities, solvent-impact on ASD drying and eventual product quality is often neglected in the process design. This study aims to investigate for the first time the phase behavior and drying process of API/polymer/solvents systems from a thermodynamic perspective. Unwanted phase changes during the drying process of the ASD containing hydroxypropyl methylcellulose acetate succinate and naproxen prepared from acetone/water or ethanol/water solvent mixtures were predicted using the thermodynamic model PC-SAFT. The predicted phase behavior and drying curves were successfully validated by confocal Raman spectroscopy. Copyright © 2020 American Chemical Society.
    view abstract10.1021/acs.molpharmaceut.0c00418
  • Viscosity of ASDs at humid conditions
    Wolbert, F. and Stecker, J. and Luebbert, C. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 154 (2020)
    Many amorphous solid dispersions (ASDs) are thermodynamically unstable. Thus, the active pharmaceutical ingredient (API) might crystallize over time. The crystallization kinetics and therewith the long-term stability of ASDs depends on the storage conditions temperature and relative humidity (RH) as they determine the molecular mobility of the API in the polymer. To quantify the molecular mobility, the rheological behavior of two different ASDs with ibuprofen and either poly(vinyl acetate) or poly(vinylpyrrolidone-co-vinyl acetate) was analyzed as function of temperature and relative humidity by means of an oscillatory rheometer. The plasticizing effect of ibuprofen and absorbed water on the zero-shear viscosity of the polymer could be fully explained by the reduction of the glass-transition temperature of the mixture compared to the one of the pure polymer. Moreover, this work proposes an approach to predict the zero-shear viscosity of an ASD based on only the temperature dependence of the zero-shear viscosity of the pure polymer as well as the predicted water content in the ASD at certain RH using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). © 2020 Elsevier B.V.
    view abstract10.1016/j.ejpb.2020.07.024
  • Combined co-solvent and pressure effect on kinetics of a peptide hydrolysis: An activity-based approach
    Knierbein, M. and Wangler, A. and Luong, T.Q. and Winter, R. and Held, C. and Sadowski, G.
    Physical Chemistry Chemical Physics 21 (2019)
    The application of co-solvents and high pressure has been reported to be an efficient means to tune the kinetics of enzyme-catalyzed reactions. Co-solvents and pressure can lead to increased reaction rates without sacrificing enzyme stability, while temperature and pH operation windows are generally very narrow. Quantitative prediction of co-solvent and pressure effects on enzymatic reactions has not been successfully addressed in the literature. Herein, we are introducing a thermodynamic approach that is based on molecular interactions in the form of activity coefficients of substrate and of enzyme in the multi-component solution. This allowed us to quantitatively predict the combined effect of co-solvent and pressure on the kinetic constants, i.e.The Michaelis constant KM and the catalytic constant kcat, of an α-CT-catalyzed peptide hydrolysis reaction. The reaction was studied in the presence of different types of co-solvents and at pressures up to 2 kbar, and quantitative predictions could be obtained for KM, kcat, and finally even primary Michaelis-Menten plots using activity coefficients provided by the thermodynamic model PC-SAFT. This journal is © the Owner Societies.
    view abstract10.1039/c9cp03868j
  • Cosolvent and pressure effects on enzyme-catalysed hydrolysis reactions
    Held, C. and Stolzke, T. and Knierbein, M. and Jaworek, M.W. and Luong, T.Q. and Winter, R. and Sadowski, G.
    Biophysical Chemistry 252 (2019)
    Thermodynamics and kinetics of biochemical reactions depend not only on temperature, but also on pressure and on the presence of cosolvents in the reaction medium. Understanding their effects on biochemical processes is a crucial step towards the design and optimization of industrially relevant enzymatic reactions. Such reactions typically do not take place in pure water. Cosolvents might be present as they are either required as stabilizer, as solubilizer, or in their function to overcome thermodynamic or kinetic limitations. Further, a vast number of enzymes has been found to be piezophilic or at least pressure-tolerant, meaning that nature has adapted them to high-pressure conditions. In this manuscript, we review existing data and we additionally present some new data on the combined cosolvent and pressure influence on the kinetics of biochemical reactions. In particular, we focus on cosolvent and pressure effects on Michaelis constants and catalytic constants of α-CT-catalysed peptide hydrolysis reactions. Two different substrates were considered in this work, N-succinyl-L-phenylalanine-p-nitroanilide and H-phenylalanine-p-nitroanilide. Urea, trimethyl-N-amine oxide, and dimethyl sulfoxide have been under investigation as these cosolvents are often applied in technical as well as in demonstrator systems. Pressure effects have been studied from ambient pressure up to 2 kbar. The existing literature data and the new data show that pressure and cosolvents must not be treated as independent effects. Non-additive interactions on a molecular level lead to a partially compensatory effect of cosolvents and pressure on the kinetic parameters of the hydrolysis reactions considered. © 2019
    view abstract10.1016/j.bpc.2019.106209
  • Density variations of TMAO solutions in the kilobar range: Experiments, PC-SAFT predictions, and molecular dynamics simulations
    Knierbein, M. and Held, C. and Hölzl, C. and Horinek, D. and Paulus, M. and Sadowski, G. and Sternemann, C. and Nase, J.
    Biophysical Chemistry 253 (2019)
    We present measurements, molecular dynamics (MD) simulations, and predictions using Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) of the density of aqueous solutions in a pressure range from 1 bar to 5000 bar, a pressure regime that is highly relevant for both biochemical applications and the fundamental understanding of solvation. The accurate determination of density data of pressurized solutions remains challenging. We determined relative density changes from the variations in X-ray absorption through the sample and developed a new water parameter set for PC-SAFT modeling that is appropriate for high pressure conditions in the kilobar regime. As a showcase, we studied trimethylamine N-oxide (TMAO) solutions and demonstrated that their compressibility decreases with the TMAO content. This result is linked to the stabilizing effect of TMAO on the local H-bond network of water. Experiments and calculations, which represent two independent methods, are in very good agreement and are in accordance with results of force field molecular dynamics simulations of the same systems. © 2019 Elsevier B.V.
    view abstract10.1016/j.bpc.2019.106222
  • Determination of the Total Vapor Pressure of Hydrophobic Deep Eutectic Solvents: Experiments and Perturbed-Chain Statistical Associating Fluid Theory Modeling
    Dietz, C.H.J.T. and Creemers, J.T. and Meuleman, M.A. and Held, C. and Sadowski, G. and Van Sint Annaland, M. and Gallucci, F. and Kroon, M.C.
    ACS Sustainable Chemistry and Engineering 7 (2019)
    Head-space gas chromatography mass spectrometry (HS-GC-MS) was used for the first time to measure the total vapor pressure of hydrophobic deep eutectic solvents (DESs). The new method was developed as a valid alternative for thermogravimetric analysis (TGA), as TGA did not allow obtaining reliable total vapor pressure data for the hydrophobic DESs studied in this work. The main advantage of HS-GC-MS is that the partial pressure of each DES constituent and the contribution of each DES constituent to the total vapor pressure of the mixture can be measured. The results give a clear indication of the interactions occurring between the DES constituents. Also, activity coefficients, enthalpies of evaporation, and activation energies for fluid displacement were obtained and correlated to the measured vapor pressure data. It was confirmed that the total vapor pressures of the hydrophobic DESs are very low in comparison to vapor pressures of commonly used volatile organic solvents like toluene. The total vapor pressures of the hydrophobic DESs were successfully predicted with perturbed-chain statistical associating fluid theory (PC-SAFT) when using PC-SAFT parameters for the individual DES constituents. © 2019 American Chemical Society.
    view abstract10.1021/acssuschemeng.8b05449
  • Heterosegmental Modeling of Long-Chain Molecules and Related Mixtures using PC-SAFT: 1. Polar Compounds
    Haarmann, N. and Enders, S. and Sadowski, G.
    Industrial and Engineering Chemistry Research 58 (2019)
    A broad range of fatty acids as well as fatty-acid-based, long-chain compounds are synthesized on the basis of triglycerides, which are mainly found in natural fats and oils. These long-chain compounds comprise, for instance, fatty-acid methyl and ethyl esters and fatty aldehydes. Saturated representatives of these individual families are composed of an identical head domain which is connected to an n-alkylic residue that only varies in chain length within a homologous series. In this work, this fact was taken into account for modeling of thermodynamic properties using a heterosegmental approach of the Perturbed Chain Statistical Associating Fluid Theory. For this purpose, the n-alkylic residue within a homologous series was modeled using the pure-component parameters of n-alkanes, whereas the parameters for each identical head domain were universally determined. With this heterosegmental approach, polar interactions among the identical head domains were explicitly taken into account. Due to its group-contribution-like character, the heterosegmental approach enables the prediction of thermodynamic properties of other compounds within a homologous series. Applying the new approach, vapor pressures and liquid densities of the pure long-chain compounds could be represented in very good agreement with the available experimental data. Furthermore, the interactions between the n-alkylic residue and water can be described using independent solubility data of the binary n-alkane + water mixtures. Excess enthalpies and excess volumes of the binary long-chain compound + n-alkane mixtures as well as mutual solubilities in the binary methyl alkanoate + water mixtures were predicted to be in remarkable agreement with the available experimental data for a broad range of chain lengths. Copyright © 2018 American Chemical Society.
    view abstract10.1021/acs.iecr.8b03799
  • Highlighting 10 Years of NIST Cooperation and Service to the Thermophysical Properties Data Community
    Brennecke, J.F. and Kofke, D.A. and Kroon, M. and Mathias, P.M. and Paulechka, E. and Sadowski, G. and Siepmann, J.I. and Wu, J.
    Journal of Chemical and Engineering Data 64 (2019)
    view abstract10.1021/acs.jced.9b00920
  • Introducing JCED's Latin America Special Issue
    Brennecke, J.F. and Kofke, D.A. and Kroon, M. and Mathias, P.M. and Sadowski, G. and Siepmann, J.I. and Wu, J.
    Journal of Chemical and Engineering Data 64 (2019)
    view abstract10.1021/acs.jced.9b00335
  • Liquid-Liquid Equilibria for Separation of Alcohols from Esters Using Deep Eutectic Solvents Based on Choline Chloride: Experimental Study and Thermodynamic Modeling
    Samarov, A. and Prikhodko, I. and Shner, N. and Sadowski, G. and Held, C. and Toikka, A.
    Journal of Chemical and Engineering Data 64 (2019)
    Deep eutectic solvent (DES) formed by choline chloride and glutaric acid was tested for the separation of azeotropic mixtures of ethanol-ethyl acetate, n-propanol-n-propyl acetate, n-butanol-n-butyl acetate, ethanol-ethyl propionate, n-propanol-n-propyl propionate, and n-butanol-n-butyl propionate. For this aim, the experimental data of liquid-liquid equilibria (LLE) were obtained at a temperature of 313.15 K and atmospheric pressure. Liquid-liquid tie-lines were determined and analyzed. The extraction performance of DES was characterized with distribution coefficients and values of selectivity with respect to alcohol. The NRTL model for LLE data correlation was used. Perturbed-chain statistical associating fluid theory had also been applied for modeling LLE using a "pseudo-component" approach for the DES. Both models were shown to give reasonable estimates for the selectivity values. Copyright © 2019 American Chemical Society.
    view abstract10.1021/acs.jced.9b00884
  • Measurement and Modeling of Lactose Solubility in Aqueous Electrolyte Solutions
    Choscz, C. and Held, C. and Eder, C. and Sadowski, G. and Briesen, H.
    Industrial and Engineering Chemistry Research 58 (2019)
    Lactose solubility has a significant influence on lactose crystallization. Changes in lactose solubility have an immediate impact on saturation concentration and hence supersaturation, which is used to control the crystallization process. The possibility to model and predict changes in solubility, which are caused by electrolytes, provides a chance to optimize the crystallization processes accordingly. This study explores the influence of different whey salts and salt mixtures on lactose solubility in aqueous solutions. Temperatures from 20 to 50 °C in combination with different salt concentrations are studied. Furthermore, a semipredictive modeling approach using the ePC-SAFT model is presented based on the experimental results. This approach requires pure-component parameters for lactose, dissociated ions, and water, as well as binary interaction parameters for lactose-water, water-ion, and lactose-ion, the latter of which were fitted to lactose solubility data in ternary water-lactose-salt solutions. These parameters have then been applied to successfully predict lactose solubility in multicomponent salt solutions. Until now, a modeling approach for the systems under investigation has not existed in the literature. Copyright © 2019 American Chemical Society.
    view abstract10.1021/acs.iecr.9b04031
  • Measurement and Prediction of Excess Properties of Binary Mixtures Methyl Decanoate + an Even-Numbered n-Alkane (C6-C16) at 298.15 K
    Haarmann, N. and Sosa, A. and Ortega, J. and Sadowski, G.
    Journal of Chemical and Engineering Data 64 (2019)
    The molar excess volumes vE of the three binary mixtures methyl decanoate + n-alkane (n-dodecane, n-tetradecane, and n-hexadecane) were measured at temperature T = 298.15 K and atmospheric pressure using a vibrating tube densitometer. Furthermore, the molar excess enthalpies hE of the six binary mixtures methyl decanoate + n-alkane (n-hexane, n-octane, n-decane, n-dodecane, n-tetradecane, and n-hexadecane) were measured at the same ambient conditions using a Calvet microcalorimeter. Both excess properties showed an increase with the increasing chain length of the n-alkane. Two equations of state, that is, a heterosegmental approach of Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT) and SAFT-γMie, were applied to predict the excess properties of the respective binary mixtures. Very satisfying agreement between the experimental data and modeling results was obtained for both equations of state. © 2019 American Chemical Society.
    view abstract10.1021/acs.jced.9b00185
  • Predicting the high concentration co-solvent influence on the reaction equilibria of the ADH-catalyzed reduction of acetophenone
    Wangler, A. and Loll, R. and Greinert, T. and Sadowski, G. and Held, C.
    Journal of Chemical Thermodynamics 128 (2019)
    The use of co-solvents for the enhancement of the reaction parameters reaction rate, yield and enantioselectivity is an established optimization strategy in biotechnology. To determine the influence of co-solvents on even one of these reaction parameters requires a great amount of experimental data. Thus, predictive and physically sound models are desired to decrease the amount of experimental effort. This work aims at providing such a framework, which was applied to the ADH (alcohol dehydrogenase)-catalyzed reduction of acetophenone at 303.15 K and 1 bar in water (neat) and under the influence of up to 20 wt-% of polyethylene glycol (PEG) and 15 wt-% trisodium citrate (Na3Cit). In a first step, the equilibrium composition was measured at constant pH. It was then shown that high concentration of PEG or Na3Cit changed the equilibrium position significantly (up to a factor of 13) compared to neat reaction mixtures. To be able to predict this strong co-solvent influence on the reaction equilibrium, the experimentally determined equilibrium compositions of the neat reaction were converted into a thermodynamic equilibrium constant Kth using the activity coefficients γi of the reacting agents. The latter were predicted by electrolyte Perturbed-Chain Statistical Associating Fluid Theory (ePC–SAFT). These finally allowed quantitatively predicting the high concentration co-solvent influence on the equilibrium position. © 2018 Elsevier Ltd
    view abstract10.1016/j.jct.2018.08.021
  • Protein-protein interactions and water activity coefficients can be used to aid a first excipient choice in protein formulations
    Schleinitz, M. and Sadowski, G. and Brandenbusch, C.
    International Journal of Pharmaceutics 569 (2019)
    With respect to all biopharmaceuticals marketed to date, monoclonal antibodies represent the largest fraction with more than 48% market share (2012). However, the development of biopharmaceutical formulations is a challenging task, and time-consuming and cost-intensive high-throughput screenings are still state-of-the-art in formulation design. These screening techniques are almost exclusively based on heuristic decisions thus the benefit in terms of mechanistic understanding is often unclear. It requires novel, physical-sound methods to enhance/optimize future formulation development, ideally by understanding molecular interactions in these complex solutions. A suitable and evaluated measure-of-choice to characterize protein-protein interactions in aqueous protein solutions is the second osmotic virial coefficient B22 which can be measured using static light scattering techniques. Furthermore B22 can be modeled/predicted via the extended mxDLVO model for protein-protein interactions in the presence of single excipients and excipient-mixtures. Building up on this approach, giving an additional insight into water-water and water-excipient interactions, the thermodynamic equation-of-state ePC-SAFT is used to calculate water activity coefficients in the presence of excipient-mixtures. Immunoglobulin G (IgG) was chosen as a model protein to predict B22-values for IgG in the presence of model excipient-mixtures (trehalose-NaCl, L-histidine-trehalose, L-histidine-NaCl). The combination of water activity coefficients and B22 allows to quickly identify a first guess on suitable formulation conditions that then can be further evaluated with existing methods/knowledge. © 2019 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2019.118608
  • Reply to Comment on "perturbed-Chain SAFT: An Equation of State Based on a Perturbation Theory for Chain Molecules"
    Gross, J. and Sadowski, G.
    Industrial and Engineering Chemistry Research 58 (2019)
    view abstract10.1021/acs.iecr.9b01515
  • Second osmotic virial coefficients of therapeutic proteins in the presence of excipient-mixtures can be predicted to aid an efficient formulation design
    Schleinitz, M. and Teschner, D. and Sadowski, G. and Brandenbusch, C.
    Journal of Molecular Liquids 283 (2019)
    Early- and late-stage formulation development for biopharmaceuticals (e.g. therapeutic proteins) remains a challenging task, especially when one has to select suitable excipients to solubilize and stabilize the protein in solution. State-of-the-art formulation development includes cost-intensive high-throughput screening methods to identify suitable excipients and formulation conditions. These methods often deliver a “working” formulation but unlikely the “optimal” formulation. Within this work, we developed a novel method that allows identifying suitable excipients based on the second osmotic virial coefficient B 22 as the measure of choice for protein-protein interactions in aqueous solution in the presence of excipients (salts, sugars, amino acids, etc.). B 22 is easily accessible by light scattering methods and advanced thermodynamic models like the extended mxDLVO model. Aqueous immunoglobulin G solutions including sugars, amino acids, surfactants and salts as excipients were used as model systems within this work. Applying the extended mxDLVO, the model allows predicting protein-protein interactions with high accuracy for mixtures of up to three excipients in one formulation. These measurements allow for quick identification of suitable excipients and their concentrations and are giving a greater insight in molecular interactions under the respective formulation conditions. An application of this method in future formulation development has the potential to reduce time-consuming and cost-intensive screening methods and finally lead to optimal formulations. © 2019 Elsevier B.V.
    view abstract10.1016/j.molliq.2019.03.064
  • Selecting Excipients Forming Therapeutic Deep Eutectic Systems - A Mechanistic Approach
    Wolbert, F. and Brandenbusch, C. and Sadowski, G.
    Molecular Pharmaceutics (2019)
    The majority of all newly identified active pharmaceutical ingredients (APIs) have a low solubility in water (partly smaller than marble). In order to enhance their solubility and bioavailability, the formulation of these APIs, as part of therapeutic deep eutectic systems (THEDES), has been recently shown to be a promising approach. By choosing the right excipient, the melting point of the API/excipient mixture can be lowered below body temperature or even room temperature, resulting in a liquid formulation. To date, because of a lack of mechanistic understanding of how THEDES are formed, the identification of suitable excipients for a given API is almost exclusively based on heuristic decisions and trial-and-error-based approaches. This is both very time-consuming and expensive. The purpose of this work is to reduce the experimental effort to identify suitable excipients for a given API solely based on the melting properties (melting temperature and melting enthalpy) of the API and excipient and accounting for intermolecular interactions via a predictive thermodynamic model [in this case, UNIFAC(Do)]. Lidocaine, ibuprofen, and phenylacetic acid were considered as model APIs, whereas thymol, vanillin, lauric acid, para-toluic acid, benzoic acid, and cinnamic acid were considered as model excipients. The formation of THEDES from these components was predicted and confirmed using differential scanning calorimetry. The results indicate that the experimental effort for the identification of suitable API/excipient combinations can be drastically reduced by thermodynamic modeling, leading to more efficient and tailor-made formulations in the future. © 2019 American Chemical Society.
    view abstract10.1021/acs.molpharmaceut.9b00336
  • Simultaneous Prediction of Cosolvent Influence on Reaction Equilibrium and Michaelis Constants of Enzyme-Catalyzed Ketone Reductions
    Wangler, A. and Hüser, A. and Sadowski, G. and Held, C.
    ACS Omega 4 (2019)
    Understanding and quantification of cosolvent influences on enzyme-catalyzed reactions are driven by a twofold interest. On the one hand, cosolvents can simulate the cellular environment for deeper understanding of in cellulo reaction conditions. On the other hand, cosolvents are applied in biotechnology to tune yield and kinetics of reactions. Further, cosolvents are even present inherently, for example, for reactions with cofactor regeneration or for enzymes that need cosolvents in a function of a stabilizer. As the experimental determination of yield and kinetics is costly and time consuming, this work aims at providing a thermodynamic predictive approach that might allow screening cosolvent influences on yield and Michaelis constants. Reactions investigated in this work are the reduction of butanone and 2-pentanone under the influence of 17 wt % of the cosolvent polyethylene glycol 6000, which is also often used as a crowder to simulate cellular environments. The considered reactions were catalyzed by a genetically modified alcohol dehydrogenase (ADH 270). Predictions of cosolvent influences are based on accounting for a cosolvent-induced change of molecular interactions among the reacting agents as well as between the reacting agents and the solvent. Such interactions were characterized by activity coefficients of the reacting agents that were predicted by means of electrolyte perturbed-chain statistical associating fluid theory. This allowed simultaneously predicting the cosolvent effects on yield and Michaelis constants for two-substrate reactions for the first time. © 2019 American Chemical Society.
    view abstract10.1021/acsomega.8b03159
  • Solubility Enhancement of Vitamins in Water in the Presence of Covitamins: Measurements and ePC-SAFT Predictions
    Wysoczanska, K. and MacEdo, E.A. and Sadowski, G. and Held, C.
    Industrial and Engineering Chemistry Research 58 (2019)
    Scarce knowledge on the behavior of vitamins in aqueous solutions in the presence of additives is often a limiting factor for industrial applications such as process design and optimization. Knowing the pH-solubility profiles of vitamins is fundamental for understanding and controlling their behavior in aqueous solutions. In the present work, pH-dependent solubilities of the vitamins ascorbic acid (VC), riboflavin (VB2), nicotinic acid (VB3acid), folic acid (VB9), and cyanocobalamin (VB12) were measured at T = 298.15 K and p = 1 bar. These results were compared to the pH-solubility profiles obtained with modified Henderson-Hasselbalch equations using pKa values from the literature. Further, the solubilities of poorly soluble VB2, VB9, and VB12 were increased by the addition of covitamins VC, VB3acid, and nicotinamide (VB3amide). As observed, VB3amide increases the vitamin solubility much stronger than VC and VB3acid. These covitamins are called "hydrotropes" in several works in the literature, and they increase the solubility of other vitamins by manipulating the pH of the saturated solutions and by molecular cross-interactions. The interplay between both pH and cross-interactions depends strongly on the kind and concentration of covitamin. At low concentrations, VC and VB3amide (<0.2 m) increased solubility by pH change. At higher concentrations of VC and VB3amide added, mainly cross-interactions between vitamin and covitamin determine the strength of solubility increase. To separate these effects and to further reduce experimental effort, electrolyte perturbed-chain statistical association fluid theory was used to predict vitamin solubility. The pH-solubility profiles and the solubilities of vitamins in water at T = 298.15 K and p = 1 bar upon addition of covitamins were predicted with reasonable accuracy. This success resulted from accounting for different charged and neutral vitamin species according to the pH and from considering explicitly the vitamin-water and vitamin-covitamin interactions. It could be shown that "hydrotropic solubilization" of a vitamin is the increase of vitamin solubility caused by pH shift and by cross-interactions between the saturated species of a vitamin and the added covitamin. Copyright © 2019 American Chemical Society.
    view abstract10.1021/acs.iecr.9b04302
  • Solubility of pharmaceutical ingredients in triglycerides
    Brinkmann, J. and Huxoll, F. and Luebbert, C. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 145 (2019)
    Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8–18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU = 10.5 wt% at 25 °C in tricaprylin) TGs compared to unsaturated ones (wIBU = 4.0 wt% at 25 °C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures. API solubilities in TGs and TG mixtures (mixtures of tricaprylin and tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility. © 2019 Elsevier B.V.
    view abstract10.1016/j.ejpb.2019.10.012
  • Structure and thermodynamics of aqueous urea solutions from ambient to kilobar pressures: From thermodynamic modeling, experiments, and first principles simulations to an accurate force field description
    Hölzl, C. and Kibies, P. and Imoto, S. and Noetzel, J. and Knierbein, M. and Salmen, P. and Paulus, M. and Nase, J. and Held, C. and Sadowski, G. and Marx, D. and Kast, S.M. and Horinek, D.
    Biophysical Chemistry 254 (2019)
    Molecular simulations based on classical force fields are a powerful method for shedding light on the complex behavior of biomolecules in solution. When cosolutes are present in addition to water and biomolecules, subtle balances of weak intermolecular forces have to be accounted for. This imposes high demands on the quality of the underlying force fields, and therefore force field development for small cosolutes is still an active field. Here, we present the development of a new urea force field from studies of urea solutions at ambient and elevated hydrostatic pressures based on a combination of experimental and theoretical approaches. Experimental densities and solvation shell properties from ab initio molecular dynamics simulations at ambient conditions served as the target properties for the force field optimization. Since urea is present in many marine life forms, elevated hydrostatic pressure was rigorously addressed: densities at high pressure were measured by vibrating tube densitometry up to 500 bar and by X-ray absorption up to 5 kbar. Densities were determined by the perturbed-chain statistical associating fluid theory equation of state. Solvation properties were determined by embedded cluster integral equation theory and ab initio molecular dynamics. Our new force field is able to capture the properties of urea solutions at high pressures without further high-pressure adaption, unlike trimethylamine-N-oxide, for which a high-pressure adaption is necessary. © 2019
    view abstract10.1016/j.bpc.2019.106260
  • Thermodynamic Activity-Based Solvent Design for Bioreactions
    Wangler, A. and Held, C. and Sadowski, G.
    Trends in Biotechnology 37 (2019)
    To improve the kinetics of enzyme-catalyzed reactions, cosolvents are commonly added to reaction mixtures. The search for a good cosolvent is still empirical and experimentally based. We discuss a thermodynamic activity-based approach that improves biocatalytic processes by predicting cosolvent influences on Michaelis constants, ultimately reducing time and cost. © 2019 Elsevier Ltd
    view abstract10.1016/j.tibtech.2019.04.015
  • Thermodynamic Approach for Co-crystal Screening
    Veith, H. and Schleinitz, M. and Schauerte, C. and Sadowski, G.
    Crystal Growth and Design 19 (2019)
    Co-crystallization is a promising strategy to enhance the water solubility and bioavailability of active pharmaceutical ingredients (APIs). Once possible coformers have been identified, suitable process conditions for an effective generation of pure co-crystals have to be found. In this work, two screening approaches have been developed to find the best-suited solvent and optimum process conditions for co-crystal formation: a shortcut approach based on mass balances and a second one which additionally accounts for thermodynamic nonidealities between the API, the coformer, and the solvent via the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). The enhanced efficiency of the two approaches compared to conventional ones is demonstrated for the two co-crystal-forming systems carbamazepine/acetylsalicylic acid and carbamazepine/salicylic acid. Appropriate conditions for co-crystal formation were identified in the solvents ethanol, ethyl acetate, acetonitrile, and methanol using the novel screening approaches. Phase diagrams were predicted using PC-SAFT and validated by experiments. It will be shown that the co-crystal screening approach based on thermodynamic predictions yields an appropriate preselection of suitable solvents and thus can be used to determine best-performing solvents for co-crystal production with minimal experimental effort. © 2019 American Chemical Society.
    view abstract10.1021/acs.cgd.9b00103
  • Thermodynamic Modeling of Triglycerides using PC-SAFT
    Brinkmann, J. and Luebbert, C. and Zaitsau, D.H. and Verevkin, S.P. and Sadowski, G.
    Journal of Chemical and Engineering Data 64 (2019)
    Vapor pressures for the saturated triglycerides (TGs) tricaprylin, tricaprin, and liquid densities of tricaprylin were experimentally determined. TG pure-component parameters for the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) were fitted to that data and validated with densities of the binary mixtures octanol/tricaprin and octanol/trilaurin at different temperatures and TG mass fractions. Furthermore, pure-component parameters of the unsaturated TGs triolein and trilinolein were estimated by a group-contribution method. Correctly predicted solid-liquid equilibria of mixtures containing the before-mentioned TGs revealed that intermolecular interactions among TGs are quantitatively described by PC-SAFT. © 2019 American Chemical Society.
    view abstract10.1021/acs.jced.8b01046
  • Thermodynamic properties of aqueous osmolyte solutions at high-pressure conditions
    Knierbein, M. and Venhuis, M. and Held, C. and Sadowski, G.
    Biophysical Chemistry 253 (2019)
    Living organisms can be encountered in nature under extreme conditions. At the seabed, pressure may reach 1000 bar. Yet microorganisms can be found that still function under these conditions. On the one hand, it is known that high pressure even has a positive effect on piezophile enzymes increasing their activity. On the other hand, such microorganisms might contain up to very high concentrations of osmolytes that counteract osmotic stress. To better understand high-pressure influences on biochemical systems, fundamental knowledge about pressure effects on thermodynamic properties of such osmolytes is important. However, literature data is scarce and experiments at high-pressure conditions are challenging. Hence, new high-pressure density data of aqueous osmolyte solutions were measured in this work at temperatures between 298.15 K and 318.15 K and at osmolyte concentrations up to 3 mol/kg water. Further, the thermodynamic model PC-SAFT has been applied recently to successfully model vapor pressures of water and density of water up to 10 kbar [M. Knierbein et al., Density variations of TMAO solutions in the kilobar range: experiments, PC-SAFT predictions, and molecular dynamics simulations, Biophysical chemistry, (2019)]. This allowed accurately predicting effects of temperature and osmolyte concentration on thermodynamic properties (especially mixture densities) up to very high pressures. Common osmolytes (trimethylamine-N-oxide, urea, ectoine, glycerol, glycine) as well as the dipeptides acetyl-N-methylglycine amide, acetyl-N-methylalanine amide, and acetyl-N-methylleucine amide were under investigation. © 2019
    view abstract10.1016/j.bpc.2019.106211
  • Thermodynamic Properties of Systems Comprising Esters: Experimental Data and Modeling with PC-SAFT and SAFT-γMie
    Haarmann, N. and Siewert, R. and Samarov, A.A. and Verevkin, S.P. and Held, C. and Sadowski, G.
    Industrial and Engineering Chemistry Research 58 (2019)
    In this work, new experimental vapor-pressure data of 14 esters were obtained using the transpiration method. Besides dimethyl fumarate, dimethyl maleate, diethyl maleate, benzyl ethanoate, benzyl propanoate, and benzyl butanoate, eight representatives of the homologous series of ethyl alkanoates were investigated. The pure-component vapor pressures and liquid densities were modeled by means of Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and SAFT-γMie. Satisfying modeling results could be achieved with both equations of state. Furthermore, the molar excess enthalpies of 12 binary mixtures benzyl ethanoate + n-alkane were modeled. Only one binary interaction parameter was fitted for PC-SAFT to quantitatively predict the molar excess enthalpies of all binary mixtures under study, while SAFT-γMie predicts these properties in qualitative agreement with the experimental data. Finally, the liquid-liquid equilibria of three binary mixtures ester (benzyl ethanoate, dimethyl maleate, and diethyl maleate) + water were investigated. These systems show a very low and almost temperature-independent solubility of the ester in the aqueous phase, whereas the moderate solubility of water in the organic phase is temperature-dependent. Promisingly, both PC-SAFT and SAFT-γMie predicted broad and unsymmetrical miscibility gaps for these mixtures, which is in qualitative agreement with the experimental data. © 2019 American Chemical Society.
    view abstract10.1021/acs.iecr.9b00714
  • Toward Thermodynamic Predictions of Aqueous Vitamin Solubility: An Activity Coefficient-Based Approach
    Wysoczanska, K. and Sadowski, G. and Macedo, E.A. and Held, C.
    Industrial and Engineering Chemistry Research 58 (2019)
    Research on water-soluble vitamins is still required, especially due to the diversity of their structures that influence strongly physicochemical properties of water-vitamin mixtures. Such influences are still underexplored. Further, solubility of vitamins in aqueous environment is of crucial importance for life sciences and process design, but still experimental data of vitamin solubility is rather limited in literature. In this work, solubilities of the vitamins ascorbic acid, riboflavin, nicotinic acid, folic acid, and cyanocobalamin were predicted with Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). PC-SAFT parameters for vitamins were estimated by fitting them to solubility-independent data, namely experimental liquid-density data and osmotic-coefficient data of aqueous vitamin solutions measured in this work. PC-SAFT predicted solubilities were validated by new experimental solubility data at T = 298.15 K and p = 1 bar. PC-SAFT predictions were in quantitative agreement to experimental vitamin solubility in water. Further, PC-SAFT allowed predicting the temperature influence on the solubility of vitamins in water with reasonable accuracy. © 2019 American Chemical Society.
    view abstract10.1021/acs.iecr.9b00742
  • Choosing Appropriate Solvents for ASD Preparation
    Luebbert, C. and Real, D. and Sadowski, G.
    Molecular Pharmaceutics 15 (2018)
    Amorphous solid dispersions (ASDs) are often used for formulating poorly water-soluble active pharmaceutical ingredients (APIs). In an ASD, the amorphous API is embedded in a suitable matrix excipient in order to stabilize the amorphous state and control the dissolution performance. ASDs can be prepared by commonly dissolving the API and the polymer in a suitable organic solvent which is evaporated afterward (e.g., via spray drying) aiming at a homogeneous API distribution in the polymer matrix. Sometimes, unexpected solvent influences on the heterogeneity of the dry ASD are observed. Thermodynamic predictions using the Perturbed-Chain Statistical Associating Fluid Theory combined with experimental investigations via Raman spectroscopy, differential scanning calorimetry, and microscopy performed in this work revealed the amorphous phase separation (APS) between the solvent and the polymer as causing the ASD heterogeneities. It will be shown that thermodynamic modeling allows for identifying appropriate solvents that will neither show APS with the polymeric excipient nor at any time of the drying process of ASD formulations. © 2018 American Chemical Society.
    view abstract10.1021/acs.molpharmaceut.8b00892
  • Co-solvent effects on reaction rate and reaction equilibrium of an enzymatic peptide hydrolysis
    Wangler, A. and Canales, R. and Held, C. and Luong, T.Q. and Winter, R. and Zaitsau, D.H. and Verevkin, S.P. and Sadowski, G.
    Physical Chemistry Chemical Physics 20 (2018)
    This work presents an approach that expresses the Michaelis constant KaM and the equilibrium constant Kth of an enzymatic peptide hydrolysis based on thermodynamic activities instead of concentrations. This provides KaM and Kth values that are independent of any co-solvent. To this end, the hydrolysis reaction of N-succinyl-l-phenylalanine-p-nitroanilide catalysed by the enzyme α-chymotrypsin was studied in pure buffer and in the presence of the co-solvents dimethyl sulfoxide, trimethylamine-N-oxide, urea, and two salts. A strong influence of the co-solvents on the measured Michaelis constant (KM) and equilibrium constant (Kx) was observed, which was found to be caused by molecular interactions expressed as activity coefficients. Substrate and product activity coefficients were used to calculate the activity-based values KaM and Kth for the co-solvent free reaction. Based on these constants, the co-solvent effect on KM and Kx was predicted in almost quantitative agreement with the experimental data. The approach presented here does not only reveal the importance of understanding the thermodynamic non-ideality of reactions taking place in biological solutions and in many technological applications, it also provides a framework for interpreting and quantifying the multifaceted co-solvent effects on enzyme-catalysed reactions that are known and have been observed experimentally for a long time. © the Owner Societies.
    view abstract10.1039/c7cp07346a
  • Effect of different organic salts on amino acids partition behaviour in PEG-salt ATPS
    Wysoczanska, K. and Do, H.T. and Held, C. and Sadowski, G. and Macedo, E.A.
    Fluid Phase Equilibria 456 (2018)
    The phase diagrams of six different polyethylene glycol (PEG)–salt aqueous two-phase systems (ATPS) were measured at T = 298.15 K and p = 1 bar. PEG of different molecular weight (4000, 6000 and 8000) and organic salts (potassium citrate, potassium sodium tartrate) were used to form the biphasic systems. The results were compared with data for PEG–sodium citrate ATPS, reported in the literature (PEG 4000, PEG 6000) and measured in this work (PEG 8000). The partition of four dinitrophenyl-amino acids was measured in these ATPS for different tie-line lengths. Based on these data, cation and anion effects were evaluated in terms of the relative hydrophobicity of the phases using ΔG*(CH2) calculations. The distribution coefficients have been obtained spectrophotometrically. Studies on the partitioning indicate the advantage of citrate salts over tartrate salts as well as sodium-based salts over potassium-based salts. This consistently results from the (liquid-liquid) phase behaviour of these systems. © 2017 Elsevier B.V.
    view abstract10.1016/j.fluid.2017.10.007
  • In-situ determination of crystallization kinetics in ASDs via water sorption experiments
    Luebbert, C. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 127 (2018)
    Amorphous solid dispersions (ASD) are intended to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients. However, the development of long-term stable ASDs is often limited by the unwanted crystallization of the incorporated active pharmaceutical ingredient. Robust detection and quantification of crystal formation - especially at temperatures and humidites relevant for long-term storage tests - are essential for understanding crystallization phenomena. In this work, the crystallization kinetics in spray-dried nifedipine/poly (vinyl acetate) ASDs was investigated by measuring the time-dependent water sorption behavior at constant storage conditions. By coupling these experiments with thermodynamic predictions of the water sorption in amorphous and crystallized ASDs using the Perturbed-Chain Statistical Associating Fluid Theory, the amount of crystallized nifedipine as function of time could be determined in-situ just by weighing the ASD samples and without any calibration. The experimental findings were validated by X-ray diffraction measurements. Metastable ASDs with nifedipine contents between 70 wt% and 90 wt% were investigated at relative humidities between 60% RH and 90% RH and in a temperature range between 30 °C and 40 °C. Storage at high temperature and at high RH, and high nifedipine contents dramatically increased the crystallization rates. © 2018
    view abstract10.1016/j.ejpb.2018.02.028
  • Influence of Low-Molecular-Weight Excipients on the Phase Behavior of PVPVA64 Amorphous Solid Dispersions
    Lehmkemper, K. and Kyeremateng, S.O. and Degenhardt, M. and Sadowski, G.
    Pharmaceutical Research 35 (2018)
    Purpose: The oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved by the preparation of amorphous solid dispersions (ASDs) where the API is dissolved in polymeric excipients. Desired properties of such ASDs like storage stability, dissolution behavior, and processability can be optimized by additional excipients. In this work, the influence of so-called low-molecular-weight excipients (LMWEs) on the phase behavior of ASDs was investigated. Method: Binary ASDs of an amorphous API, naproxen (NAP) or acetaminophen (APAP), embedded in poly-(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) were chosen as reference systems. Polyethylene glycol 1500 (PEG1500), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1000), propylene glycol monocaprylate type II (Capryol™ 90), and propylene glycol monolaurate type I (Lauroglycol™ FCC) were used as LMWEs. The API solubility in the excipients and the glass-transition temperature of the ASDs were modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Kwei equation, respectively, and compared to corresponding experimental data. Results: The API solubility curves in ternary systems with 90/10 wt%/wt% PVPVA64/LMWE ratios were very close to those in pure PVPVA64. However, the glass-transition temperatures of API/PVPVA64/LMWE ASDs were much lower than those of API/PVPVA64 ASDs. These effects were determined experimentally and agreed with the predictions using the PC-SAFT and Kwei models. Conclusion: The impact of the LMWEs on the thermodynamic stability of the ASDs is quite small while the kinetic stability is significantly decreased even by small LMWE amounts. PC-SAFT and the Kwei equation are suitable tools for predicting the influence of LMWEs on the ASD phase behavior. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
    view abstract10.1007/s11095-017-2316-y
  • Introducing the "emerging Investigators" Special Issue
    Kofke, D. and Brennecke, J. and Kroon, M. and Mathias, P.M. and Paulechka, E. and Sadowski, G. and Siepmann, J.I. and Wu, J.
    Journal of Chemical and Engineering Data 63 (2018)
    view abstract10.1021/acs.jced.8b00507
  • Investigating phase separation in amorphous solid dispersions via Raman mapping
    Luebbert, C. and Klanke, C. and Sadowski, G.
    International Journal of Pharmaceutics 535 (2018)
    The bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs) can be significantly improved by so-called amorphous solid dispersions (ASDs). However, the long-term stability of ASDs might be impaired by API recrystallization and/or amorphous phase separation (APS). So far, no methods have been reported to quantify APS in ASDs. In this work, phase-separation kinetics as well as the compositions of the two amorphous phases evolving due to APS were quantitatively determined for the first time using confocal Raman spectroscopy. Raman spectra were evaluated via non-linear multivariate Indirect Hard Modeling and verified by differential scanning calorimetry and hot-stage microscopy. APS in water-free ASDs of ibuprofen and poly (DL-lactic-co-glycolic acid) was investigated considering the influence of temperature and polymer architecture (linear vs. star-shaped). Water absorbed at 40 °C and 75% relative humidity (RH) promotes APS which was quantified for formulations of felodipine/poly(vinyl pyrrolidone) and ibuprofen/poly(vinyl pyrrolidone). © 2017 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2017.11.014
  • Mutual Impact of Phase Separation/Crystallization and Water Sorption in Amorphous Solid Dispersions
    Luebbert, C. and Wessner, M. and Sadowski, G.
    Molecular Pharmaceutics 15 (2018)
    The molecular integration of poorly water soluble active pharmaceutical ingredients (APIs) in a suitable polymeric matrix is a possible approach to enhance the dissolution behavior and solubility of these APIs. Like all newly developed pharmaceutical formulations, these formulations (often denoted as amorphous solid dispersions (ASDs)) need to undergo storage stability tests at defined relative humidity (RH) and temperature conditions. In a previous work (Int. J. Pharm. 2017; 532, 635-646), it was shown that thermodynamic modeling can be successfully used to predict the long-term stability of ASDs against API crystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This work in turn demonstrates the prediction of water sorption in ASDs accounting for the potential occurrence of API crystallization and MIAPS. The water sorption and phase behavior of ASDs containing the APIs felodipine and ibuprofen incorporated in three different hydrophilic polymers poly(vinylpyrrolidone), poly(vinyl acetate), and poly(vinylpyrrolidone-co-vinyl acetate) at the conditions 25 °C/60% RH and 40 °C/75% RH were predicted using the perturbed-chain statistical-associating fluid theory (PC-SAFT). The predictions were successfully validated via two-year-lasting water sorption experiments. It was shown that crystallization of the API and MIAPS on the one hand and water sorption in the ASDs on the other hand dramatically influence each other and that this behavior can even be quantitatively predicted by PC-SAFT, which already provides valuable insights at early stages of formulation development. © 2018 American Chemical Society.
    view abstract10.1021/acs.molpharmaceut.7b01076
  • Mutual Influence of Furfural and Furancarboxylic Acids on Their Solubility in Aqueous Solutions: Experiments and Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) Predictions
    Rose, H.B. and Greinert, T. and Held, C. and Sadowski, G. and Bommarius, A.S.
    Journal of Chemical and Engineering Data 63 (2018)
    Furan compounds are of mounting global interest due to their biorenewable nature and their potential to replace petroleum-based compounds as feedstocks in manufacturing. In this work the solubilities of furfural and the furancarboxylic acids 2-furoic acid (FA), 5-formyl-2-furancarboxylic acid (FFA), and 2,5-furandicarboxylic acid (FDCA) in aqueous solutions and organic solvents were investigated experimentally and by modeling with perturbed-chain statistical associating fluid theory (PC-SAFT). The PC-SAFT pure-component parameters of the solutes FA, FFA, and FDCA and one binary parameter between each solute and each solvent were adjusted to fit experimentally determined solubilities of each solute in each organic solvent or in water. Pure-component parameters of furfural were fitted to experimental density data and vapor-pressure data, and a binary interaction parameter was fitted to capture the solubility behavior of furfural in water. Modeling of pH effects enhanced predictions of the mutual influences of the acids on their solubilities in ternary aqueous systems. Mutual solubility influences of furfural and the furancarboxylic acids were accurately modeled with one constant binary parameter for the acid-furfural mixtures. All PC-SAFT modeling results were validated with new experimental solubility data at 35 °C, which were measured by HPLC analysis of equilibrated saturated solutions. © 2018 American Chemical Society.
    view abstract10.1021/acs.jced.7b01039
  • Oil desulfurization using deep eutectic solvents as sustainable and economical extractants via liquid-liquid extraction: Experimental and PC-SAFT predictions
    Warrag, S.E.E. and Pototzki, C. and Rodriguez, N.R. and van Sint Annaland, M. and Kroon, M.C. and Held, C. and Sadowski, G. and Peters, C.J.
    Fluid Phase Equilibria 467 (2018)
    The reduction of the sulfur content in crude oil is of utmost importance in order to meet the stringent environmental regulations. Thiophene and its derivatives are considered key substances to be separated from the crude oil. In previous works, six deep eutectic solvents (DESs) based on tetraethylammonium chloride, tetrahexylammonium bromide and methyltriphenylphosphonium bromide as hydrogen bond acceptors (HBAs) and polyols (ethylene glycol and glycerol) as hydrogen bond donors (HBDs) were successfully applied for the extraction of thiophene from {n-alkane + thiophene} mixtures via liquid-liquid extraction. One of the objectives of this work was to study the effect of the aliphatic hydrocarbon type/length (e.g. n-hexane vs n-octane) on the extraction performance of the same DESs. Extraction performance was evaluated by the selectivity and the thiophene distribution coefficient. Based on new experimental data, higher selectivities and lower thiophene distribution coefficients were obtained when thiophene was extracted from n-octane instead of n-hexane. Another objective was to predict the phase behavior of the ternary systems {n-alkane + thiophene + DES} using Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). The PC-SAFT “pseudo-pure component” approach was applied, in which a DES was considered as a pseudo-pure compound (not a mixture). The pure-component parameters of the DESs were obtained by fitting to liquid density data, which were measured at temperatures between 298.2 K and 323.2 K. Binary interaction parameters were fitted to experimental binary LLE data for the systems {n-alkane + DES} and {thiophene + DES} at 298.2 K and atmospheric pressure, while the LLE data of the ternary systems {n-alkane + thiophene + DES} were fully predicted. It was found that the distribution coefficients and selectivity of the ternary systems containing DESs could be qualitatively well predicted using this model. © 2018 Elsevier B.V.
    view abstract10.1016/j.fluid.2018.03.018
  • Peer Review Appreciation at JCED
    Brennecke, J. and Kofke, D. and Kroon, M. and Mathias, P.M. and Sadowski, G. and Ilja Siepmann, J. and Wu, J.
    Journal of Chemical and Engineering Data 63 (2018)
    view abstract10.1021/acs.jced.8b00701
  • Physical stability of API/polymer-blend amorphous solid dispersions
    Lehmkemper, K. and Kyeremateng, S.O. and Bartels, M. and Degenhardt, M. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 124 (2018)
    The preparation of amorphous solid dispersions (ASDs) is a well-established strategy for formulating active pharmaceutical ingredients by embedding them in excipients, usually amorphous polymers. Different polymers can be combined for designing ASDs with desired properties like an optimized dissolution behavior. One important criterion for the development of ASD compositions is the physical stability. In this work, the physical stability of API/polymer-blend ASDs was investigated by thermodynamic modeling and stability studies. Amorphous naproxen (NAP) and acetaminophen (APAP) were embedded in blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and either poly(vinylpyrrolidone) (PVP) or poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64). Parameters for modeling the API solubility in the blends and the glass-transition temperature curves of the water-free systems with Perturbed-Chain Statistical Associating Fluid Theory and Kwei equation, respectively, were correlated to experimental data. The phase behavior for standardized storage conditions (0%, 60% and 75% relative humidity (RH)) was predicted and compared to six months-long stability studies. According to modeling and experimental results, the physical stability was reduced with increasing HPMCAS content and increasing RH. This trend was observed for all investigated systems, with both APIs (NAP and APAP) and both polymer blends (PVP/HPMCAS and PVPVA64/HPMCAS). PC-SAFT and the Kwei equation turned out to be suitable tools for modeling and predicting the physical stability of the investigated API/polymer-blends ASDs. © 2017 Elsevier B.V.
    view abstract10.1016/j.ejpb.2017.12.002
  • Prediction and Experimental Validation of Co-Solvent Influence on Michaelis Constants: A Thermodynamic Activity-Based Approach
    Wangler, A. and Böttcher, D. and Hüser, A. and Sadowski, G. and Held, C.
    Chemistry - A European Journal 24 (2018)
    Co-solvents are known to influence the Michaelis constant KM of enzyme-catalyzed reactions. In the literature, co-solvent effects on KM are usually explained by interactions between enzyme and co-solvent. Very recent works replaced substrate concentrations with thermodynamic activities to separate enzyme–co-solvent from substrate–co-solvent interactions This yields the thermodynamic-activity-based Michalis constant Ka M. In this work, this approach was extended to alcohol dehydrogenase (ADH)-catalyzed reduction of acetophenone (ACP), a two-substrate reaction. It was experimentally found that polyethylene glycol (PEG) 6000 increased KM of ACP and decreased KM of nicotinamide adenine dinucleotide (NADH). To predict Ka M values, non-covalent interactions between substrates and reaction media were taken into account by electrolyte perturbed-chain statistical associating fluid theory (ePC-SAFT) modelling. In contrast to experimental KM values, their activity-based pendants Ka M were independent of co-solvent. To further verify the approach, the reduction of 2-pentanone catalyzed by the same ADH was investigated. Interestingly, the addition of PEG caused a decrease of both KM of 2-pentanone and KM of NADH. Based on Ka M values obtained from in co-solvent-free conditions and activity coefficients from ePC-SAFT, the influence of the co-solvent on KM was quantitatively predicted. Thus, the approach known for pseudo one-substrate reactions was successfully transferred to two-substrate reactions. Furthermore, the advantage of thermodynamic activities over concentrations in the field of enzyme kinetics is highlighted. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
    view abstract10.1002/chem.201803573
  • Standard Gibbs Energy of Metabolic Reactions: III the 3-Phosphoglycerate Kinase Reaction
    Wangler, A. and Schmidt, C. and Sadowski, G. and Held, C.
    ACS Omega 3 (2018)
    The glycolytic pathway is one of the most studied metabolic pathways to date. This work focuses on determining the standard Gibbs energy of reaction (δRg0) of the first adenosine triphosphate-yielding reaction step of glycolysis, namely, the 3-phosphoglycerate kinase (PGK) reaction. Trustworthy values of δRg0 are required for thermodynamic approaches to determine single reaction conversions or even fluxes of metabolic reactions. In literature, the observed δRg0,obs values are usually determined directly from the experimental equilibrium composition data without accounting for the nonideality of the reaction mixture. That is the reason why the observed δRg0,obs values do not present consistent standard data as they are a function of the concentration, pH, and pMg. In this work, a combination of experimentally determined equilibrium composition data and activity coefficients of the reacting agents was used to determine δRg0 values for the temperatures 303, 313, and 323 K at pH 7. The activity coefficients were predicted with the thermodynamic model electrolyte perturbed-chain statistical associating fluid theory (ePC-SAFT). The ePC-SAFT parameters were taken from literature or fitted to new experimental osmotic coefficients. At 313.15 K, a value for δRg0 of -16.2 ± 0.2 kJ/mol was obtained. This value is about 4 kJ/mol less negative than what is usually considered as an accepted standard value. The reason behind this discrepancy was found to be the activity coefficients of the reacting agents, which dramatically influence the equilibrium position of the PGK reaction. On the basis of the temperature-dependent δRg0 values, the standard enthalpy of reaction was determined and found to be δRh0 = â49 ± 9 kJ/mol. © 2018 American Chemical Society.
    view abstract10.1021/acsomega.7b01704
  • The Role of Polyfunctionality in the Formation of [Ch]Cl-Carboxylic Acid-Based Deep Eutectic Solvents
    Crespo, E.A. and Silva, L.P. and Martins, M.A.R. and Bülow, M. and Ferreira, O. and Sadowski, G. and Held, C. and Pinho, S.P. and Coutinho, J.A.P.
    Industrial and Engineering Chemistry Research 57 (2018)
    Aiming at providing an extensive characterization of the solid-liquid equilibria (SLE) of deep eutectic solvents (DESs), the phase diagrams of nine eutectic mixtures composed of choline chloride ([Ch]Cl) and (poly)carboxylic acids, commonly reported in the literature as DESs, were measured experimentally. Contrarily to the behavior reported for eutectic mixtures composed of [Ch]Cl (hydrogen-bond acceptor, HBA) and monofunctional hydrogen-bond donors (HBD) such as fatty acids and fatty alcohols, which have recently been shown to be almost ideal mixtures, a significant decrease of the melting temperature, at the eutectic point, was observed for most of the systems studied. This melting temperature depression was attributed to a pronounced nonideality of the liquid phase induced by the strong hydrogen-bond interactions between the two mixture components. Perturbed-chain statistical associating fluid theory (PC-SAFT) was used to describe these interactions physically. PC-SAFT allowed accurately modeling the experimental phase diagrams over the entire concentration and temperature ranges. Depending on the kind of mixture, up to two temperature-independent binary interaction parameters between HBA and HBD were applied. The PC-SAFT approach was used to provide trustworthy information on the nonideality of the liquid phase (expressed as the activity coefficients of HBA and HBD) as well as to estimate the eutectic points coordinates. The experimental data along with the modeling results allowed us to infer about the importance of the HBD's chemical structure on the formation of [Ch]Cl-based DESs. © 2018 American Chemical Society.
    view abstract10.1021/acs.iecr.8b01249
  • Thermodynamic prediction of the solvent effect on a transesterification reaction
    Lemberg, M. and Schomäcker, R. and Sadowski, G.
    Chemical Engineering Science 176 (2018)
    This work focuses on the thermodynamic prediction of solvent effects on the transesterification of butyl acetate with ethanol to butanol and ethyl acetate in the solvent heptane at 293.15 K and 303.15 K. Both, the reaction equilibrium and the reaction kinetics have been investigated experimentally by Schmidt et al. (1999). They found that the solvent heptane does not affect the reaction equilibrium but significantly influences the reaction kinetics. They described the solvent effect on the reaction kinetics by empirically correlating the experimentally-observed apparent rate constants with the dielectric constants of the different reaction mixtures. In this work we re-evaluated the experimental data and now present a thermodynamic approach to consistently predict the solvent effect on both, the reaction equilibrium and the reaction kinetics. Accounting for the activity coefficients of the reactants/products obtained from the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) allowed for considering the interactions of the reactants/products among themselves and also with the solvent heptane. Accounting for those, it is shown that the solvent effect on the reaction equilibrium as well as on the reaction rate can even be predicted in very good agreement with the experimental data. © 2017
    view abstract10.1016/j.ces.2017.10.033
  • Amorphous-amorphous phase separation in API/polymer formulations
    Luebbert, C. and Huxoll, F. and Sadowski, G. and Van Den Mooter, G. and Grohganz, H.
    Molecules 22 (2017)
    The long-term stability of pharmaceutical formulations of poorly-soluble drugs in polymers determines their bioavailability and therapeutic applicability. However, these formulations do not only often tend to crystallize during storage, but also tend to undergo unwanted amorphous-amorphous phase separations (APS). Whereas the crystallization behavior of APIs in polymers has been measured and modeled during the last years, the APS phenomenon is still poorly understood. In this study, the crystallization behavior, APS, and glass-transition temperatures formulations of ibuprofen and felodipine in polymeric PLGA excipients exhibiting different ratios of lactic acid and glycolic acid monomers in the PLGA chain were investigated by means of hot-stage microscopy and DSC. APS and recrystallization was observed in ibuprofen/PLGA formulations, while only recrystallization occurred in felodipine/PLGA formulations. Based on a successful modeling of the crystallization behavior using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the occurrence of APS was predicted in agreement with experimental findings. © 2017 by the authors; licensee MDPI, Basel, Switzerland.
    view abstract10.3390/molecules22020296
  • Characterization and Modeling of the Liquid Phase of Deep Eutectic Solvents Based on Fatty Acids/Alcohols and Choline Chloride
    Crespo, E.A. and Silva, L.P. and Martins, M.A.R. and Fernandez, L. and Ortega, J. and Ferreira, O. and Sadowski, G. and Held, C. and Pinho, S.P. and Coutinho, J.A.P.
    Industrial and Engineering Chemistry Research 56 (2017)
    The solid-liquid equilibria phase diagrams of eight eutectic systems formed by choline chloride and fatty acids, or fatty alcohols, were measured to characterize the nonideality of the liquid phase of these systems, commonly reported in the literature as examples of type III deep eutectic solvents (DESs), and to evaluate the best modeling approaches to their description. Most of these systems are shown to present only slight deviations from ideal behavior, resulting from a fine balance of the hydrogen bonding between the hydroxyl/carboxylic groups with the chloride anion and the interactions present in the pure compounds. The phase diagrams measured were modeled with an associative equation of state (EoS) and a gE model. As an EoS, the perturbed-chain statistical associating fluid theory (PC-SAFT) was used, and this model was able to accurately describe the experimental data and to provide reliable estimates of the eutectic points using just a single binary temperature-dependent interaction parameter that often correlates with the acid/alcohol chain length. The performance of PC-SAFT was further compared with the gE model, a non-random two-liquid model (NRTL), and was found to provide a better description of the experimental data, especially for the more nonideal systems. Ultimately, the data gathered, and the molecular modeling, allowed the discussion of the behavior of fatty acids or fatty alcohols as hydrogen bond donors in choline chloride-based DESs. © 2017 American Chemical Society.
    view abstract10.1021/acs.iecr.7b02382
  • Crowders and Cosolvents—Major Contributors to the Cellular Milieu and Efficient Means to Counteract Environmental Stresses
    Gao, M. and Held, C. and Patra, S. and Arns, L. and Sadowski, G. and Winter, R.
    ChemPhysChem 18 (2017)
    The free energy and conformational landscape of biomolecular systems as well as biochemical reactions depend not only on temperature and pressure, but also on the particular solution conditions. Such conditions include the effects of cosolvents (for example osmolytes) and macromolecular crowding, which are crucial components to understand the energetics and kinetics of biological processes in living system. Such conditions are also important for the understanding of many debilitating diseases, such as those where misfolding and amyloid formation of proteins are involved. Moreover, understanding their effects on biomolecular processes is prerequisite for designing industrially relevant enzymatic reactions, which seldom take place under neat conditions. Here, we review and discuss experimental and theoretical studies on the characterization of cosolvent and crowding induced effects in biologically relevant systems, approaching even the complexity of living organisms. In particular, we focus on cosolvent and crowding effects on the conformational equilibrium and folding kinetics of proteins and nucleic acids as well as on enzymatic reactions, including their effects on the temperature and pressure dependence of these processes. By presenting a few representative examples, we show how such effects are unveiled and described in thermodynamic and kinetic terms. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
    view abstract10.1002/cphc.201700762
  • Editorial
    Kofke, D.A. and Siepmann, J.I. and Kroon, M. and Mathias, P.M. and Sadowski, G. and Wu, J. and Brennecke, J.F.
    Journal of Chemical and Engineering Data 62 (2017)
    view abstract10.1021/acs.jced.6b01037
  • Impact of Polymer Type and Relative Humidity on the Long-Term Physical Stability of Amorphous Solid Dispersions
    Lehmkemper, K. and Kyeremateng, S.O. and Heinzerling, O. and Degenhardt, M. and Sadowski, G.
    Molecular Pharmaceutics 14 (2017)
    The purpose of this work is to compare the long-term physical stability of amorphous solid dispersion (ASD) formulations based on three different commercially used excipients, namely, poly(vinylpyrrolidone) K25 (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxypropyl methylcellulose acetate succinate 126G (HPMCAS), at standardized ICH storage conditions, 25 °C/0% relative humidity (RH), 25 °C/60% RH, and 40 °C/75% RH. Acetaminophen (APAP) and naproxen (NAP) were used as active pharmaceutical ingredients (APIs). 18 month long stability studies of these formulations were analyzed and compared with the API/polymer phase diagrams, which were modeled and predicted by applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor or Kwei equation. The study showed that, at dry storage, the solubility of the APIs in the polymers and the kinetic stabilizing ability of the polymers increase in the following order: HPMCAS < PVPVA64 < PVP. RH significantly reduces the kinetic stabilization as well as NAP solubility in the polymers, while the impact on APAP solubility is small. The impact of RH on the stability increases with increasing hydrophilicity of the pure polymers (HPMCAS < PVPVA64 < PVP). The experimental stability results were in very good agreement with predictions confirming that PC-SAFT and the Kwei equation are suitable predictive tools for determining appropriate ASD compositions and storage conditions to ensure long-term physical stability. © 2017 American Chemical Society.
    view abstract10.1021/acs.molpharmaceut.7b00492
  • Influence of pH Value and Ionic Liquids on the Solubility of L-Alanine and L-Glutamic Acid in Aqueous Solutions at 30 °C
    Voges, M. and Prikhodko, I. V. and Prill, S. and Hubner, M. and Sadowski, G. and Held, C.
    Journal of Chemical and Engineering Data 62 (2017)
    The solubility of the amino acids L-alanine and L-glutamic acid and its sodium salt (sodium L-glutamate monohydrate) in aqueous solutions at 30 degrees C and atmospheric pressure was investigated in the pH range between 3 and 9 and in the presence of the ionic liquids (ILs) 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([bmim][OTf]) and choline dihydrogencitrate ([ch] [dhcit]) at pH 7. The solubility of L-alanine and L-glutamic acid in the solutions without IL was measured by UV spectroscopy and with a gravimetrical method. In the presence of an IL HPLC-analysis was applied. The solid phases were characterized using Raman spectroscopy and powder X-ray diffraction to distinguish the amino acids from their salts. While the solubility of L-alanine did not depend on pH within the considered pH range, the solubility of L-glutamic acid strongly increased with increasing pH. Below pH 6.2 the solid phase was characterized to be L-glutamic acid, while sodium L-glutamate monohydrate was found to be the solid at pH higher than 6.2. It could be observed that the solubility of sodium L-glutamate monohydrate was comparatively high, and increased with increasing pH. Upon addition of the ILs under investigation ([bmim][OTf]) and [ch] [dhcit]) the solubility of L-alanine and L-glutamic acid was decreased. Original PC-SAFT was applied to predict the solubility of L-alanine and L-glutamic acid (and its sodium salt) in water, with and without the ILs under consideration, at the experimental conditions with quantitative agreement to the experimental data.
    view abstract10.1021/acs.jced.6b00367
  • Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions
    Lehmkemper, K. and Kyeremateng, S.O. and Heinzerling, O. and Degenhardt, M. and Sadowski, G.
    Molecular Pharmaceutics 14 (2017)
    The preparation of amorphous solid dispersion (ASD) formulations is a promising strategy to improve the bioavailability of an active pharmaceutical ingredient (API). By dissolving the API in a polymer it is stabilized in its amorphous form, which usually shows higher water solubility than its crystalline counterpart. To prevent recrystallization, the long-term physical stability of ASD formulations is of big interest. In this work, the solubility of the APIs acetaminophen and naproxen in the excipient polymers poly(vinylpyrrolidone) (PVP K25) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was calculated with three models: the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the Flory-Huggins model (FH), and an empirical model (Kyeremateng et al., J. Pharm. Sci, 2014, 103, 2847-2858). PC-SAFT and FH were further used to predict the influence of relative humidity (RH) on the API solubility in the polymers. The Gordon-Taylor equation was applied to model the glass-transition temperature of dry ASD and at humid conditions. The calculations were validated by 18 months-long stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. The results of the three modeling approaches for the API solubility in polymers agreed with the experimental solubility data, which are only accessible at high temperatures in dry polymers. However, at room temperature FH resulted in a lower solubility of the APIs in the dry polymers than PC-SAFT and the empirical model. The impact of RH on the solubility of acetaminophen was predicted to be small, but naproxen solubility in the polymers was predicted to decrease with increasing RH with both, PC-SAFT and FH. At 25 °C/60% RH and 40 °C/75% RH, PC-SAFT is in agreement with all results of the long-term stability studies, while FH underestimates the acetaminophen solubility in PVP K25 and PVPVA64. © 2016 American Chemical Society.
    view abstract10.1021/acs.molpharmaceut.6b00763
  • Measurement and PC-SAFT modeling of solid-liquid equilibrium of deep eutectic solvents of quaternary ammonium chlorides and carboxylic acids
    Pontes, P.V.A. and Crespo, E.A. and Martins, M.A.R. and Silva, L.P. and Neves, C.M.S.S. and Máximo, G.J. and Hubinger, M.D. and Batista, E.A.C. and Pinho, S.P. and Coutinho, J.A.P. and Sadowski, G. and Held, C.
    Fluid Phase Equilibria (2017)
    In this study the solid-liquid equilibria (SLE) of 15 binary mixtures composed of one of three different symmetrical quaternary ammonium chlorides and one of five different fatty acids were measured. The experimental data obtained showed extreme negative deviations to ideality causing large melting-temperature depressions (up to 300 K) that are characteristic for deep eutectic systems. The experimental data revealed that cross-interactions between quaternary ammonium salt and fatty acid increase with increasing alkyl chain length of the quaternary ammonium chloride and with increasing chain length of the carboxylic acid. The pronounced decrease of melting temperatures in these deep eutectic systems is mainly caused by strong hydrogen-bonding interactions, and thermodynamic modeling required an approach that takes hydrogen bonding into account. Thus, the measured phase diagrams were modeled with perturbed-chain statistical associating fluid theory based on the classical molecular homonuclear approach. The model showed very good agreement with the experimental data using a semi-predictive modeling approach, in which binary interaction parameters between quaternary ammonium chloride and carboxylic acid correlated with chain length of the components. This supports the experimental findings on the phase behavior and interactions present in these systems and it allows estimating eutectic points of such highly non-ideal mixtures. © 2017 Elsevier B.V.
    view abstract10.1016/j.fluid.2017.04.007
  • Measuring and Predicting Thermodynamic Limitation of an Alcohol Dehydrogenase Reaction
    Voges, M. and Fischer, F. and Neuhaus, M. and Sadowski, G. and Held, C.
    Industrial and Engineering Chemistry Research 56 (2017)
    The knowledge of thermodynamic limitations on enzymatic reactions and of influencing factors thereon is essential for process optimization to increase space-time yields and to reduce the amount of solvent or energy consumption. In this work, the alcohol dehydrogenase (ADH) catalyzed reaction from acetophenone and 2-propanol to 1-phenylethanol and acetone in aqueous solution was investigated in a temperature range of 293.15-303.15 K at pH 7. It serves as a model reaction to demonstrate the use of biothermodynamics in order to investigate and predict limitations of enzymatic reactions. Experimental molalities of the reacting agents at equilibrium were measured yielding the position of reaction equilibrium (Km) at different reaction conditions (temperature, initial reactant molalities). The maximum initial acetophenone molality under investigation was 0.02 mol·kg-1 due to solubility limitations with a 1- to 50-fold excess of 2-propanol. It was shown that Km strongly depends on the initial reactant molalities as well as on reaction temperature. Experimental Km values were in the range of 0.20 to 0.49. Thermodynamic key properties (thermodynamic equilibrium constant, standard Gibbs energy and standard enthalpy of reaction) were determined by measured Km values and activity coefficients of the reacting agents predicted with the thermodynamic model ePC-SAFT. In addition, ePC-SAFT was used to predict Km at different initial molalities. Experimental and predicted results were in quantitative agreement (root-mean-square error of experimental versus predicted Km was 0.053), showing that ePC-SAFT is a promising tool to identify process conditions that might increase/decrease Km values and, thus, shift the position of reactions for industrial applications. © 2017 American Chemical Society.
    view abstract10.1021/acs.iecr.7b01228
  • Modeling and analysis of dissolution of paracetamol/Eudragit® formulations
    Ji, Y. and Lemberg, M. and Prudic, A. and Paus, R. and Sadowski, G.
    Chemical Engineering Research and Design 121 (2017)
    In this work, amorphous paracetamol/Eudragit® formulations for four Eudragit® (polymeric excipients) were prepared by spray drying technique. The simultaneous dissolution kinetics of paracetamol and Eudragit® from these formulations were measured as function of pH in vitro using a rotating disk system (USP II). Paracetamol dissolution mechanisms were analyzed by comparing the dissolution rates of paracetamol and excipient. It was found that a controlled paracetamol dissolution was achieved from Eudragit® L 100-55 and Eudragit® E PO formulations at pH 5.0, 6.5, and 7.2. Furthermore, a controlled paracetamol dissolution was also achieved from Eudragit® L 100 formulations at pH 6.51 and 7.27 as well as from Eudragit® S 100 formulations at pH 7.27. Paracetamol dissolution rates were controlled by both paracetamol and excipient from Eudragit® L 100 and S 100 formulations at other pH values. Moreover, a chemical-potential-gradient model combined with PC-SAFT was used to model the dissolution kinetics of PARA from these formulations in good accordance with the experimental data. © 2017 Institution of Chemical Engineers
    view abstract10.1016/j.cherd.2017.03.007
  • Modeling binary mixtures of n-alkanes and water using PC-SAFT
    Haarmann, N. and Enders, S. and Sadowski, G.
    Fluid Phase Equilibria (2017)
    Modeling and measuring the mutual solubility in binary n-alkane + water mixtures is very challenging due to their low order of magnitude. Consequently, experimental data regarding mutual solubilities of these systems scatter remarkably. In this work, the PC-SAFT equation of state has been applied to model liquid-liquid and vapor-liquid-liquid equilibria of binary n-alkane + water mixtures. For this purpose, temperature-dependent binary interaction parameters have been fitted to the n-alkane solubility in the aqueous phase for n-alkanes ranging from n-pentane to n-undecane. Furthermore, these binary interaction parameters have been correlated with the carbon number of the n-alkane in order to predict phase equilibria of binary n-alkane + water mixtures for n-alkanes ranging from n-propane to n-pentadecane. Excellent agreement between modeling results and available experimental data has been observed for the liquid-liquid equilibria including the description of the minimum of n-alkane solubility in water as a function of temperature. Even the prediction of the vapor-liquid-liquid equilibria of the respective mixtures showed remarkably good results compared to experimental data. © 2017 Elsevier B.V.
    view abstract10.1016/j.fluid.2017.11.015
  • Moisture-induced phase separation and recrystallization in amorphous solid dispersions
    Luebbert, C. and Sadowski, G.
    International Journal of Pharmaceutics 532 (2017)
    Active Pharmaceutical Ingredients (APIs) are often dissolved in polymeric matrices to control the gastrointestinal dissolution and to stabilize the amorphous state of the API. During the pharmaceutical development of new formulations, stability studies via storage at certain temperature and relative humidity (RH) have to be carried out to verify the long-term thermodynamic stability of these formulations against unwanted recrystallization and moisture-induced amorphous–amorphous phase separation (MIAPS). This study focuses on predicting the MIAPS of API/polymer formulations at elevated RH. In a first step, the phase behavior of water-free formulations of ibuprofen (IBU) and felodipine (FEL) combined with the polymers poly(vinyl pyrrolidone) (PVP), poly(vinyl acetate) (PVAC) and poly (vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) was determined experimentally by differential scanning calorimetry (DSC). The phase behavior of these water-free formulations was modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Based on this, the API solubility and MIAPS in the above-mentioned formulations at humid conditions was predicted in perfect agreement with the results of two-year lasting stability studies at 25 °C/0% RH and 40 °C/75% RH. MIAPS was predicted and also experimentally found for the FEL/PVP, FEL/PVPVA64 and IBU/PVP formulations, whereas MIAPS was neither predicted nor measured for the IBU/PVPVA64 system and PVAC-containing formulations. It was thus shown that the results of time-consuming long-term stability tests can be correctly predicted via thermodynamic modeling with PC-SAFT. © 2017 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2017.08.121
  • PC-SAFT modeling of CO2 solubilities in hydrophobic deep eutectic solvents
    Dietz, C.H.J.T. and van Osch, D.J.G.P. and Kroon, M.C. and Sadowski, G. and van Sint Annaland, M. and Gallucci, F. and Zubeir, L.F. and Held, C.
    Fluid Phase Equilibria (2017)
    The PC-SAFT 'pseudo-pure' approach was used for the modeling of CO2 solubilities in various hydrophobic deep eutectic solvents (DESs) for the first time. Only liquid density data were used to obtain the segment number, the temperature-independent segment diameter and the dispersion-energy parameter, as water activities cannot be obtained for hydrophobic substances. VLE data were successfully predicted without the need for any adjustable binary interaction k ij. Thus, solubilities of CO2 in hydrophobic DESs could be approximated with the PC-SAFT model using parameters fitted to liquid densities only. © 2017 Elsevier B.V.
    view abstract10.1016/j.fluid.2017.03.028
  • Phase Behavior of Binary Mixtures Containing Succinic Acid or Its Esters
    Altuntepe, E. and Reinhardt, A. and Brinkmann, J. and Briesemann, T. and Sadowski, G. and Held, C.
    Journal of Chemical and Engineering Data 62 (2017)
    This work provides experimental data and thermodynamic modeling on phase equilibria of binary mixtures that are relevant for esterification reactions. The components under investigation include water, succinic acid (SA), ethanol (EtOH), 1-butanol (1-BuOH), and the diesters of SA, namely, diethyl succinate (DES) and dibutyl succinate (DBS), respectively, as well as the organic solvents acetonitrile (ACN) and tetrahydrofuran (THF). Liquid-liquid equilibria (LLE) of water/DBS were measured at ambient pressure for temperatures between 313 and 353 K. Isobaric vapor-liquid equilibria (VLE) were measured for the binary systems ACN/DES, ACN/DBS, 1-BuOH/DBS, and THF/DBS at pressures of 10 or 20 or 30 kPa. Temperature ranges for the isobaric VLE varied between 300 and 500 K. The measured data and phase equilibria reported in literature were accurately modeled using perturbed-chain statistical associating fluid theory (PC-SAFT). For this purpose, pure-component PC-SAFT parameters, which were not already reported in the literature, were adjusted to experimental literature pure-component data. Applying binary interaction parameters allowed precise phase-equilibrium modeling results of the binary systems under investigation. Two different association schemes for water were used ("2B" and "4C"). Both schemes appeared to be suitable to describe phase equilibria of aqueous mixtures; however, a binary parameter for the Wolbach-Sandler mixing rule was required for aqueous mixtures modeled with the 4C scheme. For LLE modeling the 2B scheme was found to give better modeling results. In general, the 4C association scheme for water yields better results for mixtures with two self-associating components while the 2B association scheme for water should be preferred if mixtures are considered with water and a non-self-associating component. Further, the modeling concept of "induced association" has been investigated and discussed. Especially for mixtures with esters, which are of main importance for esterification mixtures, the induced-association approach turned out to be a more accurate modeling strategy compared to the nonassociative approach. © 2017 American Chemical Society.
    view abstract10.1021/acs.jced.7b00005
  • Predicting solvent effects on the 1-dodecene hydroformylation reaction equilibrium
    Lemberg, M. and Sadowski, G. and Gerlach, M. and Kohls, E. and Stein, M. and Hamel, C. and Seidel-Morgenstern, A.
    AIChE Journal 63 (2017)
    Solvent effects on the reaction equilibrium of the 1-dodecene hydroformylation in a decane/N,N-dimethylformamide solvent system is investigated. The reaction was performed at different decane/N,N-dimethylformamide ratios and at temperatures between 368 K and 388 K. The equilibrium concentrations of all reactants and products were determined experimentally. The enthalpy and Gibbs energy of this reaction at the ideal-gas standard state were determined by quantum-chemical calculations in good agreement with literature data. Moreover, quantum-chemically calculated standard Gibbs energies of reaction at infinite dilution in liquid decane/DMF-solvent mixtures allowed a qualitative prediction of the solvent effect on the equilibrium concentrations. Based on the standard Gibbs energy of reaction at the ideal-gas standard state and on fugacity coefficients calculated using the Perturbed-Chain Statistical Associating Fluid Theory, the equilibrium concentrations of reactants and products for the 1-dodecene hydroformylation performed in decane/N,N-dimethylformamide mixtures of different compositions could be predicted in very good agreement with experimental data. © 2017 American Institute of Chemical Engineers AIChE J, 63: 4576–4585, 2017. © 2017 American Institute of Chemical Engineers
    view abstract10.1002/aic.15782
  • Predicting the Solubility of CO2 in Toluene + Ionic Liquid Mixtures with PC-SAFT
    Canales, R.I. and Held, C. and Lubben, M.J. and Brennecke, J.F. and Sadowski, G.
    Industrial and Engineering Chemistry Research 56 (2017)
    Perturbed-chain statistical associating fluid theory (PC-SAFT) was applied for modeling the vapor-liquid equilibrium of CO2 + toluene + ionic liquid (IL) mixtures and the molar volume of their liquid phases at temperatures between 298.15 K and 333.15 K and at pressures up to 80 bar. ILs used for this study contain the bis(trifluoromethylsulfonylimide) anion ([Tf2N]-) and imidazolium, pyridinium, thiolanium, and phosphonium cations. The pure-IL PC-SAFT parameters were fit to pure-IL liquid density data. Temperature-dependent binary interaction parameters were fit to binary liquid-liquid equilibrium data (i.e., toluene + IL) obtained from the literature and some points measured for this work. Temperature independent binary interaction parameters were fit to vapor-liquid equilibrium data (CO2 + IL, CO2 + toluene) from the literature. The availability of the pure-IL parameters and binary interaction parameters allowed prediction of CO2 solubility in toluene + IL mixtures with an absolute average relative deviation (AARD) of 6.8%, as well as molar volumes of CO2 + toluene + IL mixtures with an AARD of 5.0%, for the four ternary systems under investigation. © 2017 American Chemical Society.
    view abstract10.1021/acs.iecr.7b01497
  • Predicting the Solvent Effect on Esterification Kinetics
    Lemberg, M. and Sadowski, G.
    ChemPhysChem 18 (2017)
    It is well known that solvents influence reaction kinetics. The classical concentration-based kinetic modeling is unable to describe these effects. In this work, the reaction kinetics was studied for the esterifications of acetic acid and propionic acid with ethanol at 303.15 K. It was found that the reactant ratio as well as the applied solvents (acetonitrile, tetrahydrofurane, dimethylformamide) significantly affect the reaction rate. The thermodynamic model PC-SAFT was applied to account for the interactions between the reacting species and the solvents via activity coefficients. This allowed the identification of solvent-independent kinetic constants and the prediction of the solvent effect on reaction kinetics in almost quantitative agreement with experimental data. The presented approach shows the importance of taking into account thermodynamic non-idealities and significantly reduces experimental effort for finding the best solvent candidate for a given target reaction. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
    view abstract10.1002/cphc.201700507
  • Reaction Equilibrium of the ω-Transamination of (S)-Phenylethylamine: Experiments and ePC-SAFT Modeling
    Voges, M. and Abu, R. and Gundersen, M.T. and Held, C. and Woodley, J.M. and Sadowski, G.
    Organic Process Research and Development 21 (2017)
    This work focuses on the thermodynamic equilibrium of the ω-transaminase-catalyzed reaction of (S)-phenylethylamine with cyclohexanone to acetophenone and cyclohexylamine in aqueous solution. For this purpose, the equilibrium concentrations of the reaction were experimentally investigated under varying reaction conditions. It was observed that the temperature (30 and 37 °C), the pH (between pH 7 and pH 9), as well as the initial reactant concentrations (between 5 and 50 mmol·kg-1) influenced the equilibrium position of the reaction. The position of the reaction equilibrium was moderately shifted toward the product side by either decreasing temperature or decreasing pH. In contrast, the initial ratio of the reactants showed only a marginal influence on the equilibrium position. Further experiments showed that increasing the initial reactant concentrations significantly shifted the equilibrium position to the reactant side. In order to explain these effects, the activity coefficients of the reacting agents were calculated and the activity-based thermodynamic equilibrium constant Kth of the reaction was determined. For this purpose, the activity coefficients of the reacting agents were modeled at their respective experimental equilibrium concentrations using the equation of state electrolyte PC-SAFT (ePC-SAFT). The combination of the concentrations of the reacting agents at equilibrium and their respective activity coefficients provided the thermodynamically consistent equilibrium constant Kth. Unexpectedly, the experimental Km values deviated by a factor of up to four from the thermodynamic equilibrium constant Kth. The observed concentration dependency of the experimental Km values could be explained by the influence of concentration on activity coefficients. Further, these activity coefficients were found to be strongly temperature dependent, which is important for the determination of standard enthalpy of reactions, which in this work was found to be +7.7 ± 2.8 kJ·mol-1. Using the so-determined Kth and activity coefficients of the reacting agents (ePC-SAFT), the equilibrium concentrations of the reaction were predicted for varying initial reactant concentrations, which were found to be in good agreement with the experimental behavior. These results showed a non-negligible influence of the activity coefficients of the reacting agents on the equilibrium position and, thus, on the product yield. Experiments and ePC-SAFT predictions showed that the equilibrium position can only be described accurately by taking activity coefficients into account. © 2017 American Chemical Society.
    view abstract10.1021/acs.oprd.7b00078
  • Solubilization of proteins in aqueous two-phase extraction through combinations of phase-formers and displacement agents
    Kress, C. and Sadowski, G. and Brandenbusch, C.
    European Journal of Pharmaceutics and Biopharmaceutics 112 (2017)
    The aqueous two-phase extraction (ATPE) of therapeutic proteins is a promising separation alternative to cost-intensive chromatography, still being the workhorse of nowadays downstream processing. As shown in many publications, using NaCl as displacement agent in salt-polymer ATPE allows for a selective purification of the target protein immunoglobulin G (IgG) from human serum albumin (HSA, represents the impurity). However a high yield of the target protein is only achievable as long as the protein is stabilized in solution and not precipitated. In this work the combined influence of NaCl and polyethylene glycol (Mw = 2000 g/mol) on the IgG-IgG interactions was determined using composition gradient multi-angle light scattering (CG-MALS) demonstrating that NaCl induces a solubilization of IgG in polyethylene glycol 2000 solution. Moreover it is shown that the displacement agent NaCl has a significant and beneficial influence on the IgG solubility in polyethylene glycol 2000-citrate aqueous two-phase system (ATPS) which can also be accessed by these advanced B22 measurements. By simultaneous consideration of IgG solubility data with results of the ATPS phase behavior (especially volume fraction of the respective phases) allows for the selection of process tailored ATPS including identification of the maximum protein feed concentration. Through this approach an ATPS optimization is accessible providing high yields and selectivity of the target protein (IgG). © 2016 Elsevier B.V.
    view abstract10.1016/j.ejpb.2016.11.016
  • Standard Gibbs energy of metabolic reactions: II. Glucose-6-phosphatase reaction and ATP hydrolysis
    Meurer, F. and Do, H. T. and Sadowski, G. and Held, C.
    Biophysical Chemistry 223 (2017)
    ATP (adenosine triphosphate) is a key reaction for metabolism. Tools from systems biology require standard reaction data in order to predict metabolic pathways accurately. However, literature values for standard Gibbs energy of ATP hydrolysis are highly uncertain and differ strongly from each other. Further, such data usually neglect the activity coefficients of reacting agents, and published data like this is apparent (condition-dependent) data instead of activity-based standard data. In this work a consistent value for the standard Gibbs energy of ATP hydrolysis was determined. The activity coefficients of reacting agents were modeled with electrolyte Perturbed Chain Statistical Associating Fluid Theory (ePC-SAFT). The Gibbs energy of ATP hydrolysis was calculated by combining the standard Gibbs energies of hexokinase reaction and of glucose-6-phosphate hydrolysis. While the standard Gibbs energy of hexokinase reaction was taken from previous work, standard Gibbs energy of glucose-6-phosphate hydrolysis reaction was determined in this work. For this purpose, reaction equilibrium molalities of reacting agents were measured at pH 7 and pH 8 at 298.15 K at varying initial reacting agent molalities. The corresponding activity coefficients at experimental equilibrium molalities were predicted with ePC-SAFT yielding the Gibbs energy of glucose-6-phosphate hydrolysis of -13.72 +/- 0.75 kJ. mol(-1). Combined with the value for hexokinase, the standard Gibbs energy of ATP hydrolysis was finally found to be - 31.55 +/- 127 kJ. mol(-1). For both, ATP hydrolysis and glucose-6-phosphate hydrolysis, a good agreement with own and literature values were obtained when influences of pH, temperature, and activity coefficients were explicitly taken into account in order to calculate standard Gibbs energy at pH 7, 298.15 K and standard state. (C) 2017 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.bpc.2017.02.005
  • Thermodynamics of enzyme-catalyzed esterifications: I. Succinic acid esterification with ethanol
    Altuntepe, E. and Greinert, T. and Hartmann, F. and Reinhardt, A. and Sadowski, G. and Held, C.
    Applied Microbiology and Biotechnology 101 (2017)
    Succinic acid (SA) was esterified with ethanol using Candida antarctica lipase B immobilized on acrylic resin at 40 and 50 °C. Enzyme activity in the reaction medium was assured prior to reaction experiments. Reaction-equilibrium experiments were performed for varying initial molalities of SA and water in the reaction mixtures. This allowed calculating the molality-based apparent equilibrium constant Km as function of concentration and temperature. Km was shown to depend strongly on the molality of water and SA as well as on temperature. It could be concluded that increasing the molality of SA shifted the reaction equilibrium towards the products. Water had a strong effect on the activity of the enzyme and on Km. The concentration dependence of Km values was explained by the activity coefficients of the reacting agents. These were predicted with the thermodynamic models Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), NRTL, and Universal Quasichemical Functional Group Activity Coefficients (UNIFAC), yielding the ratio of activity coefficients of products and reactants Kγ. All model parameters were taken from literature. The models yielded Kγ values between 25 and 115. Thus, activity coefficients have a huge impact on the consistent determination of the thermodynamic equilibrium constants Kth. Combining Km and PC-SAFT-predicted Kγ allowed determining Kth and the standard Gibbs energy of reaction as function of temperature. This value was shown to be in very good agreement with results obtained from group contribution methods for Gibbs energy of formation. In contrast, inconsistencies were observed for Kth using Kγ values from the classical gE-models UNIFAC and NRTL. The importance of activity coefficients opens the door for an optimized reaction setup for enzymatic esterifications. © 2017, Springer-Verlag Berlin Heidelberg.
    view abstract10.1007/s00253-017-8287-4
  • Thermodynamics of enzyme-catalyzed esterifications: II. Levulinic acid esterification with short-chain alcohols
    Altuntepe, E. and Emel’yanenko, V.N. and Forster-Rotgers, M. and Sadowski, G. and Verevkin, S.P. and Held, C.
    Applied Microbiology and Biotechnology 101 (2017)
    Levulinic acid was esterified with methanol, ethanol, and 1-butanol with the final goal to predict the maximum yield of these equilibrium-limited reactions as function of medium composition. In a first step, standard reaction data (standard Gibbs energy of reaction ΔRg0) were determined from experimental formation properties. Unexpectedly, these ΔRg0 values strongly deviated from data obtained with classical group contribution methods that are typically used if experimental standard data is not available. In a second step, reaction equilibrium concentrations obtained from esterification catalyzed by Novozym 435 at 323.15 K were measured, and the corresponding activity coefficients of the reacting agents were predicted with perturbed-chain statistical associating fluid theory (PC-SAFT). The so-obtained thermodynamic activities were used to determine ΔRg0 at 323.15 K. These results could be used to cross-validate ΔRg0 from experimental formation data. In a third step, reaction-equilibrium experiments showed that equilibrium position of the reactions under consideration depends strongly on the concentration of water and on the ratio of levulinic acid: alcohol in the initial reaction mixtures. The maximum yield of the esters was calculated using ΔRg0 data from this work and activity coefficients of the reacting agents predicted with PC-SAFT for varying feed composition of the reaction mixtures. The use of the new ΔRg0 data combined with PC-SAFT allowed good agreement to the measured yields, while predictions based on ΔRg0 values obtained with group contribution methods showed high deviations to experimental yields. © 2017, Springer-Verlag GmbH Germany.
    view abstract10.1007/s00253-017-8481-4
  • Applied Catastrophic Phase Inversion (ACPI) – A Continuous Noncentrifugal Phase Separation in Biphasic Whole-Cell Biocatalysis
    Brandenbusch, C. and Vahle, L. and Glonke, S. and Sadowski, G.
    Chemie-Ingenieur-Technik 88 (2016)
    view abstract10.1002/cite.201650496
  • Applied catastrophic phase inversion: a continuous non-centrifugal phase separation step in biphasic whole-cell biocatalysis
    Glonke, S. and Sadowski, G. and Brandenbusch, C.
    Journal of Industrial Microbiology and Biotechnology 43 (2016)
    Biphasic whole-cell biotransformations are known to be efficient alternatives to common chemical synthesis routes, especially for the production of, e.g. apolar enantiopure organic compounds. They provide high stereoselectivity combined with high product concentrations owing to the presence of an organic phase serving as substrate reservoir and product sink. Industrial implementation suffers from the formation of stable Pickering emulsions caused by the presence of cells. State-of-the-art downstream processing includes inefficient strategies such as excessive centrifugation, use of de-emulsifiers or thermal stress. In contrast, using the catastrophic phase inversion (CPI) phenomenon (sudden switch of emulsion type caused by addition of dispersed phase), Pickering-type emulsions can be destabilized efficiently. Within this work a model system using bis(2-ethylhexyl) phthalate (BEHP) as organic phase in combination with E. coli, JM101 was successfully separated using a continuous mixer settler setup. Compared to the state-of-the-art centrifugal separations, this process allows complete phase separation with no detectable water content or cells in the organic phase with no utilities/additives required. Furthermore, the concentration of the product is not affected by the separation. It is therefore a simple applicable method that can be used for separation of stable Pickering-type emulsions based on the knowledge of the point of inversion. © 2016, Society for Industrial Microbiology and Biotechnology.
    view abstract10.1007/s10295-016-1837-4
  • Cation Effect on the Water Activity of Ternary (S)-Aminobutanedioic Acid Magnesium Salt Solutions at 298.15 and 310.15 K
    Held, C. and Tsurko, E.N. and Neueder, R. and Sadowski, G. and Kunz, W.
    Journal of Chemical and Engineering Data 61 (2016)
    Vapor pressure osmometry was applied to the system aminomethanamidine hydrochloride (guanidinium hydrochloride, GndmCl) + (S)-aminobutanedioic acid hemimagnesium salt (magnesium l-aspartate, Mg-(l-Asp)2) + water for varying molalities of GndmCl and Mg-(l-Asp)2 (mMg-(Asp)2 = 0.1, 0.2, and 0.3 mol/kg and mGndmCl = 0.1-1.2 mol/kg) at T = 298.15 and 310.15 K. From vapor pressure osmometry, activities of water, activity coefficients of water, and the corresponding osmotic coefficients of the mixtures Mg-(l-Asp)2 + water and Mg-(l-Asp)2 + GndmCl + water have been calculated, both being directly related to the chemical potentials of the different species and therefore to their Gibbs energy. Electrolyte perturbed-chain statistical associating fluid theory (ePC-SAFT) accounting for Coulomb and short-range (hard chain, dispersion, association) interactions was used to model the own experimental data of binary Mg-(l-Asp)2 + water and ternary GndmCl + Mg-(l-Asp)2 + water solutions. ePC-SAFT was further applied to model osmotic coefficients of NaGlu + KCl + water, NaGlu + NaCl + water, NaAsp + NaCl + water, NaAsp + KCl + water, aminoethanoic acid + NaNO3 + water, and aminoethanoic acid + NaSCN + water as well as thermodynamic properties of these solutions such as fugacity coefficients and activity coefficients of the mixture components. Without fitting any parameters to data of the ternary salt + aminoethanoic acid + water system, osmotic coefficients, φ, and activity coefficients of water, γ1, and aminoethanoic acid have been predicted, and φ and γ1 were in good agreement with the experimental data. In contrast, a negative binary interaction parameter kij had to be introduced to model φ of ternary systems salt + amino acid salt + water in accurate agreement with the experimental data. © 2016 American Chemical Society.
    view abstract10.1021/acs.jced.6b00295
  • Compatible solutes: Thermodynamic properties relevant for effective protection against osmotic stress
    Held, C. and Sadowski, G.
    Fluid Phase Equilibria 407 (2016)
    Organisms developed very different strategies to protect themselves against osmotic stress. To sustain high salt concentrations of their surrounding some organisms accumulate so-called compatible solutes (CSs), which increase the internal osmotic pressure without disturbing the organism's metabolism. At constant temperature, osmotic pressure is mainly determined by the concentration of the compatible solute and the osmotic coefficient of the aqueous solution, and to a minor extent also by solution densities. Thus, osmotic coefficients and densities were measured for aqueous CS solutions in a broad range of concentration and at three temperatures (273. K, 310. K, 323. K) at atmospheric pressure. Further, the solubility of CSs in water was measured as function of temperature to determine the maximum CS concentration that can be applied in aqueous solutions. CSs under investigation were trimethylamine N-oxide (TMAO), trehalose, citrulline, N,. N-dimethylglycine, DMSO, glycerol, methylglycine, and ectoine. The data was used to calculate real osmotic pressures induced by these CSs. PC-SAFT was applied to model thermodynamic properties and phase equilibria of aqueous CS solutions in quantitative agreement to experimental data. Among the CSs investigated in this work, TMAO induced the highest osmotic pressure and thus can be considered the best protector against osmotic stress. The data was finally analyzed concerning the influence of CSs molecular size, charge, and hydrophobicity on osmotic pressure. This included also the comparison to incompatible solutes (urea, glycine). © 2015 Elsevier B.V.
    view abstract10.1016/j.fluid.2015.07.004
  • Drug Release Kinetics and Mechanism from PLGA Formulations
    Ji, Y. and Lesniak, A.K. and Prudic, A. and Paus, R. and Sadowski, G.
    AIChE Journal 62 (2016)
    The release kinetics of indomethacin (IND) and hydrochlorothiazide (HCT) from drug/PLGA formulations with different copolymer composition and molecular weight of PLGA were measured in vitro by using a rotating disk system (USP II). The release mechanism of IND and HCT from their PLGA formulations was analyzed using a chemical-potential-gradient model combined with the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Furthermore, the release kinetics of IND and HCT from the PLGA formulations with different copolymer composition and molecular weight of PLGA were correlated and predicted in good accordance with the experimental data. It was found that the chemical-potential-gradient model combined with the PC-SAFT helped to understand the drug release mechanism from the drug/PLGA formulations. It also well correlated and predicted the drug release kinetics as function of copolymer composition and molecular weight of PLGA as well as of drug type. It helps to save time and costs for determination of the long-term drug release kinetics, especially for sustained drug release as obtained from the drug/PLGA formulations in this work. © 2016 American Institute of Chemical Engineers AIChE J, 62: 4055–4065, 2016. © 2016 American Institute of Chemical Engineers
    view abstract10.1002/aic.15282
  • Homogeneously catalyzed hydroamination in a Taylor–Couette reactor using a thermormorphic multicomponent solvent system
    Färber, T. and Riechert, O. and Zeiner, T. and Sadowski, G. and Behr, A. and Vorholt, A.J.
    Chemical Engineering Research and Design 112 (2016)
    In order to design an innovative continuous process for the conversion of the renewable β-myrcene, three methodical steps are shown in this paper to find a setup for the demanding homogeneously catalyzed hydroamination. First step is the theoretical and practical design of a suitable thermomorphic multicomponent solvent (TMS)-systems for recycling the catalyst system. The necessary phase equilibria were successfully investigated by modelling using the Perturbed Chain – Statistical Associating Fluid Theory (PC-SAFT) and measuring liquid–liquid equilibria of the ternary systems substrates/solvents mixtures at the separation temperature. In the next step the promising TMS-system was subsequently used to investigate the recycling of the catalyst in continuous operation. A Taylor–Couette reactor (TCR) was developed and modified for the application in homogeneous transition metal catalysis. The reactor was integrated in a miniplant setup and a continuous recycling of the catalyst phase as well as an efficient synthesis of the desired terpenyl amines is achieved in 3 complete cycles. The results show that the TCR is suitable for the hydroamination and generates high conversion and yields (XMyr = 82%, YHA = 80%). Recycling experiments were conducted successfully in the miniplant setup to show the long-term operation in a period of 24 h. © 2016 Institution of Chemical Engineers
    view abstract10.1016/j.cherd.2016.06.022
  • Inclusion of mPRISM potential for polymer-induced protein interactions enables modeling of second osmotic virial coefficients in aqueous polymer-salt solutions
    Herhut, M. and Brandenbusch, C. and Sadowski, G.
    Biotechnology Journal 11 (2016)
    The downstream processing of therapeutic proteins is a challenging task. Key information needed to estimate applicable workup strategies (e.g. crystallization) are the interactions of the proteins with other components in solution. This information can be deduced from the second osmotic virial coefficient B22, measurable by static light scattering. Thermodynamic models are very valuable for predicting B22 data for different process conditions and thus decrease the experimental effort. Available B22 models consider aqueous salt solutions but fail for the prediction of B22 if an additional polymer is present in solution. This is due to the fact that depending on the polymer concentration protein-protein interactions are not rectified as assumed within these models. In this work, we developed an extension of the xDLVO model to predict B22 data of proteins in aqueous polymer-salt solutions. To show the broad applicability of the model, lysozyme, γ-globulin and D-xylose ketol isomerase in aqueous salt solution containing polyethylene glycol were considered. For all proteins considered, the modified xDLVO model was able to predict the experimentally observed non-monotonical course in B22 data with high accuracy. When used in an early stage in process development, the model will contribute to an efficient and cost effective downstream processing development. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/biot.201500086
  • Influence of electrolytes on liquid-liquid equilibria of water/1-butanol and on the partitioning of 5-hydroxymethylfurfural in water/1-butanol
    Mohammad, S. and Grundl, G. and Müller, R. and Kunz, W. and Sadowski, G. and Held, C.
    Fluid Phase Equilibria 428 (2016)
    The influence of electrolytes on liquid-liquid equilibria (LLE) of water/1-butanol and on the partitioning of 5-hydroxymethylfurfural (HMF) between water-rich and 1-butanol-rich phases was investigated in this study. For that purpose, the LLE of the ternary systems water/1-butanol/HMF, water/1-butanol/salt, and the LLE of the quaternary system water/1-butanol/HMF/salt were measured at 298.15 K under atmospheric pressure. The investigated salts were composed of one of the anions Cl−, CH3COO−, NO3 − and SO4 2− and either Li+ or Na+. By investigating the LLE of the system water/1-butanol/salt it was found that 1-butanol was salted-out from the aqueous phase by all salts, and the strength of the salting-out increased in the following order NO3 − <  CH3COO− ≈ Cl− <  SO4 2−, independently of the cation. Based on the LLE data, the partition coefficient KHMF w of HMF between 1-butanol and aqueous phase was determined. Li2SO4 caused a pronounced salting-out of HMF from the aqueous phase, whereas only a moderate influence was observed for NaCl and CH3COONa. LiCl even caused a salting-in at LiCl molalities above 6 mol/kgH2O. electrolyte Perturbed-Chain Statistical Associating Fluid Theory (ePC-SAFT) was successfully used to model the influence of salts on the LLE water/1-butanol. Without fitting parameters to LLE data of the quaternary system water/1-butanol/HMF/salt, ePC-SAFT allowed predicting the salt influence on the partitioning of HMF in these systems in good agreement with the experimental data. © 2016 Elsevier B.V.
    view abstract10.1016/j.fluid.2016.05.001
  • Influence of Salts on the Partitioning of 5-Hydroxymethylfurfural in Water/MIBK
    Mohammad, S. and Held, C. and Altuntepe, E. and Köse, T. and Sadowski, G.
    Journal of Physical Chemistry B 120 (2016)
    This study investigates the influence of electrolytes on the performance of extracting 5-hydroxymethylfurfural (HMF) from aqueous media using methyl isobutyl ketone (MIBK). For that purpose, liquid-liquid phase equilibria (LLE) of quaternary systems containing HMF, water, MIBK and salts were measured at atmospheric pressure and 298.15 K. The salts under investigation were composed of one of the anions NO3-, SO4 2-, Cl-, or CH3COO- and of one of the alkali cations Li+, Na+, or K+. On the basis of these LLE data, the partition coefficient of HMF between the aqueous and the MIBK phase KHMF was determined. It could be shown that KHMF significantly depends on the kind and concentration of the added salt. Weak electrolytes (e.g., sulfates, acetates) caused salting-out, whereas nitrates caused salting-in of HMF to the aqueous phase. Unexpectedly, LiCl caused salting-out at low LiCl concentrations and salting-in at LiCl concentrations higher than 3 mol/kg H2O. The model electrolyte perturbed-chain SAFT (ePC-SAFT) was used to predict the salt influence on the LLE in the quaternary systems water/MIBK/HMF/salt in good agreement with the experimental data. On the basis of ePC-SAFT, it could be concluded that the different salting-out/salting-in behavior of the various salts is mainly caused by their different tendency to form ion pairs in aqueous solutions. © 2016 American Chemical Society.
    view abstract10.1021/acs.jpcb.5b11588
  • Modeling and prediction of protein solubility using the second osmotic virial coefficient
    Herhut, M. and Brandenbusch, C. and Sadowski, G.
    Fluid Phase Equilibria 422 (2016)
    The development of a precipitation or crystallization step requires knowing the solubility of the target protein and its crystallization behavior in aqueous solutions at different pH, temperatures and in the presence of precipitating agents, especially salts. Within this work, a solubility model for proteins based on the second osmotic virial coefficient B 22 is developed. For this, a relation between protein solubility and B 22 was combined with the extended DLVO model. This solubility model was then used to model and also predict the protein solubility of lysozyme and monoclonal antibody for different salts, salt concentrations, and pH. The modeled as well predicted B 22 and protein solubility data of lysozyme in the presence of sodium chloride and sodium p-toluenesulfonate and of a monoclonal antibody in the presence of ammonium sulfate at different pH shows good agreement with experimental data. © 2016 Elsevier B.V.
    view abstract10.1016/j.fluid.2016.01.020
  • Non-monotonic course of protein solubility in aqueous polymer-salt solutions can be modeled using the sol-mxDLVO model
    Herhut, M. and Brandenbusch, C. and Sadowski, G.
    Biotechnology Journal 11 (2016)
    Protein purification is often performed using cost-intensive chromatographic steps. To discover economic alternatives (e.g., crystallization), knowledge on protein solubility as a function of temperature, pH, and additives in solution as well as their concentration is required. State-of-the-art models for predicting protein solubility almost exclusively consider aqueous salt systems, whereas "salting-in" and "salting-out" effects induced by the presence of an additional polymer are not considered. Thus, we developed the sol-mxDLVO model. Using this newly developed model, protein solubility in the presence of one salt and one polymer, especially the non-monotonic course of protein solubility, could be predicted. Systems considered included salts (NaCl, Na-p-Ts, (NH4)2SO4) and the polymer polyethylene glycol (MW: 2000 g/mol, 12000 g/mol) and proteins lysozyme from chicken egg white (pH 4 to 5.5) and D-xylose ketol-isomerase (pH 7) at 298.15 K. The results show that by using the sol-mxDLVO model, protein solubility in polymer-salt solutions can be modeled in good agreement with the experimental data for both proteins considered. The sol-mxDLVO model can describe the non-monotonic course of protein solubility as a function of polymer concentration and salt concentration, previously not covered by state-of-the-art models. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/biot.201500123
  • Novel Displacement Agents for Aqueous 2-Phase Extraction Can Be Estimated Based on Hybrid Shortcut Calculations
    Kress, C. and Sadowski, G. and Brandenbusch, C.
    Journal of Pharmaceutical Sciences 105 (2016)
    The purification of therapeutic proteins is a challenging task with immediate need for optimization. Besides other techniques, aqueous 2-phase extraction (ATPE) of proteins has been shown to be a promising alternative to cost-intensive state-of-the-art chromatographic protein purification. Most likely, to enable a selective extraction, protein partitioning has to be influenced using a displacement agent to isolate the target protein from the impurities. In this work, a new displacement agent (lithium bromide [LiBr]) allowing for the selective separation of the target protein IgG from human serum albumin (represents the impurity) within a citrate–polyethylene glycol (PEG) ATPS is presented. In order to characterize the displacement suitability of LiBr on IgG, the mutual influence of LiBr and the phase formers on the aqueous 2-phase system (ATPS) and partitioning is investigated. Using osmotic virial coefficients (B22 and B23) accessible by composition gradient multiangle light-scattering measurements, the precipitating effect of LiBr on both proteins and an estimation of both protein partition coefficients is estimated. The stabilizing effect of LiBr on both proteins was estimated based on B22 and experimentally validated within the citrate–PEG ATPS. Our approach contributes to an efficient implementation of ATPE within the downstream processing development of therapeutic proteins. © 2016 American Pharmacists Association®
    view abstract10.1016/j.xphs.2016.06.006
  • PC-SAFT Modeling of CO2 Solubilities in Deep Eutectic Solvents
    Zubeir, L.F. and Held, C. and Sadowski, G. and Kroon, M.C.
    Journal of Physical Chemistry B 120 (2016)
    Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), a physically based model that accounts for different molecular interactions explicitly, was applied to describe for the first time the phase behavior of deep eutectic solvents (DESs) with CO2 at temperatures from 298.15 to 318.15 K and pressures up to 2 MPa. DESs are mixtures of two solid compounds, a hydrogen bond donor (HBD) and a hydrogen bond acceptor (HBA), which form liquids upon mixing with melting points far below that of the individual compounds. In this work, the HBD is lactic acid and the HBAs are tetramethylammonium chloride, tetraethylammonium chloride, and tetrabutylammonium chloride. Two different modeling strategies were considered for the PC-SAFT modeling. In the first strategy, the so-called pseudo-pure component approach, a DES was considered as a pseudo-pure compound, and its pure-component parameters were obtained by fitting to pure DES density data. In the second strategy, the so-called individual-component approach, a DES was considered to consist of two individual components (HBA and HBD), and the pure-component parameters of the HBA and HBD were obtained by fitting to the density of aqueous solutions containing only the individual compounds of the DES. In order to model vapor-liquid equilibria (VLE) of DES + CO2 systems, binary interaction parameters were adjusted to experimental data from the literature and to new data measured in this work. It was concluded that the individual-component strategy allows quantitative prediction of the phase behavior of DES + CO2 systems containing those HBD:HBA molar ratios that were not used for kij fitting. In contrast, applying the pseudo-pure component strategy required DES-composition specific kij parameters. © 2016 American Chemical Society.
    view abstract10.1021/acs.jpcb.5b07888
  • Phase Equilibria for the Hydroesterification of 10-Undecenoic Acid Methyl Ester
    Lemberg, M. and Sadowski, G.
    Journal of Chemical and Engineering Data 61 (2016)
    This paper investigates phase equilibria of interest for the hydroesterification of 10-undecenoic acid methyl ester with methanol and carbon monoxide to dodecanedioic acid dimethyl ester in a solvent system composed of methanol and n-dodecane. Carbon monoxide solubilities were measured in 10-undecenoic acid methyl ester, dodecanedioic acid dimethyl ester, and a mixture of methanol/dodecanedioic acid dimethyl ester at 363 and 393 K and at pressures up to 15 MPa. Vapor-liquid equilibrium measurements in the systems methanol/10-undecenoic acid methyl ester, methanol/dodecanedioic acid dimethyl ester, n-dodecane/10-undecenoic acid methyl ester, n-dodecane/dodecanedioic acid dimethyl ester, and 10-undecenoic acid methyl ester/dodecanedioic acid dimethyl ester were performed at temperatures between 342 and 437 K and at pressures of 2 or 80 kPa. The measured data were accurately modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). © 2016 American Chemical Society.
    view abstract10.1021/acs.jced.6b00360
  • Polymorphs, Hydrates, Cocrystals, and Cocrystal Hydrates: Thermodynamic Modeling of Theophylline Systems
    Lange, L. and Sadowski, G.
    Crystal Growth and Design 16 (2016)
    Polymorphic transitions and hydrate formation often occur in systems of cocrystal-forming components. To increase the efficiency of cocrystal formation and purification processes, the complex phase behavior of such systems was modeled using perturbed-chain statistical associating fluid theory (PC-SAFT). This is demonstrated for theophylline, a well-studied pharmaceutical, exhibiting polymorphs, as well as formation of a hydrate, cocrystals, and even cocrystal hydrates. The solubility of theophylline in water was modeled including hydrate formation (1:1) as well as polymorphic transitions of theophylline between the anhydrate forms IV, II, and I. The solubilities of theophylline(IV), the thermodynamically stable form at ambient conditions, and the theophylline/glutaric acid (1:1) cocrystal could be predicted without performing additional measurements. Moreover, the complex phase behavior of the theophylline/citric acid/water system could be correlated accounting for the formation of the theophylline hydrate (1:1), citric acid (1:1) hydrate, theophylline/citric cocrystal (1:1), and the corresponding cocrystal hydrate (1:1:1). By accounting for the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT is able to model the solubility behavior of all above-mentioned components in good agreement with the experimental data. © 2016 American Chemical Society.
    view abstract10.1021/acs.cgd.6b00554
  • Predicting the aqueous solubility of pharmaceutical cocrystals as a function of pH and temperature
    Lange, L. and Lehmkemper, K. and Sadowski, G.
    Crystal Growth and Design 16 (2016)
    The solubility of pharmaceutical cocrystals in aqueous solution is influenced by pH-dependent dissociation and salt formation which complicates the design of cocrystal formation and purification processes. To increase the efficiency of those processes, the aqueous solubility of pharmaceutical cocrystals was predicted in this work using perturbed-chain statistical associating fluid theory (PC-SAFT). Modeling results and experimental data of pH-dependent solubilities were compared for the weak base nicotinamide, the weak acid succinic acid, their 2:1 cocrystal, as well as for all occurring salts at 298.15 and 310.15 K. It was found that the pH-dependent acid-base equilibria of nicotinamide and succinic acid directly influence the solubility of their cocrystal and their salts. By accounting for the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT is able to predict the solubility behavior of all above-mentioned components in good agreement with the experimental data. © 2016 American Chemical Society.
    view abstract10.1021/acs.cgd.6b00024
  • Predicting the Effect of pH on Stability and Solubility of Polymorphs, Hydrates, and Cocrystals
    Lange, L. and Schleinitz, M. and Sadowski, G.
    Crystal Growth and Design 16 (2016)
    Cocrystal formation processes from aqueous solutions are often affected by pH-dependent dissociation, polymorphic transitions, and formation of hydrates and salts. To enhance the efficiency of those processes, the aqueous stability and solubility of pharmaceutical cocrystals were predicted in this study using the perturbed-chain statistical associating fluid theory (PC-SAFT). The solubilities in the binary systems caffeine/water and oxalic acid/water were modeled including hydrate formation and polymorphic transitions between the corresponding anhydrate forms I and II. Moreover, pH-dependent solubilities of these hydrate-forming components, their 2:1 cocrystal, and all appearing salts were measured and modeled at 298.15 K. It was found that the pH-dependent acid-base equilibria of caffeine and oxalic acid directly influence the stability and solubility of their cocrystal, their hydrates, and salts. In consideration of the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT enables solubility predictions of the before-mentioned components as well as if any cocrystal is formed at given conditions of pH and temperature. © 2016 American Chemical Society.
    view abstract10.1021/acs.cgd.6b00664
  • Predicting the solubility of pharmaceutical cocrystals in solvent/anti-solvent mixtures
    Lange, L. and Heisel, S. and Sadowski, G.
    Molecules 21 (2016)
    In this work, the solubilities of pharmaceutical cocrystals in solvent/anti-solvent systems were predicted using PC-SAFT in order to increase the efficiency of cocrystal formation processes. Modeling results and experimental data were compared for the cocrystal system nicotinamide/succinic acid (2:1) in the solvent/anti-solvent mixtures ethanol/water, ethanol/acetonitrile and ethanol/ethyl acetate at 298.15 K and in the ethanol/ethyl acetate mixture also at 310.15 K. The solubility of the investigated cocrystal slightly increased when adding small amounts of anti-solvent to the solvent, but drastically decreased for high anti-solvent amounts. Furthermore, the solubilities of nicotinamide, succinic acid and the cocrystal in the considered solvent/anti-solvent mixtures showed strong deviations from ideal-solution behavior. However, by accounting for the thermodynamic non-ideality of the components, PC-SAFT is able to predict the solubilities in all above-mentioned solvent/anti-solvent systems in good agreement with the experimental data. © 2016 by the authors; licensee MDPI.
    view abstract10.3390/molecules21050593
  • Protein partition coefficients can be estimated efficiently by hybrid shortcut calculations
    Kress, C. and Sadowski, G. and Brandenbusch, C.
    Journal of Biotechnology 233 (2016)
    The extraction of therapeutic proteins like monoclonal antibodies in aqueous two-phase systems (ATPS) is a suitable alternative to common cost intensive chromatographic purification steps within the downstream processing. Thereby the protein partitioning can be selectively changed using a displacement agent (additional salt) in order to allow for a successful purification of the target protein. Within this work a new shortcut strategy for the calculation of protein partition coefficients in polymer-salt ATPS is presented. The required protein-solute (phase-forming component, displacement agent) interactions are covered by the cross virial coefficient B23 measured by composition gradient multi-angle light scattering (CG-MALS). Using this shortcut calculation allows for an efficient determination of the partition coefficients of the target protein immunoglobulin G (IgG) and the impurity human serum albumin (HSA) within PEG-citrate and PEG-phosphate ATPS independently on the protein concentration. We demonstrate that the selection of a suitable displacement agent allowing for a selective purification of IgG from HSA is accessible by B23. Based on the determination of the protein–protein interactions via CG-MALS covered by the second osmotic virial coefficient B22 a further optimization of ATPS preventing protein precipitation is enabled. The results show that our approach contributes to an efficient downstream processing development. © 2016 Elsevier B.V.
    view abstract10.1016/j.jbiotec.2016.06.032
  • Recovery of cis,cis-muconic acid from organic phase after reactive extraction
    Gorden, J. and Zeiner, T. and Sadowski, G. and Brandenbusch, C.
    Separation and Purification Technology 169 (2016)
    Reactive extraction has been shown as an applicable first step in the downstream processing for the recovery of dicarboxylic acids from aqueous solutions, leading to yields of XRE = 0.95 ± 0.05 for cis,cis-muconic acid. A next step towards a downstream processing concept is the examination of strategies to recover the dicarboxylic acid from the organic phase. A reasonable strategy has to lead to high yields and allow for a recycle of the organic phase for further reactive extraction steps. This work presents two recovery strategies for the cis,cis-muconic acid after reactive extraction. A pH-shift uses the strong pH dependency of the reactive extraction itself. A buffered aqueous phase as re-extraction phase leads to a yield of XREEX = 0.99 ± 0.080 at pH &gt; 7. The second approach is the addition of water soluble amines as an additional reactive component. A complex of water soluble amines and the acid is re-extracted into an aqueous phase. Propylamine showed the best performance (XREEX = 1 ± 0.069) of all water soluble amines investigated. An analysis of the distribution behavior of the water soluble amines showed that a recycle of the organic phase for further reactive extraction steps is feasible for both strategies. The results allow for a further development of an in situ downstream processing concept for biocatalytic produced dicarboxylic acids. © 2016 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.seppur.2016.05.032
  • Salt influence on MIBK/water liquid-liquid equilibrium: Measuring and modeling with ePC-SAFT and COSMO-RS
    Mohammad, S. and Held, C. and Altuntepe, E. and Köse, T. and Gerlach, T. and Smirnova, I. and Sadowski, G.
    Fluid Phase Equilibria 416 (2016)
    In biotechnological processes, salts might be present during reaction steps and in downstream processes. Salts are known to have a strong impact on phase equilibria of aqueous systems.In this work, the liquid-liquid equilibria (LLE) of ternary salt/MIBK/water mixtures were measured at 298.15 K and 1 bar up to the salt solubility limit. The salts studied in this work were NaCl, LiCl, KCl, NaNO3, LiNO3, Na2SO4, CH3COONa, and CH3COOLi. From these LLE measurements it was found that a high amount of salt is dissolved in the aqueous phase whereas only a very small amount of salt was detected in the MIBK phase. Further, the salting-out behavior of MIBK from the aqueous phase upon addition of different salts was investigated to study ion-specific effects.Two ion-specific models, ePC-SAFT and an extended version of COSMO-RS for electrolytes were used for modeling the binary system MIBK/water and ternary salt/MIBK/water systems. In case of the COSMO-RS based approach, the modeling results were fully predictive. In contrast, ion-specific binary interaction parameters between MIBK and ions were fitted to experimental LLE data of the ternary systems salt/MIBK/water when using ePC-SAFT. The results show that the COSMO-RS based approach allows for predicting the salt influence on LLE with acceptable accuracy, whereas ePC-SAFT allows for almost quantitative correlations of experimental data. © 2015 Elsevier B.V.
    view abstract10.1016/j.fluid.2015.11.018
  • Standard Gibbs Energy of Metabolic Reactions: I. Hexokinase Reaction
    Meurer, F. and Bobrownik, M. and Sadowski, G. and Held, C.
    Biochemistry 55 (2016)
    The standard Gibbs energy of reaction enables calculation of the driving force of a (bio)chemical reaction. Gibbs energies of reaction are required in thermodynamic approaches to determine fluxes as well as single reaction conversions of metabolic bioreactions. The hexokinase reaction (phosphorylation of glucose) is the entrance step of glycolysis, and thus its standard Gibbs energy of reaction (ΔRg°) is of great impact. ΔRg° is accessible from equilibrium measurements, and the very small concentrations of the reacting agents cause usually high error bars in data reduction steps. Even worse, works from literature do not account for the nonideal behavior of the reacting agents (activity coefficients were assumed to be unity); thus published ΔRg° values are not standard data. Consistent treatment of activity coefficients of reacting agents is crucial for the accurate determination of standard Gibbs energy from equilibrium measurements. In this work, equilibrium molalities of hexokinase reaction were measured with an enzyme kit. These results were combined with reacting agents' activity coefficients obtained with the thermodynamic model ePC-SAFT. Pure-component parameters for adenosine triphosphate (ATP) and adenosine diphosphate (ADP) were fitted to experimental osmotic coefficients (water + Na2ATP, water + NaADP). ΔRg° of the hexokinase reaction at 298.15 K and pH 7 was found to be -17.83 ± 0.52 kJ·mol-1. This value was compared with experimental literature data; very good agreement between the different ΔRg° values was obtained by accounting for pH, pMg, and the activity coefficients of the reacting agents. © 2016 American Chemical Society.
    view abstract10.1021/acs.biochem.6b00471
  • Thermodynamics of a model biological reaction: A comprehensive combined experimental and theoretical study
    Emel'yanenko, V.N. and Yermalayeu, A.V. and Voges, M. and Held, C. and Sadowski, G. and Verevkin, S.P.
    Fluid Phase Equilibria 422 (2016)
    In this work we applied experimental and theoretical thermodynamics to methyl ferulate hydrolysis, a model biological reaction, in order to calculate the equilibrium constant and reaction enthalpy. In the first step, reaction data was collected. Temperature-dependent equilibrium concentrations of methyl ferulate hydrolysis have been measured. These were combined with activity coefficients predicted with electrolyte PC-SAFT in order to derive thermodynamic equilibriums constants K a as a function of temperature.In a second step, thermochemical properties of the highly pure reaction participants methyl ferulate and ferulic acid were measured by complementary thermochemical methods including combustion and differential scanning calorimetry. Vapor pressures and sublimation enthalpies of these compounds were measured by transpiration and TGA methods over a broad temperature range. Thermodynamic data on methyl ferulate and ferulic acid available in the literature were evaluated and combined with our own experimental results. Further, the standard molar enthalpy of methyl ferulate hydrolysis reaction calculated according to the Hess's Law applied to the reaction participants was found to be in agreement with the experimental reaction enthalpy from the equilibrium study.In a final step, the gas-phase equilibrium constant of methyl ferulate hydrolysis at 298.15 K was calculated with the G3MP2 method. This value was adjusted to the liquid phase using the experimental vapor pressures of the reaction participants. As a result, the liquid phase K a value calculated by quantum chemistry with additional data on the pure reaction participants was in good agreement with the experimental K a reported in the literature for the aqueous phase. The thermodynamic procedure based on the quantum-chemical calculations is found to be a valuable option for assessment of thermodynamic properties of biologically relevant chemical reactions. © 2016 Elsevier B.V.
    view abstract10.1016/j.fluid.2016.01.035
  • Thermodynamics of Bioreactions
    Held, C. and Sadowski, G.
    Annual Review of Chemical and Biomolecular Engineering 7 (2016)
    Thermodynamic principles have been applied to enzyme-catalyzed reactions since the beginning of the 1930s in an attempt to understand metabolic pathways. Currently, thermodynamics is also applied to the design and analysis of biotechnological processes. The key thermodynamic quantity is the Gibbs energy of reaction, which must be negative for a reaction to occur spontaneously. However, the application of thermodynamic feasibility studies sometimes yields positive Gibbs energies of reaction even for reactions that are known to occur spontaneously, such as glycolysis. This article reviews the application of thermodynamics in enzyme-catalyzed reactions. It summarizes the basic thermodynamic relationships used for describing the Gibbs energy of reaction and also refers to the nonuniform application of these relationships in the literature. The review summarizes state-of-the-art approaches that describe the influence of temperature, pH, electrolytes, solvents, and concentrations of reacting agents on the Gibbs energy of reaction and, therefore, on the feasibility and yield of biological reactions. Copyright © 2016 by Annual Reviews. All rights reserved.
    view abstract10.1146/annurev-chembioeng-080615-034704
  • Thermodynamics of the alanine aminotransferase reaction
    Voges, M. and Schmidt, F. and Wolff, D. and Sadowski, G. and Held, C.
    Fluid Phase Equilibria 422 (2016)
    The thermodynamic equilibrium of the aminotransferase reaction from l-alanine and 2-oxoglutarate to l-glutamate and pyruvate in aqueous solution was investigated in a temperature range between 25 and 37 °C and pH between at 5 and 9.Prior to considering the reaction equilibria, measurements were carried out to ensure the enzyme activity in the aqueous reaction media. After that, equilibrium concentrations of reacting agents were measured by HPLC-analysis. At constant temperature and pH, reaction equilibrium was shown to depend on the absolute molalities (0.005-0.130 mol kg-1) as well as on the ratio of initial molalities of the reactants. It could be concluded that reaction equilibrium was shifted towards the product site upon increasing reactant molalities, increasing temperature, and increasing pH. Further, yields of pyruvate were increased upon excess initial molality of l-alanine compared to 2-oxoglutarate.The thermodynamic equilibrium constant Ka* was determined by extrapolating the ratio of product equilibrium molalites and reactant equilibrium molalites to infinite dilution of all reacting agents. The activity-coefficient ratio of products and reactants in the reaction media was predicted with ePC-SAFT. Combining Ka* and the activity-coefficient ratio allowed quantitatively predicting the influence of temperature, pH, and reacting-agent molalities on the reaction equilibrium. © 2016 Elsevier B.V.
    view abstract10.1016/j.fluid.2016.01.023
  • VOC Sorption in Stretched Cross-Linked Natural Rubber
    Gushterov, N. and Doghieri, F. and Quitmann, D. and Niesing, E. and Katzenberg, F. and Tiller, J.C. and Sadowski, G.
    Industrial and Engineering Chemistry Research 55 (2016)
    Sorption of volatile organic compound (VOC) vapors in natural rubber (NR) was measured at 20 °C using a magnetic suspension balance. Experiments were performed with non-cross-linked NR, as well as NR cross-linked with dicumyl peroxide. Stretching the cross-linked NR samples leads to crystal formation and therefore to a constraint to volume swelling of the amorphous domains. To investigate the influence of NR stretching and therefore of crystal formation on the VOC sorption, measurements of nonstretched NR were compared to data for cross-linked NR samples stretched with different extension ratios. Analysis of the VOC sorption data revealed a reduced VOC sorption in the stretched NR compared to fully amorphous, nonstretched NR. The sorption data were modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT) accounting for network elasticity by an additional Helmholtz-energy contribution. Influence of crystallinity content on VOC solubility in stretched NR was finally accounted for following a recently proposed approach and thus accounting for an additional contribution to pressure in the amorphous phase as a result of constraint imposed by crystalline domains. Comparison of modeling results with measured solubility for several VOCs in NR confirmed the overall consistency of the modeling approach used. © 2016 American Chemical Society.
    view abstract10.1021/acs.iecr.6b01710
  • A novel approach for analyzing the dissolution mechanism of solid dispersions
    Ji, Y. and Paus, R. and Prudic, A. and Lübbert, C. and Sadowski, G.
    Pharmaceutical Research 32 (2015)
    Purpose To analyze the dissolution mechanism of solid dispersions of poorly water-soluble active pharmaceutical ingredients (APIs), to predict the dissolution profiles of the APIs and to find appropriate ways to improve their dissolution rate. Methods The dissolution profiles of indomethacin and naproxen from solid dispersions in PVP K25 were measured in vitro using a rotating-disk system (USP II). A chemical-potential-gradient model combined with the thermodynamic model PC-SAFT was developed to investigate the dissolution mechanism of indomethacin and naproxen from their solid dispersions at different conditions and to predict the dissolution profiles of these APIs. Results The results show that the dissolution of the investigated solid dispersions is controlled by dissolution of both, API and PVP K25 as they codissolve according to the initial API loading. Moreover, the dissolution of indomethacin and naproxen was improved by decreasing the API loading in polymer (leading to amorphous solid dispersions) and increasing stirring speed, temperature and pH of the dissolution medium. The dissolution of indomethacin and naproxen from their amorphous solid dispersions is mainly controlled by the surface reaction, which implies that indomethacin and naproxen dissolution can be effectively improved by formulation design and by improving their solvation performance. Conclusions The chemical-potential-gradient model combined with PC-SAFTcan be used to analyze the dissolution mechanism of solid dispersions and to describe and predict the dissolution profiles of API as function of stirring speed, temperature and pH value of the medium. This work helps to find appropriate ways to improve the dissolution rate of poorly-soluble APIs. © Springer Science+Business Media New York 2015.
    view abstract10.1007/s11095-015-1644-z
  • Different recycling concepts in the homogeneously catalysed synthesis of terpenyl amines
    Färber, T. and Schulz, R. and Riechert, O. and Zeiner, T. and Górak, A. and Sadowski, G. and Behr, A.
    Chemical Engineering and Processing: Process Intensification 98 (2015)
    The homogeneously catalysed hydroamination reaction of β-myrcene with morpholine to terpenyl amines was investigated. Two different techniques to avoid catalyst losses from the liquid phase were applied: Thermomorphic Multicomponent Solvent (TMS)-systems, in which the temperature-sensitivity of the binodal curve is exploited and Liquid-Liquid Two-Phase (LLTP)-systems, in which the reaction happens at the phase interface. The highest β-myrcene conversion of more than 90% and a product yield of more than 80% was measured in a TMS-system consisting of n-heptane and acetonitrile. The same conversion was reached in a LLTP-system consisting of water and β-myrcene, whereas a product yield of 55% was achieved. Experimental data of the liquid-liquid phase equilibria resulted in thermodynamic fundamentals for the design of chemical reactors for the production of amines. Theoretical prediction of equilibrium compositions using PC-SAFT equation of state agree excellent with measured values. © 2015 Elsevier B.V.
    view abstract10.1016/j.cep.2015.09.016
  • Dissolution of crystalline pharmaceuticals: Experimental investigation and thermodynamic modeling
    Paus, R. and Ji, Y. and Braak, F. and Sadowski, G.
    Industrial and Engineering Chemistry Research 54 (2015)
    In this work, a two-step chemical-potential-gradient model based on nonequilibrium thermodynamic principles was developed to investigate the dissolution mechanism of crystalline active pharmaceutical ingredients (APIs). The perturbed-chain statistical associating fluid theory was used to calculate the required solubilities and chemical potentials of the investigated APIs. The statistical rate theory was used to describe the mass-transfer rate of the APIs at the solid-liquid interface during the dissolution process. Dissolution profiles of indomethacin, naproxen, and glibenclamide in water and in buffered solutions at pH 5.0, 6.5, and 7.2 were measured using a rotating-disk system (USP II). The specific dissolution mechanisms of the APIs, such as surface reaction and diffusion, were analyzed by applying the proposed model to identify the rate-controlling step. The results show that the dissolution mechanisms of indomethacin, naproxen, and glibenclamide change with varying pH values of the solution medium. On the basis of the calculated rate constants, the dissolution profiles were modeled with a high degree of accuracy when compared with the experimental data. © 2014 American Chemical Society.
    view abstract10.1021/ie503939w
  • Influence of humidity on the phase behavior of API/polymer formulations
    Prudic, A. and Ji, Y. and Luebbert, C. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 94 (2015)
    Amorphous formulations of APIs in polymers tend to absorb water from the atmosphere. This absorption of water can induce API recrystallization, leading to reduced long-term stability during storage. In this work, the phase behavior of different formulations was investigated as a function of relative humidity. Indomethacin and naproxen were chosen as model APIs and poly(vinyl pyrrolidone) (PVP) and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) as excipients. The formulations were prepared by spray drying. The water sorption in pure polymers and in formulations was measured at 25 °C and at different values of relative humidity (RH = 25%, 50% and 75%). Most water was absorbed in PVP-containing systems, and water sorption was decreasing with increasing API content. These trends could also be predicted in good agreement with the experimental data using the thermodynamic model PC-SAFT. Furthermore, the effect of absorbed water on API solubility in the polymer and on the glass-transition temperature of the formulations was predicted with PC-SAFT and the Gordon-Taylor equation, respectively. The absorbed water was found to significantly decrease the API solubility in the polymer as well as the glass-transition temperature of the formulation. Based on a quantitative modeling of the API/polymer phase diagrams as a function of relative humidity, appropriate API/polymer compositions can now be selected to ensure long-term stable amorphous formulations at given storage conditions. © 2015 Published by Elsevier B.V.
    view abstract10.1016/j.ejpb.2015.06.009
  • Measurement and modeling of phase equilibria in systems of acetonitrile, n-alkanes, and β-myrcene
    Riechert, O. and Zeiner, T. and Sadowski, G.
    Industrial and Engineering Chemistry Research 54 (2015)
    This work presents a modeling approach using the Perturbed Chain-Statistical Associating Fluid Theory (PC-SAFT) for new liquid-liquid equilibria (LLE) data of ternary systems containing β-myrcene, acetonitrile, and n-alkanes, as well as binary mixtures thereof. The modeling approach is based on parameter estimations from binary systems and allows a general prediction of acetonitrile/n-alkane systems' LLE and their ternary mixtures' LLE with β-myrcene. The binary mixtures' vapor-liquid equilibria (VLE) of β-myrcene with acetonitrile and n-alkanes were measured at 100 mbar. The ternary systems' LLE were measured at ambient pressure and 298.15 K. Experimentally investigated alkanes are n-hexane, n-heptane, and n-octane. The approach was validated by successfully predicting the ternary system containing n-dodecane. © 2015 American Chemical Society.
    view abstract10.1021/ie502557g
  • Modeling aqueous two-phase systems: III. Polymers and organic salts as ATPS former
    Reschke, T. and Brandenbusch, C. and Sadowski, G.
    Fluid Phase Equilibria 387 (2015)
    In this work the electrolyte perturbed chain statistical associating fluid theory (ePC-SAFT) is applied to model aqueous two-phase systems (ATPS) containing one of 6 different polymers and one of 8 different organic salts at temperatures between 278.15. K and 313.15. K. To accurately model the thermodynamic properties of organic-salt solutions, a novel modeling approach was applied, which accounts for the non-spherical shape of the anions. Applying this approach, 14 organic salt solutions have been modeled with an overall average relative deviation of 0.23% for solution densities and 1.51% for osmotic coefficients. The modeling of the polymers (PEG, PEGDME, PPG, and poly(ethylene glycol-. co-propylene glycol)) has been carried out using a copolymer approach accounting for different molecular interactions of the polymer segments. Applying this approach, ATPS containing polymers and organic salts were modeled accurately. The overall absolute average deviation of the modeling with respect to the concentrations of the phase-forming components was 2.10. wt%. The influence of polymer molecular weight, polymer composition, kind of salt, pH, and temperature on the equilibrium composition and densities of the two phases was modeled correctly with ePC-SAFT. Moreover, it is shown that by applying ion-specific model parameters, ePC-SAFT is even capable of predicting ATPS containing salts which were not used for the parameter estimation. © 2014 Elsevier B.V..
    view abstract10.1016/j.fluid.2014.12.011
  • Partition coefficients of pharmaceuticals as functions of temperature and pH
    Laube, F. and Klein, T. and Sadowski, G.
    Industrial and Engineering Chemistry Research 54 (2015)
    Liquid-liquid extraction is a potential separation process for the purification of active pharmaceutical ingredients (APIs). The design of an extraction step requires knowledge of the API partition coefficient, which strongly depends on the solvent system and process conditions. Usually, cost-intensive experiments have to be performed to select the most suitable solvent system and the best process conditions. The number of experiments can be reduced by predicting the partition coefficient using perturbed chain statistical associating theory (PC-SAFT). In this work, modeling results and experimental data were compared for the partition coefficients of the APIs nicotinamide and salicylamide in different solvent systems at temperatures from 293.15 to 328.15 K and at pH values varying between 5.2 and 10.3. The results show that PC-SAFT is able to predict the API partition coefficients for different solvent systems as functions of temperature and pH. © 2015 American Chemical Society.
    view abstract10.1021/acs.iecr.5b00068
  • Phase Equilibria in Systems of Morpholine, Acetonitrile, and n -Alkanes
    Riechert, O. and Zeiner, T. and Sadowski, G.
    Journal of Chemical and Engineering Data 60 (2015)
    This work presents investigations on the liquid-liquid equilibria (LLE) of ternary systems composed of morpholine, acetonitrile, and an n-alkane at 298.15 K and atmospheric pressure. The investigated n-alkanes were n-hexane, n-heptane, and n-octane. The experimental data were compared to predictions using the perturbed chain-statistical associating fluid theory (PC-SAFT). The predictions are based on pure-component parameters fitted to vapor pressures and liquid densities as well as on binary parameters fitted to binary systems' phase equilibria. For that purpose, the vapor-liquid equilibrium of the morpholine/acetonitrile system was measured at 100 mbar and modeled with PC-SAFT. Binary interaction parameters for acetonitrile/n-alkane systems were obtained from a correlation as a function of the n-alkane carbon number. This correlation, together with the other pure-component and binary parameters, was used to make predictions on ternary systems with n-alkanes longer than n-octane, for which data were taken from literature. All ternary LLE predictions were in satisfactory agreement with experimental data. © 2015 American Chemical Society.
    view abstract10.1021/acs.jced.5b00175
  • Predicting the Solubility Advantage of Amorphous Pharmaceuticals: A Novel Thermodynamic Approach
    Paus, R. and Ji, Y. and Vahle, L. and Sadowski, G.
    Molecular Pharmaceutics 12 (2015)
    For the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs) to be improved, the transformation of crystalline APIs to the amorphous state has often been shown to be advantageous. As it is often difficult to measure the solubility of amorphous APIs, the application of thermodynamic models is the method of choice for determining the solubility advantage. In this work, the temperature-dependent solubility advantage of an amorphous API versus its crystalline form was predicted for five poorly soluble APIs in water (glibenclamide, griseofulvin, hydrochlorothiazide, indomethacin, and itraconazole) based on modeling the API/solvent phase diagrams using the perturbed-chain statistical associating fluid theory (PC-SAFT). Evaluation of the performance of this approach was performed by comparing the predicted solubility advantage to experimental data and to the solubility advantage calculated by the commonly applied Gibbs-energy-difference method. For all of the systems considered, PC-SAFT predictions of the solubility advantage are significantly more accurate than the results obtained from the Gibbs-energy-difference method. © 2015 American Chemical Society.
    view abstract10.1021/mp500824d
  • Process boundaries of irreversible scCO2-assisted phase separation in biphasic whole-cell biocatalysis
    Brandenbusch, C. and Glonke, S. and Collins, J. and Hoffrogge, R. and Grunwald, K. and Bühler, B. and Schmid, A. and Sadowski, G.
    Biotechnology and Bioengineering 112 (2015)
    The formation of stable emulsions in biphasic biotransformations catalyzed by microbial cells turned out to be a major hurdle for industrial implementation. Recently, a cost-effective and efficient downstream processing approach, using supercritical carbon dioxide (scCO2) for both irreversible emulsion destabilization (enabling complete phase separation within minutes of emulsion treatment) and product purification via extraction has been proposed by Brandenbusch et al. (2010). One of the key factors for a further development and scale-up of the approach is the understanding of the mechanism underlying scCO2-assisted phase separation. A systematic approach was applied within this work to investigate the various factors influencing phase separation during scCO2 treatment (that is pressure, exposure of the cells to CO2, and changes of cell surface properties). It was shown that cell toxification and cell disrupture are not responsible for emulsion destabilization. Proteins from the aqueous phase partially adsorb to cells present at the aqueous-organic interface, causing hydrophobic cell surface characteristics, and thus contribute to emulsion stabilization. By investigating the change in cell-surface hydrophobicity of these cells during CO2 treatment, it was found that a combination of catastrophic phase inversion and desorption of proteins from the cell surface is responsible for irreversible scCO2 mediated phase separation. These findings are essential for the definition of process windows for scCO2-assisted phase separation in biphasic whole-cell biocatalysis. © 2015 Wiley Periodicals, Inc.
    view abstract10.1002/bit.25655
  • Solid Dispersion - a Pragmatic Method to Improve the Bioavailability of Poorly Soluble Drugs
    Ke, P. and Qi, S. and Sadowski, G. and Ouyang, D.
    Computational Pharmaceutics: Application of Molecular Modeling in Drug Delivery (2015)
    view abstract10.1002/9781118573983.ch5
  • Solubility and Caloric Properties of Cinnarizine
    Paus, R. and Hart, E. and Ji, Y. and Sadowski, G.
    Journal of Chemical and Engineering Data 60 (2015)
    The solubility of cinnarizine has been investigated in acetonitrile, butyl acetate, 1-butanol, 2-propanol, and water in a temperature range from 288.15 K to 313.15 K. During crystallization from these solvents two different crystal morphologies of cinnarizine were observed. The caloric properties (melting temperature, melting enthalpy, and the difference in the heat capacity of solid and liquid cinnarizin) were measured by differential scanning calorimetry. The temperature-dependent solubility of cinnarizine in different organic solvents and in water was modeled using the perturbed-chain statistical associating fluid theory and was in good agreement with the experimental data. © 2015 American Chemical Society.
    view abstract10.1021/acs.jced.5b00075
  • Solvent effects on esterification equilibria
    Riechert, O. and Husham, M. and Sadowski, G. and Zeiner, T.
    AIChE Journal 61 (2015)
    Solvents are known to have strong impacts on the yields of equilibrium reactions. This work focuses on the thermodynamic investigation of these solvent effects on esterification reactions of acetic acid and propionic acid with ethanol. Esterification of acetic acid was performed in the solvents acetone, acetonitrile (ACN), dimethylformamide (DMF), and tetrahydrofurane as well as in mixtures thereof. ACN promotes the esterification of acetic acid, whereas it is strongly suppressed by DMF. The esterification of propionic acid was investigated with various reactant concentrations in acetone. The experimental equilibrium data in pure solvents and solvent mixtures were modeled using the thermodynamic equilibrium constant K<inf>a</inf> and the reactant/product activity coefficients predicted by the perturbed chain-statistical associating fluid theory (PC-SAFT). For a given K<inf>a</inf>, PC-SAFT is able to predict the influence of the solvent and even solvent mixtures on the equilibrium concentrations of esterification in almost quantitative agreement with the experimental data. © 2015 American Institute of Chemical Engineers.
    view abstract10.1002/aic.14873
  • Solving phase equilibrium problems by means of avoidance-based multiobjectivization
    Preuss, M. and Wessing, S. and Rudolph, G. and Sadowski, G.
    Springer Handbook of Computational Intelligence (2015)
    Phase-equilibrium problems are good examples for real-world engineering optimization problems with a certain characteristic. Despite their low dimensionality, finding the desired optima is difficult as their basins of attraction are small and surrounded by the much larger basin of the global optimum, which unfortunately resembles a physically impossible and therefore unwanted solution. We tackle such problems by means of a multi-objectivization-assisted multimodal optimization algorithm which explicitly uses problem knowledge concerning where the sought solutions are not in order to find the desired ones. The method is successfully applied to three phase equilibrium problems and shall be suitable also for tackling difficult multimodal optimization problems from other domains. © Springer-Verlag Berlin Heidelberg 2015.
    view abstract10.1007/978-3-662-43505-2_58
  • The dynamic influence of cells on the formation of stable emulsions in organic–aqueous biotransformations
    Collins, J. and Grund, M. and Brandenbusch, C. and Sadowski, G. and Schmid, A. and Bühler, B.
    Journal of Industrial Microbiology and Biotechnology 42 (2015)
    Emulsion stability plays a crucial role for mass transfer and downstream processing in organic–aqueous bioprocesses based on whole microbial cells. In this study, emulsion stability dynamics and the factors determining them during two-liquid phase biotransformation were investigated for stereoselective styrene epoxidation catalyzed by recombinant Escherichia coli. Upon organic phase addition, emulsion stability rapidly increased correlating with a loss of solubilized protein from the aqueous cultivation broth and the emergence of a hydrophobic cell fraction associated with the organic–aqueous interface. A novel phase inversion-based method was developed to isolate and analyze cellular material from the interface. In cell-free experiments, a similar loss of aqueous protein did not correlate with high emulsion stability, indicating that the observed particle-based emulsions arise from a convergence of factors related to cell density, protein adsorption, and bioreactor conditions. During styrene epoxidation, emulsion destabilization occurred correlating with product-induced cell toxification. For biphasic whole-cell biotransformations, this study indicates that control of aqueous protein concentrations and selective toxification of cells enables emulsion destabilization and emphasizes that biological factors and related dynamics must be considered in the design and modeling of respective upstream and especially downstream processes. © 2015, Society for Industrial Microbiology and Biotechnology.
    view abstract10.1007/s10295-015-1621-x
  • Thermodynamic Modeling for Efficient Cocrystal Formation
    Lange, L. and Sadowski, G.
    Crystal Growth and Design 15 (2015)
    The purpose of this work is to increase the efficiency of the cocrystal formation process by thermodynamic modeling using perturbed-chain statistical associating fluid theory (PC-SAFT). By accounting for the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT is able to model and predict the solubility behavior of pharmaceutical cocrystals based solely on the knowledge of a single cocrystal solubility point in any solvent and at any temperature. Furthermore, the cocrystal solubility in other solvents and for other temperatures can be predicted without the need for additional measurements. The (+)-mandelic acid/(-)-mandelic acid (1:1), caffeine/glutaric acid (1:1), and carbamazepine/nicotinamide (1:1) cocrystal systems were modeled, and the results were in excellent agreement with the experimental data. (Figure Presented). © 2015 American Chemical Society.
    view abstract10.1021/acs.cgd.5b00735
  • Thermodynamic phase behaviour of indomethacin/PLGA formulations
    Prudic, A. and Lesniak, A.-K. and Ji, Y. and Sadowski, G.
    European Journal of Pharmaceutics and Biopharmaceutics 93 (2015)
    In the current study, the phase behaviour of indomethacin and poly(lactic-co-glycolic acid) (PLGA) formulations was investigated as a function of the molecular weight and the copolymer composition of PLGA. The formulations were prepared by ball milling, and the phase behaviour, comprised of the glass-transition temperature of the formulations and the solubility of indomethacin in PLGA, was measured using modulated differential scanning calorimetry (mDSC). The results determined that the solubility of indomethacin in PLGA at room temperature was very low and increased with a corresponding decrease in the molecular weight of PLGA. The copolymer composition of PLGA had a minor effect on the indomethacin solubility. The effect of PLGA's molecular weight and copolymer composition on the solubility of indomethacin could be modelled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) with a high degree of accuracy when compared with the experimental data. The glass-transition temperatures had a negative deviation from the weighted mean of the glass-transition temperatures of the pure substances, which could be described by the Kwei-equation. © 2015 Published by Elsevier B.V.
    view abstract10.1016/j.ejpb.2015.01.029
  • A thermodynamic investigation of the glucose-6-phosphate isomerization
    Hoffmann, P. and Held, C. and Maskow, T. and Sadowski, G.
    Biophysical Chemistry 195 (2014)
    In this work, ΔRg+ values for the enzymatic G6P isomerization were determined as a function of the G6P equilibrium molality between 25 °C and 37 °C. The reaction mixtures were buffered at pH = 8.5. In contrast to standard literature work, ΔRg+ values were determined from activity-based equilibrium constants instead of molality-based apparent values. This yielded a ΔRg+ value of 2.55 ± 0.05 kJ mol- 1 at 37 °C, independent of the solution pH between 7.5 and 8.5. Furthermore, ΔRh + was measured at pH = 8.5 and 25 °C yielding 12.05 ± 0.2 kJ mol- 1. Accounting for activity coefficients turned out to influence ΔRg+ up to 30% upon increasing the G6P molality. This result was confirmed by predictions using the thermodynamic model ePC-SAFT. Finally, the influence of the buffer and of potassium glutamate as an additive on the reaction equilibrium was measured and predicted with ePC-SAFT in good agreement. © 2014 Elsevier B.V.
    view abstract10.1016/j.bpc.2014.08.002
  • Calculation of complex phase equilibria of DMF/alkane systems using the PCP-SAFT equation of state
    Schäfer, E. and Sadowski, G. and Enders, S.
    Chemical Engineering Science 115 (2014)
    The Perturbed Chain Polar Statistical Association Fluid Theory (PCP-SAFT) equation of state is applied to calculate phase equilibria data for several DMF/alkane systems. DMF/alkane systems exhibit a peculiar phase behavior, due to overlapping liquid-liquid and vapor-liquid coexistence regions. Hetero- and homoazeotropes appear and disappear depending on temperature/pressure conditions and the chain length of the alkane. The vapor-liquid, liquid-liquid and vapor-liquid-liquid equilibria of DMF/alkanes systems including alkanes from C5 to C10 were studied in detail over wide temperature and pressure ranges. A single, linear expression for the binary interaction parameter kij as function of temperature and alkane chain length was used to model the experimental data. This expression was determined only by using experimental liquid-liquid equilibria (LLE) data of DMF/alkane systems. Using that, the PCP-SAFT equation of state provides very satisfying results for the description of the phase behavior in all considered systems. © 2013 Elsevier Ltd.
    view abstract10.1016/j.ces.2013.04.053
  • Density of Mixtures Containing Sugars and Ionic Liquids: Experimental Data and PC-SAFT Modeling
    Carneiro, A.P. and Rodríguez, O. and Held, C. and Sadowski, G. and A. Macedo, E.
    Journal of Chemical and Engineering Data 59 (2014)
    The potential use of ionic liquids (ILs) for biomass and carbohydrate processing has been discovered in the past decade. Many advantages have been pointed out in their application for biorefining purposes. The phase equilibria and volumetric properties of mixtures containing ILs and biomass-derived compounds such as sugars or sugar alcohols are relevant for process design. In this work, the density, at atmospheric pressure, of binary mixtures containing sugars (glucose and fructose) or sugar alcohols (xylitol and sorbitol) and ionic liquids (1-ethyl-3-methylimidazolium ethylsulfate and Aliquat336) is presented within large temperature (278 K to 343 K) and composition ranges (up to sugar or sugar alcohol mass fraction of 0.30). The density data followed a bilinear trend with respect to temperature and composition. The data were therefore represented using planar regression with a very good accuracy, average relative deviation (ARD) < 0.1 % in most of the cases. The perturbed-chain statistical association fluid theory (PC-SAFT) equation of state was applied to model solutions containing ILs. The pure-component parameters for Aliquat336 were fitted to pure-IL density data. Applying temperature-dependent kij parameters, PC-SAFT allowed satisfactory modeling of the measured density data and literature solubility data of sugars and sugar alcohols in Aliquat336. © 2014 American Chemical Society.
    view abstract10.1021/je500079y
  • Environmental memory of polymer networks under stress
    Quitmann, D. and Gushterov, N. and Sadowski, G. and Katzenberg, F. and Tiller, J.C.
    Advanced Materials 26 (2014)
    Generally reversible stimuli-responsive materials do not memorize the stimulus. In this study we describe an example in which stretched and constrained semi-crystalline polymer networks respond to solvent gases with stress and simultaneously memorize the concentration and the chemical nature of the solvent itself in their microstructure (see figure). This written solvent signature can even be deleted by temperature. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/adma.201305698
  • EPC-SAFT revised
    Held, C. and Reschke, T. and Mohammad, S. and Luza, A. and Sadowski, G.
    Chemical Engineering Research and Design 92 (2014)
    So far, the electrolyte PC-SAFT equation of state developed in Cameretti et al. (2005) has been applied to model solution densities, vapor-liquid equilibria (VLE), liquid-liquid equilibria (LLE), and solid-liquid equilibria (SLE) of solutions containing electrolytes. For that purpose, two ion-specific parameters were used to characterize any ion: the diameter of the solvated ion and the dispersion-energy parameter between ion and solvent. Dispersion was only considered between ions and solvents. Considering the small number of adjustable parameters, this approach yielded acceptable results especially for low and moderate electrolyte concentrations. However, for high salt concentrations, a distinct deviation between modeled and experimental data was observed. In this work a new modeling approach is suggested that accounts explicitly also for dispersion interactions between anions and cations. This yields a much more precise description of electrolyte solutions at higher concentrations compared to original ePC-SAFT. With this new approach it is also possible to directly model weak electrolyte solutions without using an additional approach that accounts for ion-pair formation. The new approach for applying ePC-SAFT is now able to model phase equilibria (VLE, LLE, SLE) of ternary electrolyte solutions containing water, organic solvents, salts, and amino acids even at high salt concentrations in good agreement with experimental data. © 2014 The Institution of Chemical Engineers.
    view abstract10.1016/j.cherd.2014.05.017
  • High-pressure gas solubility in multicomponent solvent systems for hydroformylation. Part II: Syngas solubility
    Vogelpohl, C. and Brandenbusch, C. and Sadowski, G.
    Journal of Supercritical Fluids 88 (2014)
    High-pressure solubility of syngas with a molar ratio of hydrogen (H 2) and carbon monoxide (CO) of 1:1 was investigated in various solvents like n-decane, dimethylformamide (DMF), 1-dodecene and n-dodecanal as well as in mixtures of n-decane and DMF and in a mixture of 1-dodecene, n-dodecanal, n-decane and DMF at temperatures between 302 K and 367 K and at pressures of up to 14 MPa. Moreover, the H2 solubility in 1-dodecene and n-dodecanal was measured in the same pressure and temperature range. The solubility measurements were performed in a high-pressure volume-variable view cell using a visual synthetic method. For modeling and prediction of the gas solubility (H2, CO, and syngas (H2/CO)) in the considered solvents, the Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT) was used. The systems containing one gas (H2 or CO) and one solvent were modeled accurately by applying temperature-independent binary interaction parameters (kij's). These kij's were used to predict the syngas solubility in pure solvents and their mixtures without further adjustments. The kij between H2 and CO was always set to zero. The results showed that PC-SAFT is able to predict the syngas solubility in pure solvents with an average relative deviation of 3.1-12.0%. Syngas solubility in the n-decane/DMF mixture was predicted with a deviation of 7.2%. © 2014 Elsevier B.V.
    view abstract10.1016/j.supflu.2014.01.017
  • Influence of copolymer composition on the phase behavior of solid dispersions
    Prudic, A. and Kleetz, T. and Korf, M. and Ji, Y. and Sadowski, G.
    Molecular Pharmaceutics 11 (2014)
    The incorporation of poorly soluble active pharmaceutical ingredients (APIs) into excipients (e.g., polymers) to formulate an amorphous solid dispersion is a promising strategy to improve the oral bioavailability of the API. The application of copolymer excipients allows access to combinations of different monomers and thus to the design of excipients to improve solid-dispersion properties. In this work, the thermodynamic phase behavior of solid dispersions was investigated as a function of the API, type of monomer, and copolymer composition. The glass-transition temperatures and API solubilities in the solid dispersions of naproxen and indomethacin in polyvinylpyrrolidone, polyvinyl acetate, and copolymers with different weight fractions of vinylpyrrolidone and vinyl actetate were investigated. It is shown that the thermodynamic phase behavior of API/copolymer solid dispersions is a function of monomer type and copolymer composition. This effect was also predicted by using the perturbed-chain statistical associating fluid theory (PC-SAFT). The glass-transition temperature of the solid dispersions was calculated with the Gordon-Taylor equation. © 2014 American Chemical Society.
    view abstract10.1021/mp500412d
  • Interfacial tension of binary mixtures exhibiting azeotropic behavior: Measurement and modeling with PCP-SAFT combined with Density Gradient Theory
    Schäfer, E. and Sadowski, G. and Enders, S.
    Fluid Phase Equilibria 362 (2014)
    This work focuses on modeling and experimental investigation of temperature dependent interfacial properties of binary DMF/n-alkane (C7, C10, C12) mixtures. The systems consisting of solvents with very different polarity show azeotropic behavior. New experimental vapor-liquid and liquid-liquid interfacial tension data are provided between 298.15 and 328.15K using the drop volume method. The Perturbed Chain Polar Statistical Associating Fluid Theory (PCP-SAFT) equation of state was combined with the Density Gradient Theory (DGT) to calculate phase equilibria and interfacial properties. Modeling results are in good agreement with the corresponding experimental data. Thereby, the binary parameter βij within the DGT framework does not equal one. Investigating density and concentration profiles in the interface revealed characteristic trends which are related to the azeotropic behavior of the mixtures. © 2013 Elsevier B.V.
    view abstract10.1016/j.fluid.2013.09.042
  • Measuring and modeling aqueous electrolyte/amino-acid solutions with ePC-SAFT
    Held, C. and Reschke, T. and Müller, R. and Kunz, W. and Sadowski, G.
    Journal of Chemical Thermodynamics 68 (2014)
    In this work thermodynamic properties of electrolyte/amino acid/water solutions were measured and modeled. Osmotic coefficients at 298.15 K were measured by means of vapor-pressure osmometry. Amino-acid solubility at 298.15 K was determined gravimetrically. Considered aqueous systems contained one of the four amino acids: glycine, L-/DL-alanine, L-/DL-valine, and L-proline up to the respective amino-acid solubility limit and one of 13 salts composed of the ions Li+, Na+, K+, NH4 +, Cl-, Br-, I-, NO3 -, and SO4 2- at salt molalities of 0.5, 1.0, and 3.0 mol · kg-1, respectively. The data show that the salt influence is more pronounced on osmotic coefficients than on amino-acid solubility. The electrolyte Perturbed-Chain Statistical Association Theory (ePC-SAFT) was applied to model thermodynamic properties in aqueous electrolyte/amino-acid solutions. In previous works, this model had been applied to binary salt/water and binary amino acid/water systems. Without fitting any additional parameters, osmotic coefficients and amino-acid solubility in the ternary electrolyte/amino acid/water systems could be predicted with overall deviations of 3.7% and 9.3%, respectively, compared to the experimental data. © 2013 Elsevier Ltd. All rights reserved.
    view abstract10.1016/j.jct.2013.08.018
  • Model-based prediction of optimal conditions for 1-octene hydroformylation
    Hentschel, B. and Peschel, A. and Xie, M. and Vogelpohl, C. and Sadowski, G. and Freund, H. and Sundmacher, K.
    Chemical Engineering Science 115 (2014)
    In reactive multiphase systems, the reactive phase can be manipulated not only by temperature and pressure, but also via coexisting "service" phases. For the exploitation of the full potential of such systems, a model-based reactor design that includes an accurate calculation of the equilibrium composition using advanced thermodynamic models is mandatory. This is of special importance when innovative solvent systems with complex phase behavior are considered. In this work, an equation based model containing reaction kinetics and an advanced equation of state, namely the perturbed-chain statistical associating fluid theory (PC-SAFT), was implemented for large-scale optimization. Exemplified on the hydroformylation of 1-octene it is demonstrated how such a model framework can be used as basis for optimal reactor design.After fitting the PC-SAFT parameters to pure component data the model was used to study the influence of product formation on the solubilities of H2 and CO. Finally, the reaction conditions were optimized in order to maximize the differential selectivity to the desired product n-nonanal. It is shown that the performance of the hydroformylation reaction system can be significantly increased by optimally controlling temperature, total pressure, and the amount of H2 and CO in the gas phase. © 2013 Elsevier Ltd.
    view abstract10.1016/j.ces.2013.03.051
  • Modeling aqueous two-phase systems: I. Polyethylene glycol and inorganic salts as ATPS former
    Reschke, T. and Brandenbusch, C. and Sadowski, G.
    Fluid Phase Equilibria 368 (2014)
    In this work the ePC-SAFT equation of state is applied to model aqueous two-phase systems (ATPS) containing polyethylene glycol (PEG) and one of 16 different inorganic salts at temperatures between 277.15. K and 333.15. K. To ensure an accurate modeling of thermodynamic properties in PEG containing solutions, a novel modeling approach for PEG is applied considering different molecular interactions of PEG chain segments and PEG end-group segments. Applying this approach, the influence of PEG molecular weight, kind of salt, pH, as well as of temperature on the phase split as well as on the densities of the two phases can be modeled accurately. The overall absolute average deviation of the concentrations of the phase-forming components obtained by ePC-SAFT is 2.25. wt%. Moreover, it could be shown that by applying ion-specific model parameters, ePC-SAFT is even capable of predicting ATPS which were not used for the parameter estimation. © 2014 .
    view abstract10.1016/j.fluid.2014.02.016
  • Modeling aqueous two-phase systems: II. Inorganic salts and polyether homo- and copolymers as ATPS former
    Reschke, T. and Brandenbusch, C. and Sadowski, G.
    Fluid Phase Equilibria 375 (2014)
    In this work the electrolyte perturbed chain statistical associating fluid theory (ePC-SAFT) was applied to model aqueous two-phase systems (ATPS) containing combinations of polyethylene glycol dimethyl ether (PEGDME), polypropylene glycol (PPG) and three poly(ethylene glycol-co-propylene glycol) copolymers in combination with 12 different inorganic salts for temperatures ranging from 278. K to 333. K. For the polymer modeling, a copolymer approach was applied splitting the polymer in different segment types accounting for their different molecular interactions. Using this approach allows for quantitative modeling of phase properties of aqueous homopolymer and copolymer solutions. ATPS consisting of water, salt and one out of the five polymers were successfully modeled by using only one binary interaction parameter between each polymer segment type and each ion. Applying these parameter set, the influence of (co)polymer composition, polymer molecular weight, and temperature on the phase composition and phase densities could be modeled accurately. © 2014.
    view abstract10.1016/j.fluid.2014.04.040
  • Modeling imidazolium-based ionic liquids with ePC-SAFT. Part II. Application to H2S and synthesis-gas components
    Ji, X. and Held, C. and Sadowski, G.
    Fluid Phase Equilibria 363 (2014)
    ePC-SAFT was used to model the gas solubility in ionic liquids (ILs). The gases under consideration were CO, H2, H2S and O2, and the imidazolium-based ILs studied were [Cnmim][Tf2N], [Cnmim][PF6] and [Cnmim][BF4] (n=2, 4, 6 and 8). For the ePC-SAFT modeling, each IL was considered to be completely dissociated into a cation and an anion. Each ion was modeled as a non-spherical species exerting repulsive, dispersive and Coulomb forces. CO, H2 and O2 were modeled as non-spherical molecules exerting repulsive and dispersive forces, and H2S was modeled as a non-spherical, associating molecule. ePC-SAFT reasonably predicts the gas solubility in the considered gas/IL mixtures. In order to describe the experimental gas solubilities quantitatively in a broad temperature and pressure range, one ion-specific binary interaction parameter between the IL-anion and the gas was applied, which was allowed to depend linearly on temperature. © 2013.
    view abstract10.1016/j.fluid.2013.11.019
  • Modelling polylactide/water/dioxane systems for TIPS scaffold fabrication
    Cocchi, G. and Angelis, M.G.D. and Sadowski, G. and Doghieri, F.
    Fluid Phase Equilibria 374 (2014)
    The representation of liquid-liquid equilibria (LLE) in ternary systems composed by water, 1,4-dioxane and different grades of poly(lactic acid) (PDLLA and PLLA), has been addressed through the PC-SAFT equation of state (EoS), in which the scheme of induced association is used to represent the interaction between solvent (dioxane) and non-solvent (water). The model parameters devoted to the description of pure component properties, as well as those pertinent to the representation of thermodynamic behaviour of solvent/non-solvent mixtures, were tuned on the basis of specific pressure-volume-temperature (PVT) data for the corresponding systems. Only the binary parameters for polymer-solvent and polymer/non-solvent pairs were adjusted to obtain a useful representation of experimental LLE data for the ternary systems. A suitable description of the thermodynamic properties of ternary mixtures was obtained using temperature-independent binary interaction parameters in the range 25-80. °C, and the consistency of the approach in the entire composition range was verified against experimental solubility data specifically measured for the polymer/non-solvent pair. The model shows good ability in the description of the thermodynamic properties of the system and it represents a reliable tool for the prediction of LLE also at conditions different from those considered for its set-up. This approach thus represents a useful designing tool for processes, such as thermally induced phase separation (TIPS), used in the preparation of microporous polymeric scaffolds. © 2014 Elsevier B.V.
    view abstract10.1016/j.fluid.2014.04.007
  • PC-SAFT parameters from ab initio calculations
    Umer, M. and Albers, K. and Sadowski, G. and Leonhard, K.
    Fluid Phase Equilibria 362 (2014)
    We use highly accurate ab initio calculations of binding enthalpies and entropies of gas phase clusters of alcohols to demonstrate how they can be used to obtain association parameters for PC-SAFT. The thermochemical results demonstrate that cooperativity effects and state dependent cluster distributions cause a strongly varying average enthalpy and entropy per bond as function of temperature and density for alcohols. In contrast to this, the two association parameters of PC-SAFT lead to density independent bond enthalpy and entropy and are thus effective parameters. Therefore, we choose to compute the cluster distribution at a universal state point and show that the thus obtained association parameters can be used to reduce the number of adjustable parameters from 5 to 3 with only a marginal loss of accuracy for most of the studied systems, and even an estimation of thermodynamic properties without adjusted parameters is possible. The ab initio calculations suggest that the 2B association scheme is more appropriate for 1-alkanols than the 3B one. © 2013 Elsevier B.V.
    view abstract10.1016/j.fluid.2013.08.037
  • Predicting the extraction behavior of pharmaceuticals
    Laube, F.S. and Sadowski, G.
    Industrial and Engineering Chemistry Research 53 (2014)
    Liquid-liquid extraction is a potential separation process for the purification and isolation of pharmaceuticals. However, as considerable experimental effort is required to choose an adequate extractant, liquid-liquid extraction is rarely used in the pharmaceutical industry. By applying a thermodynamic model to predict the extraction behavior of pharmaceuticals, the experimental effort required to select a suitable extractant can be decreased substantially. This work demonstrates that PC-SAFT is able to predict the extraction behavior of pharmaceuticals based solely on solid solubility data of the pharmaceutical in pure solvents. Because these data are required for pharmaceutical licensing and registration, they are usually available. To demonstrate the power of the modeling tool, six ternary two-phase systems containing a pharmaceutical intermediate or its impurity were modeled with PC-SAFT. The modeling results for the extraction behavior of the two pharmaceuticals were found to be in good agreement with the experimental data. © 2013 American Chemical Society.
    view abstract10.1021/ie403284y
  • Thermodynamic model for polyelectrolyte hydrogels
    Arndt, M.C. and Sadowski, G.
    Journal of Physical Chemistry B 118 (2014)
    The composition and swelling behavior of hydrogels may be dramatically influenced by external stimuli. Polyelectrolyte hydrogels consisting of charged polymers are particularly well-known for a high sensitivity to the presence of ionic species. For a thermodynamic description of such systems, the polyelectrolyte Perturbed-Chain Statistical Association Fluid Theory (pePC-SAFT) equation of state was augmented and merged with an extension of the modeling of hydrogels. This combined approach allowed for two effects to be taken into account: first, charges along the polymer chain and their interaction with mobile ions of the same or opposite charge in aqueous solutions and, second, the elastic interactions of swellable networks and their effect on Helmholtz energy and pressure. Thus, predictions of the degree of counterion condensation on the polymer chains could be made both for vapor-liquid equilibria of aqueous polyelectrolyte solutions and for polyelectrolyte hydrogels in aqueous salt solutions. The influence of temperature and molecular weight thereon was predicted successfully, and the impact of the degree of neutralization and the effect of additional salts were examined in comparison to literature data. With the inclusion of the influence of the Donnan potential, our model gave good predictions of swellable polyelectrolyte hydrogel systems in salt solutions. Poly(acrylic acid) and poly(methacrylic acid) gels were studied along with their corresponding sodium salts. Their swelling behavior in aqueous NaCl and NaNO3 solutions was examined. © 2014 American Chemical Society.
    view abstract10.1021/jp501798x
  • Thermodynamic phase behavior of API/polymer solid dispersions
    Prudic, A. and Ji, Y. and Sadowski, G.
    Molecular Pharmaceutics 11 (2014)
    To improve the bioavailability of poorly soluble active pharmaceutical ingredients (APIs), these materials are often integrated into a polymer matrix that acts as a carrier. The resulting mixture is called a solid dispersion. In this work, the phase behaviors of solid dispersions were investigated as a function of the API as well as of the type and molecular weight of the carrier polymer. Specifically, the solubility of artemisinin and indomethacin was measured in different poly(ethylene glycol)s (PEG 400, PEG 6000, and PEG 35000). The measured solubility data and the solubility of sulfonamides in poly(vinylpyrrolidone) (PVP) K10 and PEG 35000 were modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The results show that PC-SAFT predictions are in a good accordance with the experimental data, and PC-SAFT can be used to predict the whole phase diagram of an API/polymer solid dispersion as a function of the kind of API and polymer and of the polymers molecular weight. This remarkably simplifies the screening process for suitable API/polymer combinations. © 2014 American Chemical Society.
    view abstract10.1021/mp400729x
  • Thermodynamic properties of aqueous glucose-urea-salt systems
    Sadeghi, M. and Held, C. and Ghotbi, C. and Abdekhodaie, M.J. and Sadowski, G.
    Journal of Solution Chemistry 43 (2014)
    In this work, the thermodynamic behavior of aqueous solutions containing the solutes NaCl, glucose, and/or urea is investigated. These substances are vital components for living bodies and further they are main components of blood serum. Osmotic coefficients were determined by cryoscopic measurements in single-solute and multi-solute aqueous solutions containing salts (NaCl, KCl, CaCl2), glucose, and/or urea. The results show that NaCl determines the osmotic coefficients in the urea/glucose/NaCl/water system. Investigation of the effect of different salts on osmotic coefficients revealed ion-specific effects. At physiologically important solute concentrations in typical blood serum solutions, the osmotic coefficients were found to be in the range of 0.90-0.93. In a second step, the state of water in different glucose/salt/water and urea/salt/water systems was investigated. Depending on the kind of salt, the chemical potential of water in urea/salt/water is either higher or lower than in glucose/salt/water systems at equal nonelectrolyte concentrations. This result was found to be independent of the salt molality. Finally, the investigated systems were modeled with the Pitzer model and the ePC-SAFT equation of state, which allowed predicting of the properties of these multi-solute aqueous solutions. © 2014 Springer Science+Business Media New York.
    view abstract10.1007/s10953-014-0192-1
  • Using complex layer melt crystallization models for the optimization of hybrid distillation/melt crystallization processes
    Beierling, T. and Micovic, J. and Lutze, P. and Sadowski, G.
    Chemical Engineering and Processing: Process Intensification 85 (2014)
    Layer melt crystallization is a highly selective method for the separation of narrow boiling mixtures which are difficult to separate with conventional separation techniques like distillation due to low driving forces. Contrawise, layer melt crystallization has the drawback of limited capacity due to the direct connection between crystal product and required cooled surface. Here, the combination of the high throughput distillation and highly selective layer melt crystallization into an integrated hybrid process can lead to enormous benefits. Since the separation efficiency of the crystallization is not predictable, it has to be described with empirical correlation. Here, studies from literature use strongly simplified correlations by, e.g. assuming complete separation. This bears the serious risk of overestimating the efficiency of the hybrid process. Further, the effective post purification step sweating was not implemented into hybrid processes in studies from literature. This study fills this gap in literature. A distilliation/melt crystallization hybrid process is optimized by realistically describing crystallization separation efficiency and by implementing sweating. The required crystallization models are presented and experimentally validated. The optimization of the hybrid process is done with different modelling depths and the results underline impressively the importance of the adequate description of the crystallization separation efficiency. © 2014 Elsevier B.V.
    view abstract10.1016/j.cep.2014.07.011
  • Vapor-liquid equilibria of water + alkylimidazolium-based ionic liquids: Measurements and perturbed-chain statistical associating fluid theory modeling
    Passos, H. and Khan, I. and Mutelet, F. and Oliveira, M.B. and Carvalho, P.J. and Santos, L.M.N.B.F. and Held, C. and Sadowski, G. and Freire, M.G. and Coutinho, J.A.P.
    Industrial and Engineering Chemistry Research 53 (2014)
    The industrial application of ionic liquids (ILs) requires the knowledge of their physical properties and phase behavior. This work addresses the experimental determination of the vapor-liquid equilibria (VLE) of binary systems composed of water + imidazolium-based ILs. The ILs under consideration are 1-butyl-3-methylimidazolium trifluoromethanesulfonate, 1-butyl-3- methylimidazolium thiocyanate, 1-butyl-3-methylimidazolium tosylate, 1-butyl-3-methylimidazolium trifluoroacetate, 1-butyl-3-methylimidazolium bromide, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium methanesulfonate, and 1-butyl-3-methylimidazolium acetate, which allows the evaluation of the influence of the IL anion through the phase behavior. Isobaric VLE data were measured at 0.05, 0.07, and 0.1 MPa for IL mole fractions ranging between 0 and 0.7. The observed increase in the boiling temperatures of the mixtures is related with the strength of the interaction between the IL anion and water. The Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) was further used to describe the obtained experimental data. The ILs were treated as molecular associating species with two association sites per IL. The model parameters for the pure fluids and the binary interaction parameter k ij between water and ILs were determined by a simultaneous fitting to pure-IL densities, water activity coefficients at 298.15 K and VLE data at 0.1 MPa. Pure-IL densities, water activity coefficients, and VLE data were well described by PC-SAFT in broad temperature, pressure, and composition ranges. The PC-SAFT parameters were applied to predict the water activity coefficients at infinite dilution in ILs, and a satisfactory prediction of experimental data was observed. © 2014 American Chemical Society.
    view abstract10.1021/ie4041093
  • Design of hybrid distillation/melt crystallisation processes for separation of close boiling mixtures
    Micovic, J. and Beierling, T. and Lutze, P. and Sadowski, G. and Górak, A.
    Chemical Engineering and Processing: Process Intensification 67 (2013)
    Hybrid separations combining distillations and crystallisations have a significant potential for process intensification. To address the large number of degrees of freedom in the design of hybrid separations, a three-step approach is utilised. However, it can only be applied if all parameters for the rigorous modelling of crystallisation and cost functions are known a priori, which is often not the case. In this paper, we propose a four-step design method which can be applied in early process development stages when not all model parameters are available. In the first step, different process variants are generated. In the second step, the variants are evaluated using rigorous models, wherein the unknown model parameters are varied to quantify their influence on the process performance. If hybrid separations appear to be compatible, experiments are performed to determine the unknown parameters in the third step. In the last step, an optimisation is performed to find the optimal process, when necessary in dependence of unknown cost parameters. The developed tools and the feasibility of the approach are illustrated with the separation of a binary mixture of long-chain isomeric aldehydes. © 2012 Elsevier B.V.
    view abstract10.1016/j.cep.2012.07.012
  • Extension of the PC-SAFT based group contribution method for polymers to aromatic, oxygen- and silicon-based polymers
    Peters, F.T. and Herhut, M. and Sadowski, G.
    Fluid Phase Equilibria 339 (2013)
    A PC-SAFT group contribution method (GCM) for polymers developed earlier [10] is extended to aromatic, oxygen- and silicon-based (co-)polymers. Polymer parameters are determined using group contributions and applying simple arithmetic and geometric combination rules. Group contributions for six new groups are identified and parameterized: &gt;CHAr, &gt;CAr, O, &gt;CO, OH and &gt;Si< . The parameterization method is applied to liquid density and binary liquid-liquid equilibria and vapor-liquid equilibria as well as to excess enthalpies of polymers containing aromatic, oxygen- and silicon-containing monomer units in an extended spectrum of nonpolar, polar and associating solvents. Modeling results using both, GCM and fitted polymer parameters, show equally-good agreement with experimental data. © 2012 Elsevier B.V.
    view abstract10.1016/j.fluid.2012.11.031
  • High-pressure gas solubility in multicomponent solvent systems for hydroformylation. Part I: Carbon monoxide solubility
    Vogelpohl, C. and Brandenbusch, C. and Sadowski, G.
    Journal of Supercritical Fluids 81 (2013)
    High-pressure gas-solubility data of carbon monoxide (CO) in various solvents like n-hexane, propylene carbonate, dimethylformamide, 1-dodecene, n-dodecanal and n/iso-tridecanal was measured for temperatures between 295 K and 364 K and pressures up to 17 MPa. The experiments were performed in a high-pressure variable-volume view cell applying the synthetic method. The binary systems investigated were correlated using the perturbed chain statistical associating fluid theory (PC-SAFT). A temperature-independent binary interaction parameter kij was fitted to solubility data. Based on this, to CO solubility in mixtures of n-dodecanal and 1-dodecene with various molar compositions of the two liquids (3:1, 1:1, 1:3) were predicted. CO-solubility measurements for these systems confirmed that PC-SAFT is able to accurately predict the ternary data based on the knowledge of the binary subsystems, only. © 2013 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.supflu.2013.04.006
  • Liquid-liquid equilibria of 1-butanol/water/IL systems
    Nann, A. and Held, C. and Sadowski, G.
    Industrial and Engineering Chemistry Research 52 (2013)
    The liquid-liquid equilibria (LLE) of ternary 1-butanol/water/ionic liquid (IL) mixtures were measured and predicted. The LLE data were measured for ternary mixtures containing 1-butanol, water, and one of the following ILs: 1-decyl-3-methylimidazolium tetracyanoborate ([Im10.1] +[tcb]-), 4-decyl-4-methylmorpholinium tetracyanoborate ([Mo10.1]+[tcb]-), 1-decyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Im10.1]+[ntf 2]-), and 4-decyl-4-methylmorpholinium bis(trifluoromethylsulfonyl)imide ([Mo10.1]+[ntf 2]-). The LLE data were determined at atmospheric pressure for two different temperatures (308.15 and 323.15 K). To evaluate the application of the ILs studied to the extraction of 1-butanol from aqueous solutions, the 1-butanol distribution coefficients and selectivities were determined from the data. The perturbed-chain statistical associating fluid theory (PC-SAFT) was used for modeling. Previously published pure-component PC-SAFT parameters for the ILs [ J. Phys. Chem. B 2013, 117 (11), 3173-3185 ] were used for this purpose. The binary interaction parameters for 1-butanol/IL pairs were set to zero. The binary interaction parameters for 1-butanol/water and water/IL pairs were determined by fitting to the respective binary LLE data at various temperatures. Without introducing any additional parameters or refitting existing PC-SAFT parameters, the liquid-liquid equilibria of the ternary 1-butanol/water/IL mixtures were predicted and exhibited good agreement with the experimental data. Moreover, the very sensitive property distribution coefficient and the selectivity of 1-butanol were accurately predicted. © 2013 American Chemical Society.
    view abstract10.1021/ie403246e
  • Melt crystallization of isomeric long-chain aldehydes from hydroformylation
    Beierling, T. and Osiander, J. and Sadowski, G.
    Separation and Purification Technology 118 (2013)
    This work evaluates comprehensively the potential of melt crystallization for the separation of the commercially important isomeric long-chain aldehydes. This was investigated with aldehydes of different chain lengths. A broad range of physical parameters was determined and related phase-equilibria were measured and modeled. Achievable growth rates and the corresponding purities were studied in static layer-melt crystallization experiments as function of chain length, cooling rate and concentration. Since aldehydes are highly reactive compounds, two methods were evaluated to guarantee chemical stability during crystallization. Furthermore, the efficiency of sweating was experimentally investigated and mathematically modeled as a function of chain length, temperature, crystal purity and crystalline layer thickness in high accordance to the experimental data. © 2013 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.seppur.2013.06.023
  • Modeling growth rates in static layer melt crystallization
    Beierling, T. and Gorny, R. and Sadowski, G.
    Crystal Growth and Design 13 (2013)
    The prediction of growth rates as functions of process conditions can reduce experimental efforts to develop crystallization processes. There is a lack of reliable models of static layer melt crystallization in the literature. In this study, a model for the prediction of growth rates for static layer melt crystallization was developed. The essence of this model is the description of heat transport during crystal growth in a naturally convected static melt where, in contrast to other models, the implicit relation between the growth rate and the natural convection is considered. Predicting crystal growth rates requires knowledge of the crystal thermal conductivity, a sensitive physical property that is often estimated or fit to experimental data. In this study, an approach for measuring the crystal thermal conductivity was developed and successfully validated with literature data. The crystal thermal conductivities of p-xylene, n-hexadecane, n-dodecanal, and n-tridecanal were measured. With the use of these measurements, the crystal growth rates of the binary systems n-dodecanal/iso-dodecanal, n-tridecanal/iso-tridecanal, and p-xylene/m-xylene from static layer crystallization were predicted as functions of the process conditions. Good agreement with experimental data was achieved without the use of a fitted parameter. © 2013 American Chemical Society.
    view abstract10.1021/cg400959a
  • Modeling thermodynamic properties of aqueous single-solute and multi-solute sugar solutions with PC-SAFT
    Held, C. and Sadowski, G. and Carneiro, A. and Rodríguez, O. and Macedo, E.A.
    AIChE Journal 59 (2013)
    The Perturbed-Chain Statistical Association Fluid Theory is applied to simultaneously describe various thermodynamic properties (solution density, osmotic coefficient, solubility) of aqueous solutions containing a monosaccharide or a disaccharide. The 13 sugars considered within this work are: glucose, fructose, fucose, xylose, maltose, mannitol, mannose, sorbitol, xylitol, galactose, lactose, trehalose, and sucrose. Four adjustable parameters (three pure-sugar parameters and a kij between sugar and water that was allowed to depend linearly on temperature) were obtained from solution densities and osmotic coefficients of binary sugar/water solutions at 298.15 K available in literature. Using these parameters, the sugar solubility in water and in ethanol could be predicted satisfactorily. Further, osmotic coefficients and solubility in aqueous solutions containing two solutes (sugar/sugar, sugar/salt) were predicted (no additional kij parameters between the two solutes) reasonably. The model was also applied to predict the solubility of a sugar in a solvent mixture (e.g., water/ethanol) without additional fitting parameters. © 2013 American Institute of Chemical Engineers.
    view abstract10.1002/aic.14212
  • Modelling of organic-solvent flux through a polyimide membrane
    Hesse, L. and Mićović, J. and Schmidt, P. and Górak, A. and Sadowski, G.
    Journal of Membrane Science 428 (2013)
    The tremendous experimental effort to find a suitable organic solvent nanofiltration (OSN) membrane for a specific separation problem can be minimised by using model-based simulation tools to predict organic-solvents fluxes. A new predictive model, based on the Maxwell-Stefan (MS) approach, for prediction of fluxes through dense polymeric OSN membranes was developed to aid the experimental effort. Model parameters were determined from independent experiments to model solubilities and diffusivities. The flux measurements were performed using a cross-flow nanofiltration filtration unit LSta60LM (SIMA-tec) and the OSN membrane STARMEM240™. The calculated organic-solvents fluxes of toluene, ethyl acetate, ethanol, and 2-propanol show an excellent agreement with the measured fluxes at 25°C and different transmembrane pressures. © 2012 Elsevier B.V.
    view abstract10.1016/j.memsci.2012.10.052
  • Molecular interactions in 1-butanol + IL solutions by measuring and modeling activity coefficients
    Nann, A. and Mündges, J. and Held, C. and Verevkin, S.P. and Sadowski, G.
    Journal of Physical Chemistry B 117 (2013)
    Molecular interactions in 1-butanol + ionic liquid (IL) solutions have been investigated by measuring and modeling activity-coefficient data. The activity coefficients in binary solutions containing 1-butanol and an IL were determined experimentally: the ILs studied were 1-decyl-3-methyl-imidazolium tetracyanoborate ([Im10.1]+[tcb]-), 4-decyl-4-methyl-morpholinium tetracyanoborate ([Mo10.1] +[tcb]-), 1-decyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide ([Im10.1]+[ntf 2]-), and 4-decyl-4-methyl-morpholinium bis(trifluoromethylsulfonyl)imide ([Mo10.1]+[ntf 2]-). The methods used to determine the activity coefficients included vapor-pressure osmometry, headspace-gas chromatography, and gas-liquid chromatography. The results from all of these techniques were combined to obtain activity-coefficient data over the entire IL concentration range, and the ion-specific interactions of the ILs investigated were identified with 1-butanol. The highest (1-butanol)-IL interactions of the ILs considered in this work were found for [Im10.1]+[tcb]-; thus, [Im10.1]+[tcb]-showed the highest affinity for 1-butanol in a binary mixture. The experimental data were modeled with the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). PC-SAFT was able to accurately describe the pure IL and (1-butanol)-IL data. Moreover, the model was shown to be predictive and extrapolative with respect to concentration and temperature. © 2013 American Chemical Society.
    view abstract10.1021/jp307276y
  • PC-SAFT based group contribution method for binary interaction parameters of polymer/solvent systems
    Peters, F.T. and Laube, F.S. and Sadowski, G.
    Fluid Phase Equilibria 358 (2013)
    Based on the PC-SAFT equation of state, a group-contribution method is developed for the determination of binary interaction parameters (kij) between polymers and solvents (GCM-kij). Applying simple geometric combination rules, the kij values can be calculated from binary interaction parameters between polymer groups and solvent groups (kps). 80 different kps values allow the calculation of a kij for polymer/solvent systems with polymers consisting of CH3, 〉CH2, 〉CH2,HDPE, 〉(CH), 〉C〈, 〉CHAr, 〉CAr and (CO)O groups and solvents containing CH3, 〉CH2, 〉(CH), 〉CH2,Cyclo, 〉(CH)Cyclo, CH2,alkene, (CH)alkene, 〉CHAr, 〉CAr, O, 〉CO and (CO)O groups. Using earlier-published group-contributions for polymer parameters (Peters et al. [2,3]) in combination with the proposed GCM-kij for polymer/solvent systems allows for predicting liquid-liquid phase equilibria, vapor-liquid phase equilibria and excess enthalpies of binary polymer/solvent and copolymer/solvent as well as ternary polymer/solvent 1/solvent 2 systems in good agreement with experimental data. © 2013 Elsevier B.V.
    view abstract10.1016/j.fluid.2013.05.033
  • Simultaneous modeling of phase equilibria and interfacial properties using the PCP-SAFT model
    Schäfer, E. and Vogelpohl, C. and Sadowski, G. and Enders, S.
    Chemie-Ingenieur-Technik 85 (2013)
    Liquid-liquid- und gas-liquid equilibria data as well as information on interfacial properties are needed to investigate the applicability of thermomorphic solvent systems to the hydroformylation of olefins. The perturbed chain polar statistical associating fluid theory (PCP-SAFT) combined with the density gradient theory was shown to be highly appropriate to calculate these data. Only one set of parameters for each component was necessary to describe the different thermodynamic properties. Thereby, also experimental data which were not involved in parameter fitting were reproduced successfully. That is, the modeling tool can be applied to reliably generate data for experimentally unexplored thermodynamic states. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/cite.201300036
  • Solubility of pharmaceuticals and their salts as a function of pH
    Cassens, J. and Prudic, A. and Ruether, F. and Sadowski, G.
    Industrial and Engineering Chemistry Research 52 (2013)
    In this work, the solubilities of lidocaine, thiabendazole, and terfenadine and their salts were measured and modeled as a function of pH. The aqueous solubilities of lidocaine and thiabendazole were measured in the pH range between 0.5 and 9.8 using hydrochloric acid or phosphoric acid. The solubility was modeled using the ePC-SAFT equation of state. The model parameters of the nonionized pharmaceuticals were determined from their solubilities in pure organic solvents (acetone, ethanol, 2-propanol, n-hexane, n-heptane, and toluene), which were also measured. Depending on the pH value, the ionization of the pharmaceutical and the identity of the pH-changing agent were considered during the modeling. The charge of the ionized pharmaceutical was explicitly taken into account. All other model parameters were deduced from those of the nonionized pharmaceutical. Furthermore, the precipitation of the pharmaceutical salt upon a pH change was described by its solubility product. The latter was fitted to one experimental data point at a low pH value at which the pharmaceutical salt precipitated. Using this information, the solubility at any pH and the influence of ionization resulting in an increase in solubility with decreasing pH were nearly in agreement with the experimental data. © 2013 American Chemical Society.
    view abstract10.1021/ie302064h
  • Solubility of sugars and sugar alcohols in ionic liquids: Measurement and PC-SAFT modeling
    Carneiro, A.P. and Held, C. and Rodríguez, O. and Sadowski, G. and Macedo, E.A.
    Journal of Physical Chemistry B 117 (2013)
    Biorefining processes using ionic liquids (ILs) require proper solubility data of biomass-based compounds in ILs, as well as an appropriate thermodynamic approach for the modeling of such data. Carbohydrates and their derivatives such as sugar alcohols represent a class of compounds that could play an important role in biorefining. Thus, in this work, the pure IL density and solubility of xylitol and sorbitol in five different ILs were measured between 288 and 339 K. The ILs under consideration were 1-ethyl-3-methylimidazolium dicyanamide, 1-butyl-3-methylimidazolium dicyanamide ([bmim][DCA]), Aliquat dicyanamide, trihexyltetradecylphosphonium dicyanamide, and 1-ethyl-3-methylimidazolium trifluoroacetate. Comparison with the literature data was performed, showing good agreement. With the exception of [bmim][DCA], the solubility of these sugar alcohols in the other ILs is presented for the first time. The measured data as well as previously published solubility data of glucose and fructose in these ILs were modeled by means of PC-SAFT using a molecular-based associative approach for ILs. PC-SAFT was used in this work as it has shown to be applicable to model the solubility of xylitol and sorbitol in ILs (Paduszyński;et al. J. Phys. Chem. B 2013, 117, 7034-7046). For this purpose, three pure IL parameters were fitted to pure IL densities, activity coefficients of 1-propanol at infinite dilution in ILs, and/or xylitol solubility in ILs. This approach allows accurate modeling of the pure IL data and the mixture data with only one binary interaction parameter kij between sugar and the IL or sugar alcohol and the IL. In cases where only the pure IL density and activity coefficients of 1-propanol at infinite dilution in ILs were used for the IL parameter estimation, the solubility of the sugars and sugar alcohols in the ILs could be predicted (kij = 0 between sugar and the IL or sugar alcohol and the IL) with reasonable accuracy. © 2013 American Chemical Society.
    view abstract10.1021/jp404864c
  • Solvent-sensitive reversible stress-response of shape memory natural rubber
    Quitmann, D. and Gushterov, N. and Sadowski, G. and Katzenberg, F. and Tiller, J.C.
    ACS Applied Materials and Interfaces 5 (2013)
    We found that constrained shape memory natural rubber (SMNR) generates mechanical stress when exposed to solvent vapor. When the solvent vapor is removed, the material reprograms itself. This process is reversible and the stress answer is proportional to the solvent vapor concentration. Further, the stress answer is specific to the solvent. © 2013 American Chemical Society.
    view abstract10.1021/am400660f
  • Stable emulsions in biphasic whole-cell biocatalysis: The mechanism of scCO2-assisted phase separation
    Brandenbusch, C. and Glonke, S. and Collins, J. and Bühler, B. and Schmid, A. and Sadowski, G.
    Chemie-Ingenieur-Technik 85 (2013)
    Biocatalytic hydrocarbon functionalization with the potential to replace complex chemical synthesis routes on an industrial scale has become one of the major research fields in academia and industry during the last decade. For this purpose, biphasic whole-cell biotransformations, such as the stereoselective epoxidation of styrene to (S)-styrene oxide catalyzed by recombinant Escherichia coli JM101, have turned out to be one of the most promising approaches. However, their industrial implementation is hindered by the formation of very stable emulsions. Treatment with supercritical CO2 (scCO2), as recently described in [1, 2], allows efficient and complete phase separation, enabling a further workup of the product-containing organic phase. It could be shown, that the whole cells present in the system are mainly responsible for the enhanced stability of these emulsions (over 93% on total emulsion stability), and are stabilizing the emulsions by a Pickering type mechanism. To further investigate the underlying mechanism, different influence factors on the cell surface hydrophobicity were investigated. The results point to the fact that scCO2 triggers the surface hydrophobicity of the cells by irreversible desorption of surface associated macromolecules. The mechanism responsible for scCO2-assisted phase separation as well as the formation of these stable emulsions could be clarified for the first time ever. Understanding of the underlying mechanisms now allows for a precise definition of a process window for phase separation and thus the initial purification step. This enables the development of integrated bioprocesses by adjustment of both biotransformation and downstream processing parameters.
    view abstract10.1002/cite.201250744
  • The role of activity coefficients in bioreaction equilibria: Thermodynamics of methyl ferulate hydrolysis
    Hoffmann, P. and Voges, M. and Held, C. and Sadowski, G.
    Biophysical Chemistry 173-174 (2013)
    The Gibbs energy of reaction (ΔRg) is the key quantity in the thermodynamic characterization of biological reactions. Its calculation requires precise standard Gibbs energy of reaction (ΔRg +) values. The value of ΔRg+ is usually determined by measuring the apparent (concentration-dependent) equilibrium constants K, e.g., the molality-based Km. However, the thermodynamically consistent determination of ΔRg+ requires the thermodynamic (activity-based) equilibrium constant Ka. These values (Km and Ka) are equal only if the ratio of the activity coefficients of the reactants to the activity coefficients of the products (Kγ) is equal to unity. In this work, the impact of Kγ on the estimation of Ka for biological reactions was investigated using methyl ferulate (MF) hydrolysis as a model reaction. The value of Kγ was experimentally determined from Km values that were measured at different reactant concentrations. Moreover, K γ was independently predicted using the thermodynamic model ePC-SAFT. Both the experimentally determined and the predicted K γ values indicate that this value cannot be assumed to be unity in the considered reaction. In fact, in the reaction conditions considered in this work, Kγ was shown to be in the range of 3 < K γ < 6 for different reactant molalities (2 < mmol MF kg- 1 < 10). The inclusion of Kγ and thus the use of the thermodynamically correct Ka value instead of Km lead to remarkable differences (almost 40%) in the determination of ΔRg+. Moreover, the new value for ΔRg+ increases the concentration window at which the reaction can thermodynamically occur. The influence of additives was also investigated both experimentally and theoretically. Both procedures consistently indicated that the addition of NaCl (0 to 1 mol kg- 1 water) moderately decreased the value of Kγ, which means that the values of Km increase and that a higher amount of products is obtained as a result of the addition of salt. Additionally, Km was found to strongly depend on pH. A ten-fold increase in the Km values was observed in the pH range of 6 to 7; this increase corresponds to a change of more than 100% in the value of ΔRg+. © 2013 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.bpc.2012.12.006
  • Time-monitoring sensor based on oxygen diffusion in an indicator/polymer matrix
    Marek, P. and Velasco-Veléz, J.J. and Haas, T. and Doll, T. and Sadowski, G.
    Sensors and Actuators, B: Chemical 178 (2013)
    A time-monitoring sensor based on the oxidation of leuco methylene blue (LMB) to methylene blue (MB) was developed. The sensor changes its color from yellow to green in the presence of oxygen and was integrated into a poly(vinyl alcohol) matrix. The diffusion of the oxygen in the polymer matrix as well as the oxygen uptake due to the oxidation reaction determines the time monitoring of the sensor. A physical model has been developed that accounts for both the diffusion as well as the oxidation reaction. For this purpose, the reaction kinetics was determined experimentally. Moreover, the diffusion coefficient of oxygen was determined and concentration profiles in the polymer matrix modeled. Based on these modeling, the time sensor could be calibrated very precisely. This widely applicable, low-cost visual sensor is compatible with current technologies for the processing of plastics and can be integrated into different types of packaging, e.g. for application in freshness monitoring of consumer goods. © 2012 Elsevier B.V.
    view abstract10.1016/j.snb.2012.12.028
  • Toluene sorption in poly(styrene) and poly(vinyl acetate) near the glass transition
    Mueller, F. and Naeem, S. and Sadowski, G.
    Industrial and Engineering Chemistry Research 52 (2013)
    The sorption of vaporized toluene into poly(styrene) (PS) at 30 C and into poly(vinyl acetate) (PVAc) at 25 C were investigated. A Maxwell-Stefan (MS) diffusion model combined with a PC-SAFT equation of state and a mechanical spring-dashpot model was used to describe the experimental sorption profiles. The mechanical parameters of the glassy polymers, such as the Young's modulus of a neat glassy polymer and the reference viscosity at the glass transition, were determined via independent tensile creep measurements. The volatile organic compound (VOC)-concentration dependence of the viscosity was predicted using the William, Landel, and Ferry (WLF) and the Kelley-Bueche (KB) equations. The mechanical model successfully predicted the glass-transition temperature of the polymer/toluene system and the viscosity near and above the glass transition. The sorption isotherms for the pressure steps in the region of the glass transition were modeled by adjusting the MS diffusion coefficients and exhibited good agreement, both qualitative and quantitative, with the diffusion coefficients predicted by the free-volume theory. Thus, the developed diffusion model can be utilized to calculate the sorption profiles of VOCs in glassy polymers above, below, and, especially, near the glass transition. © 2013 American Chemical Society.
    view abstract10.1021/ie302322t
  • Activity coefficients of complex molecules by molecular simulation and Gibbs-Duhem integration
    Hempel, S. and Fischer, J. and Paschek, D. and Sadowski, G.
    Soft Materials 10 (2012)
    Activity coefficients of solvents and solutes in different aqueous solutions of alcohols and polymers are determined by molecular dynamic simulations. These data are often not accessible by simulation due to unacceptably high computational demands. Therefore, we applied a combination of two methods: water activity coefficients were determined directly via Overlapping Distribution Method, while counter-component activity coefficients were calculated indirectly by Gibbs-Duhem integration of the respective water activities. Results are in good agreement with experimental data. The method can easily be applied to determine activity coefficients of very complex components in water or other simple solvents. © 2012 Copyright Taylor and Francis Group, LLC.
    view abstract10.1080/1539445X.2011.599698
  • Design of hybrid distillation/melt crystallization processes for separation of close-boiling mixtures
    Micovic, J. and Beierling, T. and Lutze, P. and Sadowski, G. and Górak, A.
    Chemie-Ingenieur-Technik 84 (2012)
    Design of hybrid separations is still challenging due to large number of structural and operation degrees of freedom. To design a hybrid separation combining distillation and crystallization, a three-step approach is utilized, which can only be applied if all parameters for the rigorous modeling of crystallization and all cost functions are known a priori. Since this is often not the case in early process development stages, a four-step design method is proposed for that purpose. The developed tools and the feasibility of the approach are shown in a case study of separation of a binary mixture of long-chain isomeric aldehydes. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/cite.201200050
  • Development of a group contribution method for polymers within the PC-SAFT model
    Peters, F.T. and Laube, F.S. and Sadowski, G.
    Fluid Phase Equilibria 324 (2012)
    Based on the PC-SAFT equation of state (EOS) a group contribution method (GCM) for polymers is developed to describe thermodynamic properties of the pure polymers as well as binary (co-)polymer/solvent liquid-liquid phase equilibria (LLE). The polymer parameters are obtained from group contributions by applying simple arithmetic and geometric mixing rules. Polymer classes of poly(olefines), poly(acrylates) as well as poly(methacrylates) are considered leading to the parameter set for five specific groups CH 3, &gt;CH 2, &gt;(CH) and &gt;C< as well as the (CO)O group. The modeling approach is applied to pure polymer density and binary LLE data. Modeling results using the GCM polymer parameters are found to be in good agreement with experimental literature data. © 2012 Elsevier B.V.
    view abstract10.1016/j.fluid.2012.03.009
  • Hydroformylation of 1-dodecene in the thermomorphic solvent system dimethylformamide/decane. Phase behavior-reaction performance-catalyst recycling
    Schäfer, E. and Brunsch, Y. and Sadowski, G. and Behr, A.
    Industrial and Engineering Chemistry Research 51 (2012)
    An economically meaningful hydroformylation of long-chain olefins requires an efficient combination of both a high-yield reaction step and efficient catalyst recycling. The application of thermomorphic multicomponent solvent (TMS) systems allows for optimal reaction as well as catalyst-recycling conditions. In this work, the TMS concept was applied to the homogeneously rhodium-catalyzed hydroformylation of 1-dodecene in the TMS system dimethylformamide (DMF)/decane using Rh(acac)(CO) 2/Biphephos as the catalyst system. Thermodynamic investigations focused on the influence of the olefin (hydroformulation educt) and the aldehyde (hydroformylation product) on the phase behavior of the TMS system. Temperature dependent liquid-liquid equilibrium (LLE) data were measured for the binary systems DMF/decane and DMF/1-dodecene and for the ternary systems DMF/decane/1-dodecene and DMF/decane/dodecanal. Additionally, the corresponding LLE data were modeled applying the Perturbed Chain Polar Statistical Associating Fluid Theory (PCP-SAFT) using a heterosegmented approach for modeling the long-chain aldehyde. On the basis of the LLE data, adequate working points for hydroformylation experiments in the TMS system were selected. In these experiments, aldehyde yields of up to 87% with an n/iso ratio of up to 99:1 were achieved. Moreover, the TMS system was successfully applied to catalyst recycling in eight recycling runs with a catalyst leaching of 7 ppm rhodium at lowest. © 2012 American Chemical Society.
    view abstract10.1021/ie300484q
  • Integrated organic-aqueous biocatalysis and product recovery for quinaldine hydroxylation catalyzed by living recombinant Pseudomonas putida
    Ütkür, F.O. and Tran, T.T. and Collins, J. and Brandenbusch, C. and Sadowski, G. and Schmid, A. and Bühler, B.
    Journal of Industrial Microbiology and Biotechnology 39 (2012)
    In an earlier study, biocatalytic carbon oxyfunctionalization with water serving as oxygen donor, e.g., the bioconversion of quinaldine to 4-hydroxyquinaldine, was successfully achieved using resting cells of recombinant Pseudomonas putida, containing the molybdenumenzyme quinaldine 4-oxidase, in a two-liquid phase (2LP) system (Ütkür et al. J Ind Microbiol Biotechnol 38:1067- 1077, 2011). In the study reported here, key parameters determining process performance were investigated and an efficient and easy method for product recovery was established. The performance of the whole-cell biocatalyst was shown not to be limited by the availability of the inducer benzoate (also serving as growth substrate) during the growth of recombinant P. putida cells. Furthermore, catalyst performance during 2LP biotransformations was not limited by the availability of glucose, the energy source to maintain metabolic activity in resting cells, and molecular oxygen, a possible final electron acceptor during quinaldine oxidation. The product and the organic solvent (1-dodecanol) were identified as the most critical factors affecting biocatalyst performance, to a large extent on the enzyme level (inhibition), whereas substrate effects were negligible. However, none of the 13 alternative solvents tested surpassed 1-dodecanol in terms of toxicity, substrate/ product solubility, and partitioning. The use of supercritical carbon dioxide for phase separation and an easy and efficient liquid-liquid extraction step enabled 4-hydroxyquinaldine to be isolated at a purity of > 99.9% with recoveries of 57 and 84%, respectively. This study constitutes the first proof of concept on an integrated process for the oxyfunctionalization of toxic substrates with a water-incorporating hydroxylase. © Society for Industrial Microbiology and Biotechnology 2012.
    view abstract10.1007/s10295-012-1106-0
  • Investigation of mass transfer in organic solvent nanofiltration membranes
    Micovic, J. and Hesse, L. and Schmidt, P. and Lutze, P. and Sadowski, G. and Górak, A.
    Procedia Engineering 44 (2012)
    view abstract10.1016/j.proeng.2012.08.395
  • Liquid-liquid equilibria of systems with linear aldehydes. Experimental data and modeling with PCP-SAFT
    Schäfer, E. and Sadowski, G.
    Industrial and Engineering Chemistry Research 51 (2012)
    Liquid-liquid equilibrium (LLE) data were measured for the binary system propylene carbonate/decane (288.15 to 403.15 K) as well as for the ternary systems propylene carbonate/decane + linear aldehyde (C4, C8, C10, C12, C13) and DMF/decane + linear aldehyde (C4, C8, C10, C13) at 298.15 K using the analytic method. The reliability of the ternary LLE data is ascertained by employing Othmer-Tobias plots. Concerning the aldehyde distribution coefficients in the ternary systems, a distinctive dependency on the chain length of the aldehyde was observed. The LLE data were modeled with the Perturbed Chain Polar Statistical Associating Fluid Theory (PCP-SAFT) equation of state using a heterosegmented approach for describing the aldehyde molecules. © 2012 American Chemical Society.
    view abstract10.1021/ie301566d
  • Measuring and modeling alcohol/salt systems
    Held, C. and Prinz, A. and Wallmeyer, V. and Sadowski, G.
    Chemical Engineering Science 68 (2012)
    Liquid densities, osmotic coefficients, and mean ionic activity coefficients (MIAC) at 25. °C of single-salt alcohol (methanol and ethanol) solutions containing univalent ions were measured and modeled with the ePC-SAFT equation of state. In accordance with our previous work [Held, C., Cameretti, L.F., Sadowski, G., Fluid Phase Equlilib. 270 (2008) 87-96], only two solvent-specific ion parameters were adjusted to experimental solution densities and osmotic coefficients: the solvated ion diameter and the dispersion-energy parameter. ePC-SAFT was able to reproduce experimental data of the respective alcohol/salt systems with reasonable accuracy. Based on the solvent-specific ion-parameter sets, it is possible to predict densities and MIACs in ternary and quaternary water/alcohol(s)/salt solutions by introducing appropriate mixing rules that do not contain any additional fitting parameters. © 2011 Elsevier Ltd.
    view abstract10.1016/j.ces.2011.09.040
  • Modeling liquid-liquid equilibria of polyimide solutions
    Hesse, L. and Sadowski, G.
    Industrial and Engineering Chemistry Research 51 (2012)
    The mutual affinity of volatile organic compounds (VOCs) and the active polymer layer of dense organic solvent nanofiltration (OSN) membranes is an important property that influences the separation efficiency. Therefore, the affinity between active layer materials and VOCs was investigated by measuring the liquid-liquid equilibria (LLE) between neat polymers used as active layer materials and VOCs. The measured phase equilibria are modeled using the thermodynamic PC-SAFT (perturbed chain statistical associating fluid theory) model. This model allows for estimation of the pressure- and temperature-dependent chemical potentials of VOCs and membrane materials in feeds, membranes, and permeates. Two polyimides (P84 and Matrimid 5218) were selected as typical OSN membrane materials, and five different VOCs (n-hexane, ethyl acetate, 2-propanol, ethanol, and toluene) were considered. It was found that all miscibility gaps between the polyimides and VOCs are open miscibility gaps. The miscibility gaps of Matrimid 5218 and VOCs are much smaller than those of P84 with all VOCs. By means of the PC-SAFT equation of state, the phase behavior of the two polyimides with all considered VOCs could be well described. © 2011 American Chemical Society.
    view abstract10.1021/ie2011142
  • Modeling poly(N-isopropylacrylamide) hydrogels in water/alcohol mixtures with PC-SAFT
    Arndt, M.C. and Sadowski, G.
    Macromolecules 45 (2012)
    The PC-SAFT equation of state is used for thermodynamic modeling of poly(N-isopropylacrylamide) PNIPAAm in water and alcohols (methanol, ethanol, 1-propanol, and 2-propanol). For calculating the swelling behavior of cross-linked PNIPAAm gels, an additional contribution to the Helmholtz energy considering elastic forces is implemented and the resulting pressure difference in the gel is taken into account. The model is used to describe the gel-phase composition and the degree of swelling as a function of both the temperature and the solvent composition in good agreement with experimental data. In particular, the re-entrant phenomenon of the swelling transition in the ternary mixtures is modeled correctly and data from the literature correspond well with the computed results, suggesting a significant predictive capability of the model. © 2012 American Chemical Society.
    view abstract10.1021/ma300683k
  • Non-Fickian diffusion of toluene in polystyrene in the vicinity of the glass-transition temperature
    Mueller, F. and Krueger, K.-M. and Sadowski, G.
    Macromolecules 45 (2012)
    The diffusion process of toluene in polystyrene films is investigated in the vicinity and slightly above the glass-transition of the mixture. A detailed analysis investigates whether the diffusion follows Fick's law or other effects are superimposing the mass transport process. For that purpose, the diffusion of toluene in polystyrene films of different thicknesses at otherwise constant conditions was observed by gravimetric sorption measurements. Even slightly above the glass-transition of the toluene-loaded polymer a remaining influence of the polymer relaxation on the diffusion process (non-Fickian diffusion) is observed. The diffusion Deborah number concept was applied using an experimentally independent relaxation time for the polystyrene-toluene mixture. The results show quantitatively the same trend but finally deviate by about 1 order of magnitude. © 2012 American Chemical Society.
    view abstract10.1021/ma202283e
  • Osmotic coefficients of aqueous weak electrolyte solutions: Influence of dissociation on data reduction and modeling
    Reschke, T. and Naeem, S. and Sadowski, G.
    Journal of Physical Chemistry B 116 (2012)
    The experimental determination and modeling of osmotic coefficients in electrolyte solutions requires knowledge of the stoichiometric coefficient νi. In contrast to strong electrolytes, weak electrolytes exhibit a concentration-dependent stoichiometric coefficient, which directly influences the thermodynamic properties (e.g., osmotic coefficients). Neglecting this concentration dependence leads to erroneous osmotic coefficients for solutions of weak electrolytes. In this work, the concentration dependence of the stoichiometric coefficients and the influence of concentration on the osmotic coefficient data were accounted for by considering the dissociation equilibria of aqueous sulfuric and phosphoric acid systems. The dissociation equilibrium was combined with the ePC-SAFT equation of state to model osmotic coefficients and densities of electrolyte solutions. Without the introduction of any additional adjustable parameters, the average relative deviation between the modeled and the experimental data decreases from 12.82% to 4.28% (osmotic coefficients) and from 2.59% to 0.89% (densities) for 12 phosphoric and sulfuric systems compared to calculations that do not account for speciation. For easy access to the concentration-dependent stoichiometric coefficient, estimation schemes were formulated for mono-, di-, and triprotic acids and their salts. © 2012 American Chemical Society.
    view abstract10.1021/jp3005629
  • Phase behavior of poly(dimethylsiloxane)-poly(ethylene oxide) amphiphilic block and graft copolymers in compressed carbon dioxide
    Stoychev, I. and Peters, F. and Kleiner, M. and Clerc, S. and Ganachaud, F. and Chirat, M. and Fournel, B. and Sadowski, G. and Lacroix-Desmazes, P.
    Journal of Supercritical Fluids 62 (2012)
    The phase behavior of triblock and graft-type poly(dimethylsiloxane) (PDMS)-poly(ethylene oxide) (PEO) copolymer surfactants has been investigated in compressed carbon dioxide (CO2). For this purpose, cloud-point pressures have been measured in the pressure and temperature range from P = 10 to 40 MPa and from T = 293 to 338 K. The Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) equation of state (EoS) has been applied to model the experimental data in order to better understand the influence of the structure of the copolymers on the phase behavior of the system. The pure-component parameters for PDMS have been fitted originally to PDMS/n-pentane system. These parameters are successfully applied for PDMS in CO2 by adjusting a temperature-dependent binary interaction parameter. The phase behavior of the triblock copolymers was successfully predicted by PC-SAFT. In contrast, the phase behavior of the graft copolymers was difficult to predict accurately at this stage. © 2011 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.supflu.2011.11.008
  • Reducing the amount of PCP-SAFT fitting parameters. 1. Non-polar and dipolar components
    Albers, K. and Sadowski, G.
    Fluid Phase Equilibria 326 (2012)
    The pure-component parameters of the Perturbed Chain Polar-Statistical Associating Fluid Theory (PCP-SAFT) equation of state are usually fitted to experimental data over broad temperature ranges. In this work, PCP-SAFT parameter correlations with molar mass were developed for five homologous series of non-polar and three homologous series of dipolar substances. The correlations were identified by using parameters of at least three components within the respective series. Applying these correlations for interpolations as well as for extrapolations within a homologous series, one experimental vapor-pressure point is sufficient for the parameter estimation of the related components. Use of the obtained parameters allows for reliable modeling of pure-component properties as well as of binary phase equilibria. © 2012 Elsevier B.V.
    view abstract10.1016/j.fluid.2012.04.011
  • Reducing the amount of PCP-SAFT fitting parameters. 2. Associating components
    Albers, K. and Heilig, M. and Sadowski, G.
    Fluid Phase Equilibria 326 (2012)
    The pure-component parameters of the Perturbed Chain Polar-Statistical Associating Fluid Theory (PCP-SAFT) equation of state are preferably fitted to experimental data in broad temperature ranges, if available. In this work, an alternative strategy was developed for estimating the two association parameters. Analysis revealed that the association volume can be set to one common value within a homologous series and the association-energy parameter can be obtained using the hydrogen-bonding enthalpy given by the Conductor-like Screening Model for Real Solvents (COSMO-RS). Thus, the number of fitting parameters was reduced from five to three for associating components. Applying the association parameters obtained from COSMO-RS led to linear molar-mass correlations for the remaining parameters. Moreover, these parameter correlations can be used to further reduce the experimental effort of parameter estimation. Application to the modeling of pure-component properties and binary phase equilibria leads to convincing modeling results. © 2012 Elsevier B.V.
    view abstract10.1016/j.fluid.2012.04.014
  • Thermodynamic properties of aqueous salt containing urea solutions
    Sadeghi, M. and Held, C. and Samieenasab, A. and Ghotbi, C. and Abdekhodaie, M.J. and Taghikhani, V. and Sadowski, G.
    Fluid Phase Equilibria 325 (2012)
    Urea and inorganic ions are present in some of the physiological systems, e.g. urine. Understanding the interactions in urea/salt/water is a preliminary step to shed light on more complicated behavior of multi-component physiological systems. State-of-the-art models as well as thermophysical properties can be applied to understand the interactions in these systems. In order to determine such interactions densities, mean ionic activity coefficients (MIACs), osmotic coefficients, and solubility were measured in aqueous solutions of urea and different salts. Densities were determined at temperatures 293.15, 303.15, and 313.15K for urea concentrations up to 3molal and up to 1molal for NaCl. Osmotic coefficients and MIACs were obtained at 310.15K by using the vapor-pressure osmometry and potentiometry methods, respectively. Ternary aqueous urea solutions containing NaCl, KCl, NaBr, KBr, LiBr, NaNO 3, and LiNO 3 at two different concentrations of urea (0.3 and 1molal) as well as at three salt concentrations (0.25, 0.5, and 0.75molal) were considered. Moreover, urea solubility was also measured at 310.15K in 3 and 5molal NaCl solutions in the present work. Experimental data obtained in this work showed that the salt primarily dictates the volumetric properties and the MIAC while the solute with higher concentration determines the behavior of osmotic coefficients in these solutions. The ePC-SAFT model (without any adjustable mixture parameter) was used to accurately predict the experimental densities, activity and osmotic coefficients, and solubilities of the studied mixtures. © 2012 Elsevier B.V.
    view abstract10.1016/j.fluid.2012.04.003
  • Thermophobicity of liquids: Heats of transport in mixtures as pure component properties
    Hartmann, S. and Wittko, G. and Köhler, W. and Morozov, K.I. and Albers, K. and Sadowski, G.
    Physical Review Letters 109 (2012)
    We have measured the Soret coefficients of 41 out of 45 possible equimolar binary mixtures of 10 different organic solvents and found an additive rule for the heats of transport. These can, except for an undetermined offset, uniquely be assigned to the pure components. Based on their heats of transport, the fluids can be arranged according to their thermophobicity, similar to the standard electrode potential. A qualitative explanation of this unexpected additivity is based on the work of Morozov. © 2012 American Physical Society.
    view abstract10.1103/PhysRevLett.109.065901
  • VOC sorption in glassy polyimides-Measurements and modeling
    Hesse, L. and Naeem, S. and Sadowski, G.
    Journal of Membrane Science 415-416 (2012)
    The sorption behavior of volatile organic compounds (VOCs) in polymeric membrane materials such as polyimide, has a strong effect on the separation efficiency of dense polymeric nanofiltration membranes. To investigate the sorption behavior, this work presents gravimetrically measured and modeled sorption profiles for a series of VOCs (like n-hexane, ethanol, toluene, 2-propanol, and ethyl acetate) in two polyimides (P84 and Matrimid) at 25 °C.The experimental results show significant differences in the sorption speed of the VOCs in the two polyimides. The sorption of toluene, ethyl acetate, and ethanol in Matrimid is very fast compared to the sorption of 2-propanol, but the sorption in P84 is very slow for all the VOCs studied. The sorption behavior of the polyimide/VOC systems has been modeled using an improved one-dimensional Maxwell-Stefan diffusion model. The measured and modeled results provide detailed insight into the specific sorption behavior of the VOCs in the glassy polyimides P84 and Matrimid. © 2012 Elsevier B.V.
    view abstract10.1016/j.memsci.2012.05.054
  • Water activity coefficients in aqueous amino acid solutions by molecular dynamics simulation: 1. Force field development
    Hempel, S. and Sadowski, G.
    Molecular Simulation 38 (2012)
    New force fields for molecular dynamics (MD) simulation of aqueous zwitterionic amino acid simulations were developed. These were especially designed to calculate activity coefficient of water in amino acid solutions with high accuracy. For example, aqueous solutions of the following amino acids were considered: glycine, alanine, α-aminobutyric acid, α- aminovalerianic acid, valine and leucine. The force fields were obtained by quantum chemical calculations using B3LYP/6-31G and MP2/6-311(d,p) model theories in combination with the Merz-Kollmann-Singh scheme. To further increase the accuracy of the force field, a polarised continuum was considered in all quantum chemical calculations. Water activity coefficients obtained from MD using different all-purpose literature force fields, namely, OPLS, AMBER ff03 and GROMOS 53A6 as well as experimental data are compared with the results utilising the new force field. The new force field is shown to give better results compared with experimental data than existing force fields. Copyright © 2012 Taylor and Francis Group, LLC.
    view abstract10.1080/08927022.2011.608670
  • Diffusion of poly(ethylene glycol) and ectoine in NIPAAm hydrogels with confocal Raman spectroscopy
    Poggendorf, S. and Adama Mba, G. and Engel, D. and Sadowski, G.
    Colloid and Polymer Science 289 (2011)
    The diffusion behavior of poly(ethylene glycol) (PEG) in N-isopropylacrylamide (NIPAAm) hydrogels was investigated using confocal Raman spectroscopy with regard to temperature (25°C, 30°C and 35°C), PEG concentration (10 and 40 wt.%), PEG molecular weight (2,000 and 12,000 g/mol) and addition of the compatible solute ectoine (0.1 and 2 wt.%). Swelling and shrinking of the gels was observed by means of confocal Raman spectroscopy. The swelling behavior of NIPAAm gels in aqueous solutions of PEG and ectoine was found to resemble the swelling behavior in pure water with regard to temperature, i.e., the gel shrinks with increasing temperature. However, the presence and concentration of PEG and ectoine influence the swelling behavior by lowering the volume phase-transition temperature of the gel and facilitating shrinking. In some cases, a re-swelling of the gel was observed after the initial shrinking at the onset of PEG diffusion, which can be explained by PEG changing the chemical potential in the gel phase as it diffuses into the sample allowing the water to re-enter. The expulsion of water from the gel during shrinking and the so-caused increase of PNIPAAm and PEG concentrations in some cases led to the PEG diffusion seemingly being faster in more shrunken gels despite of their higher diffusion resistance. © Springer-Verlag 2011.
    view abstract10.1007/s00396-011-2399-7
  • Measuring and modeling activity coefficients in aqueous amino-acid solutions
    Held, C. and Cameretti, L.F. and Sadowski, G.
    Industrial and Engineering Chemistry Research 50 (2011)
    The perturbed-chain statistical association theory (PC-SAFT) is applied to simultaneously describe various thermodynamic properties (density, vapor-pressure depression, activity coefficient, solubility) of aqueous solutions containing an amino acid or an oligopeptide. The 28 organic compounds considered within this work are glycine, alanine, serine, proline, hydroxyproline, valine, leucine, arginine, lysine, threonine, asparagine, tyrosine, histidine, cysteine, methionine, aspartic acid, glutamic acid, β-ABA, β-isoABA, α-ABA, γ-ABA, β-AVA, γ-AVA, diglycine, triglycine, dialanine, Gly-Ala, and Ala-Gly. If not yet available in literature, amino-acid solubility data and activity coefficients were determined experimentally. To prove the predictivity of PC-SAFT, osmotic coefficients in aqueous solutions containing two amino acids (glycine/valine and alanine/valine) were measured and predicted without applying any additional model parameters. © 2010 American Chemical Society.
    view abstract10.1021/ie100088c
  • Miniaturized based on oxygen diffusion timing sensor for polymer packaging
    Marek, P. and Velasco-Velez, J.J. and Haas, T. and Doll, T. and Sadowski, G.
    Procedia Engineering 25 (2011)
    A non-electronic lifetime indicator for packaging has been developed using a colour reaction and diffusion in microchannels. It uses oxygen uptake in polymers after an originality seal is broken by manipulation or regular opening. The oxygen triggers a colour change that is made visible after desired timing period at corresponding diffusion lengths. This timing sensor was realized within a microchannel suitable for packaging cap. Rigorous design was based on modeling the diffusion - reaction equation and experimentally determined diffusion coefficients. To achieve appropriate functionality, temperature effects must be compensated using nanofunctioned materials as well as substrate diffusion of other gases like water. The methodology and design rules are generalized for microfluidics packaging. © 2011 Published by Elsevier Ltd.
    view abstract10.1016/j.proeng.2011.12.300
  • Minimal experimental data set required for estimating PCP-SAFT parameters
    Albers, K. and Sadowski, G.
    Industrial and Engineering Chemistry Research 50 (2011)
    The pure-component parameters of the Perturbed Chain Polar-Statistical Associating Fluid Theory (PCP-SAFT) equation of state are usually fitted to experimental data over broad temperature ranges. Against a background of limited experimental data, this article examines the amount and type of experimental data that are minimally required for safe parameter estimation. For nonassociating components, a minimal data set containing three data points is sufficient. For associating components, five data points are sufficient. The influence of vapor-pressure data on parameter estimation and the modeling results is larger than that of liquid-volume data. The temperature ranges of the experimental data can be chosen to be as small as 5 K for all of the data, except for the vapor pressures of associating components. These data require a range of at least 20 K. Application of the parameters fitted to the minimal experimental data set led to convincing results for the modeling of pure-component properties and binary mixtures. © 2011 American Chemical Society.
    view abstract10.1021/ie2010803
  • Modeling of Polymer Phase Equilibria Using Equations of State
    Sadowski, G.
    Polymer Thermodynamics: Liquid Polymer-containing Mixtures 238 (2011)
    The most promising approach for the calculation of polymer phase equilibria today is the use of equations of state that are based on perturbation theories. These theories consider an appropriate reference system to describe the repulsive interactions of the molecules, whereas van der Waals attractions or the formation of hydrogen bonds are considered as perturbations of that reference system. Moreover, the chain-like structure of polymer molecules is explicitly taken into account. This work presents the basic ideas of these kinds of models. It will be shown that they (in particular SAFT and PC-SAFT) are able to describe and even to predict the phase behavior of polymer systems as functions of pressure, temperature, polymer concentration, polymer molecular weight, and polydispersity as well as - in case of copolymers - copolymer composition.
    view abstract10.1007/12_2010_94
  • Modeling pH and solubilities in aqueous multisolute amino acid solutions
    Grosse Daldrup, J.-B. and Held, C. and Sadowski, G. and Schembecker, G.
    Industrial and Engineering Chemistry Research 50 (2011)
    The solubility of amino acids is highly depending on the prevailing pH value. However, this dependency is neglected in the state-of-the-art modeling of solubilities in multisolute solutions. In order to describe the pH-dependency of the solubilities, the PC-SAFT model is applied to aqueous solutions containing two amino acids accounting for their dissociation/association equilibria. This approach is applied to four ternary mixtures with pronounced pH-dependent solubility behavior allowing for a good description of experimental amino acid solubilities depending on temperature, cosolute concentration, and pH value. The systems considered within this work each contain two amino acids which show big differences in pI, i.e., l-glutamic acid or l/dl-aspartic acid on the one hand and glycine or l-serine on the other hand, respectively. © 2011 American Chemical Society.
    view abstract10.1021/ie1010367
  • PePC-SAFT: Modeling of polyelectrolyte systems 2. Aqueous two-phase systems
    Naeem, S. and Sadowski, G.
    Fluid Phase Equilibria 306 (2011)
    This work considers aqueous two-phase systems (ATPS) containing one polymer-polyelectrolyte as well as one salt. To model the liquid-liquid equilibria (LLE) of these systems, the recently presented model pePC-SAFT has been employed. ATPS containing poly(acrylic acid) of different degrees of neutralization or poly(vinyl pyrrolidone), respectively, were considered. The binary interaction parameters used between water-poly(acrylic acid) and water-poly(vinyl pyrrolidone) were adjusted to vapor-liquid equilibrium (VLE) data of these systems. ATPS consisting of poly(vinyl pyrrolidone)-water-sodium sulfate were predicted as function of temperature as well as of molar mass of the polymer. For poly(acrylic acid) systems, ATPS were predicted as function of charge density (degree of neutralization) for different types of salt. For these calculations, the polyelectrolyte model parameters were determined from the non-charged polymer whereas the effect of increasing charge density has been purely predicted by the model. Using this approach, it is possible to predict the shrinking of the liquid-liquid equilibrium region with increasing charging of the polyelectrolyte. © 2011 Elsevier B.V.
    view abstract10.1016/j.fluid.2011.02.024
  • Simultaneous correlation of hydrophobic interactions in HIC and protein solubility in aqueous salt solutions and mixed solvents
    Mollerup, J.M. and Breil, M.P. and Vogelpohl, C. and Sadowski, G.
    Fluid Phase Equilibria 301 (2011)
    The chromatographic retention in hydrophobic and reversed phase chromatography and the solubility of proteins display some common features. The chromatographic retention, as well as the solubility, is modulated by the thermodynamic properties of the solute in the fluid phase. The retention measurements at linear conditions provide information of the solution properties of the protein at infinite dilution, and the solubility measurements produce the supplementary information about the solution properties at the saturation limit. This provides a useful approach to simultaneous correlation of the chromatographic retention and the solubility.The experimental data, used for the correlation, comprise retention measurements of lysozyme on different HIC adsorbents using an aqueous ammonium sulphate eluant, an aqueous ammonium sulphate eluant with an admixture of ethanol, as well as published solubility data.The chromatographic retention data and the corresponding solubility data have been correlated using a chemical potential model derived from Kirkwood's theory of solutions of charged macro-ions and zwitterions in electrolyte solutions. The model correlated the chromatographic retention factor and the solubility data within the precision of the measurements. The model was applied in a pH range from 4 to 11. It was demonstrated experimentally, as well as theoretically, that an admixture of ethanol to the aqueous eluant changes the thermodynamic retention factor on various adsorbents identically when compared to the thermodynamic retention factor in an ethanol free eluant. © 2010 Elsevier B.V.
    view abstract10.1016/j.fluid.2010.11.028
  • Solubility of Complex Natural and Pharmaceutical Substances
    Ruether, F. and Sadowski, G.
    Industrial Scale Natural Products Extraction (2011)
    view abstract10.1002/9783527635122.ch2
  • Special themed issue on "responsive gels"
    Sadowski, G.
    Colloid and Polymer Science 289 (2011)
    view abstract10.1007/s00396-011-2408-x
  • Thermodynamic modeling of solubility
    Rüther, F. and Sadowski, G.
    Chemie-Ingenieur-Technik 83 (2011)
    The knowledge of the solubility in pure solvents and solvent mixtures is crucial for designing the crystallization process. However, it is practically impossible to scan all possible solvent mixtures and mixture compositions experimentally. Therefore, a physically well-founded thermodynamic model which allows for solubility predictions in pure solvents and solvent mixtures based only on a small amount of experimental data is required. In this work, we demonstrated the applicability of the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) equation of state to model and to predict the solubility, especially of pharmaceuticals and complex (bio-) molecules, in pure solvents and solvent mixtures. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/cite.201000207
  • Compatible solutes: Thermodynamic properties and biological impact of ectoines and prolines
    Held, C. and Neuhaus, T. and Sadowski, G.
    Biophysical Chemistry 152 (2010)
    Compatible solutes like ectoine and its derivatives are deployed by halophile organisms as osmolytes to sustain the high salt concentration in the environment. This work investigates the relation of the thermodynamic properties of compatible solutes and their impact as osmolytes. The ectoines considered in this work are ectoine, hydroxyectoine, and homoectoine. Besides solution densities (15-45. °C) and solubilities in water (3-80. °C), component activity coefficients in the aqueous solutions were determined in the temperature range between 0 and 50. °C. The latter is important for adjusting a certain water activity and therewith a respective osmotic pressure within a cell. The characteristic effect of ectoines is compared to that of prolines, as well as to that of incompatible solutes as salts and urea. The experimental results show that the influence on the activity (coefficient) of water is quite different for compatible and incompatible solutes: whereas compatible solutes cause decreasing water activity coefficients, incompatible solutes lead to an increase in water activity coefficients. Based on this quantity, the paper discusses the impact of various osmolytes on biological systems and contributes to the explanation why some osmolytes are more often and at other temperatures used than others. Moreover, it was found that the anti-stress effect of an osmolyte is weakened in the presence of a salt.Finally, it is shown that the thermodynamic properties of compatible solutes can be modeled and even predicted using the thermodynamic model PC-SAFT (Perturbed-Chain Statistical Associating Fluid Theory). © 2010 Elsevier B.V.
    view abstract10.1016/j.bpc.2010.07.003
  • Effect of finite extensibility on the equilibrium chain size
    Miao, B. and Vilgis, T.A. and Poggendorf, S. and Sadowski, G.
    Macromolecular Theory and Simulations 19 (2010)
    We investigate the finite-extensibility effect on the equilibrium size of a single polymer chain by using a Flory-type calculation. The finite extensibility of the chain is effectively taken into account by modifying the Gaussian stretching energy to a non-Gaussian form which recovers the harmonic spring behavior in the limit of weak stretch and diverges when the chain extension approaches the total contour length. In general, the finite extensibility decreases the equilibrium size of the chain compared to that obtained from Flory's classic theory, due to a steeper free energy or effective potential of the chain generated by the finite-extensibility effect. It is illustrated clearly that, for a chain with a short contour length and/or with strong repulsions between monomers, the finite-extensibility correction is important and necessary to be taken into account. A typical system where the finite extensibility plays an important role is suggested to be the highly charged and highly crosslinked hydrogel. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    view abstract10.1002/mats.201000009
  • Efficient phase separation and product recovery in organic-aqueous bioprocessing using supercritical carbon dioxide
    Brandenbusch, C. and Bühler, B. and Hoffmann, P. and Sadowski, G. and Schmid, A.
    Biotechnology and Bioengineering 107 (2010)
    Biphasic hydrocarbon functionalizations catalyzed by recombinant microorganisms have been shown to be one of the most promising approaches for replacing common chemical synthesis routes on an industrial scale. However, the formation of stable emulsions complicates downstream processing, especially phase separation. This fact has turned out to be a major hurdle for industrial implementation. To overcome this limitation, we used supercritical carbon dioxide (scCO2) for both phase separation and product purification. The stable emulsion, originating from a stereospecific epoxidation of styrene to (S)-styrene oxide, a reaction catalyzed by recombinant Escherichia coli, could be destabilized efficiently and irreversibly, enabling complete phase separation within minutes. By further use of scCO2 as extraction agent, the product (S)-styrene oxide could be obtained with a purity of 81% (w/w) in one single extraction step. By combining phase separation and product purification using scCO2, the number of necessary workup steps can be reduced to one. This efficient and easy to use technique is generally applicable for the workup of biphasic biocatalytic hydrocarbon functionalizations and enables a cost effective downstream processing even on a large scale. Biotechnol. Bioeng. 2010;107:642-651. © 2010 Wiley Periodicals, Inc.
    view abstract10.1002/bit.22846
  • Measurement and modeling solubility of aqueous multisolute amino-acid solutions
    Daldrup, J.-B.G. and Held, C. and Ruether, F. and Schembecker, G. and Sadowski, G.
    Industrial and Engineering Chemistry Research 49 (2010)
    The solubilities of the ternary mixtures L-alanine/L-leucine, L-alanine/L-valine, and L-leucine/L-valine in water were measured at 303 and 323 K. The solubilities of seven binary, eight ternary, and one quaternary aminoacid systems were modeled using the PC-SAFT equation of state. For this purpose, new parameters for L-aspartic acid, L-glutamic acid, L-leucine, and L-tyrosine are presented. The model excellently reproduces binary solubility data with a linear temperature-dependent binary interaction parameter for the solute-solvent interaction. PCSAFT allows for a very good prediction of the solubility behavior of ternary mixtures over a wide range of temperature and concentration. The aqueous mixture with three amino acids is then predicted without any further adjustment with an average relative deviation of 3.34%. © 2010 American Chemical Society.
    view abstract10.1021/ie900913c
  • pePC-SAFT: Modeling of polyelectrolyte systems. 1. Vapor-liquid equilibria
    Naeem, S. and Sadowski, G.
    Fluid Phase Equilibria 299 (2010)
    A molecular thermodynamic model for polyelectrolyte systems-called pePC-SAFT-is proposed. The effect of charged monomers within the polyelectrolyte chain is explicitly taken into account in the reference term by replacing the hard-chain contribution of the PC-SAFT model by a charged-hard-chain contribution. Moreover, counterion condensation is accounted for to determine the effective number of charges along the polyion as well as of free counterions. The electrostatic contribution of the free counterions is described by a Debye-Hückel term.pePC-SAFT is applied to model the phase equilibria of aqueous solutions of poly(sodium acrylate) and poly(ammonium acrylate) with and without added NaCl as function of temperature, salt concentration as well as molar mass and degree of neutralization of the polyelectrolytes. For the modelling, the pure-component parameters of the polyelectrolyte as well as the binary interaction parameter between water and the polyion were used as determined for the non-charged polymers. Using only the information of the polyelectrolyte degree of neutralization and without fitting additional parameters, the model is able to predict the vapor-liquid equilibria of polyelectrolyte systems in satisfactory agreement with experimental data. © 2010 Elsevier B.V.
    view abstract10.1016/j.fluid.2010.09.004
  • Solubility calculation of pharmaceutical compounds - A priori parameter estimation using quantum-chemistry
    Cassens, J. and Ruether, F. and Leonhard, K. and Sadowski, G.
    Fluid Phase Equilibria 299 (2010)
    Pure-component electrostatic properties for pharmaceutical compounds and intermediates (xanthene, ibuprofen, aspirin, p-hydroxyphenylacetic acid, p-toluic acid and o-anisic acid) were obtained by quantum-chemical methods. Afterwards, these properties were used for the a priori determination of the pure-component parameters for the Perturbed-Chain Polar Statistical-Associating Fluid Theory (PCP-SAFT). These parameters were applied to perform solubility calculations for binary solute-solvent mixtures. In these calculations the only parameter fitted was the binary parameter. The results show a good agreement of the modeled solubility and experimental data for the considered solutes in non-polar and polar solvents. Finally, the application of different combination rules to also predict the binary interaction parameter in the mixture was investigated. © 2010 Elsevier B.V.
    view abstract10.1016/j.fluid.2010.09.025
  • Solubility, crystallization and oiling-out behavior of PEGDME: 1. Pure-solvent systems
    Kiesow, K. and Ruether, F. and Sadowski, G.
    Fluid Phase Equilibria 298 (2010)
    Oiling out denotes a (metastable) liquid-liquid demixing during cooling crystallization prior to formation of the first crystals. This in most cases unwanted effect deteriorates the properties of the desired solid product. On the basis of the crystallization of the model substance polyethylenglycoldimethylether (PEGDME) from pure solvents, the influence of the molecular size of the solute and the type of solvent on the oiling-out behavior was systematically investigated. In this study the solubility data were determined gravimetrically as well as by using differential scanning calorimetry. The crystallization and oiling-out temperatures were detected visually in batch crystallization experiments. Oiling out was observed during the crystallization of PEGDME with a molar mass of 2000. g/mol (PEGDME2000) from diethylketone, ethyl acetate and 2-propanol, whereas no oiling out was detected during the cooling process of PEGDME with a molar mass of 1000. g/mol (PEGDME1000) from all solvents considered. Furthermore the oiling-out temperature for PEGDME2000 was not significantly influenced by the chosen solvents diethylketone, ethyl acetate and 2-propanol. In the second part of this study, it is shown that the appearance and absence of oiling out in all considered solvents can be qualitatively predicted by the pertubed chain statistical association theory (PC-SAFT) only using solubility data. © 2010 Elsevier B.V.
    view abstract10.1016/j.fluid.2010.08.005
  • Supercritical phase behavior for biotransformation processing
    Brandenbusch, C. and Sadowski, G.
    Journal of Supercritical Fluids 55 (2010)
    In recent works, supercritical carbon dioxide turned out to offer innovative and highly effective alternatives for the workup of biphasic whole-cell biotransformation reaction mixtures. Further optimization of the downstream processing, e.g. by supercritical extraction of the product, requires a reliable simulation of the phase behavior in those systems. In this work, binary and ternary systems containing carbon dioxide and organic components from the biotransformation reaction mixture, such as styrene (substrate), (S)-styrene oxide (product), 2-phenylethanol (byproduct), octane (inducer), and bis-2(ethylhexyl)phthalate (solvent) were measured and modeled for temperatures ranging from 308.15 to 350.15 K and pressures ranging from 5 to 70 MPa using the PC-SAFT equation of state. The obtained results offer the possibility to precisely predict the phase behavior in this system, thus enabling the modeling of e.g. supercritical-fluid extraction steps. © 2010 Elsevier B.V. © 2010 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.supflu.2010.10.025
  • Tensile creep measurements of glassy VOC-loaded polymers
    Mueller, F. and Heuwers, B. and Katzenberg, F. and Tiller, J.C. and Sadowski, G.
    Macromolecules 43 (2010)
    The paper describes a new apparatus to measure tensile creep curves of polymer/volatile organic compound (VOC) systems, especially designed for measurements of small VOC loadings in glassy polymers. For the first time creep curves for glassy polymer/VOC systems are recorded. The measurements were performed for the system polystyrene/toluene at different toluene loads up to wtoluene = 0.13 and at temperatures of 30, 50, and 70 °C. It was found that increasing VOC mass fractions qualitatively influence the mechanical properties of a polymer in the same way like increasing temperature does. Since at isothermal conditions these properties are affected by the glass transition of the system, this information for the polystyrene/toluene mixtures was used to modify and to verify the correlation of Kelly and Bueche to predict the glass-transition temperature of polymer/solvent systems. © 2010 American Chemical Society.
    view abstract10.1021/ma101782d
  • biothermodynamics

  • hydrogels

  • molecular simulation

  • phase equilibria

  • polymer thermodynamics

  • solubility

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