Prof. Dr. Markus Thommes

Feststoffverfahrenstechnik
TU Dortmund University

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  • Design and Characterization of a Screw Extrusion Hot-End for Fused Deposition Modeling
    Feuerbach, T. and Thommes, M.
    Molecules (Basel, Switzerland) 26 (2021)
    The filament is the most widespread feedstock material form used for fused deposition modeling printers. Filaments must be manufactured with tight dimensional tolerances, both to be processable in the hot-end and to obtain printed objects of high quality. The ability to successfully feed the filament into the printer is also related to the mechanical properties of the filament, which are often insufficient for pharmaceutically relevant excipients. In the scope of this work, an 8 mm single screw hot-end was designed and characterized, which allows direct printing of materials from their powder form and does not require an intermediate filament. The capability of the hot-end to increase the range of applicable excipients to fused deposition modeling was demonstrated by processing and printing several excipients that are not suitable for fused deposition modeling in their filament forms, such as ethylene vinyl acetate and poly(1-vinylpyrrolidone-co-vinyl acetate). The conveying characteristic of the screw was investigated experimentally with all materials and was in agreement with an established model from literature. The complete design information, such as the screw geometry and the hot-end dimensions, is provided in this work.
    view abstract10.3390/molecules26030590
  • 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
  • Elucidation of mass transfer mechanisms in pellet formation by spheronization
    Evers, M. and Mattusch, A. and Weis, D. and Garcia, E. and Antonyuk, S. and Thommes, M.
    European Journal of Pharmaceutics and Biopharmaceutics 160 (2021)
    Previously published mechanisms of pellet formation during extrusion-spheronization include a transfer of material between different granules. This research aimed to specify the origin of this transfered mass, enabling further insight into the extrusion-spheronization process. Granules of various diameters were rounded simultaniously in a spheronizer to ascertain if mass transfer between smaller and larger granules is truly in balance, or if mass transfer from smaller to larger granules is preferred. Granules were also marked with a fluorescent tracer to enable quantification of mass transfer. By using differently sized and shaped granules as starting material, different modes of mass transfer were investigated. Samples were taken after various process durations to investigate the kinetics of the tranfer mechanism. It was found that both small and large granules dispense and receive mass during spheronization. In general, small granules increase their size, while large granules maintain their size or show a slight size decrease, resulting in the particularly narrow monomodal size distribution. © 2021 Elsevier B.V.
    view abstract10.1016/j.ejpb.2021.01.013
  • Impact of incorporated drugs on material properties of amorphous solid dispersions
    Flügel, K. and Schmidt, K. and Mareczek, L. and Gäbe, M. and Hennig, R. and Thommes, M.
    European Journal of Pharmaceutics and Biopharmaceutics 159 (2021)
    Formulation development of amorphous solid dispersions (ASD) still is challenging although several poorly water-soluble drugs have been marketed using this technique. During development of novel drugs, the selection of the preparation technique and polymer matrix is commonly performed for the certain drug via screening tools. However, if general trends regarding material properties are to be investigated, this approach is not beneficial, although often utilized in literature. The main component of the ASD usually is the polymer and thus it predominantly determines the material properties of the system. Therefore, to study the impact of different drugs and their drug loads on mechanical properties and wettability, three poorly soluble model drugs with drug loads ranging from 10% to 40% were incorporated into copovidone via hot-melt extrusion. The obtained extrudates were subsequently characterized regarding mechanical properties by applying diametral compression test and nanoindentation and the results were compared to the performance during tablet compression. Incorporation of all tested drugs resulted in a similar increase in brittleness of the ASDs, whereas the Young's modulus and hardness changed differently in dependence of the incorporated drug. These observations correlated well with the performance during tablet compression and it was concluded, that the brittleness seemed to be the predominant factor influencing the compression behavior of copovidone-based ASDs. Furthermore, the degree of water absorption and wettability was assessed by applying dynamic vapor sorption experiments and contact angle measurements. Here, the incorporated drugs impacted the contact angle to different degrees and a strong correlation between the contact angle and disintegration time was observable. These results highlight the importance of thorough characterization of the ASDs as it helps to predict their performance during tablet compression and thus facilitates the optimal selection of excipients. © 2020 Elsevier B.V.
    view abstract10.1016/j.ejpb.2020.12.017
  • Implementation of formation mechanisms in DEM simulation of the spheronization process of pharmaceutical pellets
    Weis, D. and Grohn, P. and Evers, M. and Thommes, M. and García, E. and Antonyuk, S.
    Powder Technology 378 (2021)
    In the production process of pharmaceutical pellets with a narrow size distribution and a high sphericity, a combined extrusion-spheronization technique is frequently used. The rounding of the wet cylindrical extrudates in the spheronizer after the extrusion step is influenced by various interfering mechanisms, in particular plastic deformation, breakage, attrition and coalescence. Due to the complexity of these mechanisms which depend on the particle dynamics, there is no sufficient description of the particle rounding process in the spheronizer. In this study, the Discrete Element Method (DEM) which runs on the micro scale is coupled with a Particle Shape Evolution (PSE) model on the macro scale to describe how the particle shape changes due to collisions. For the DEM simulation a new contact model was used which was developed to capture the cyclic, dominant visco plastic deformation behaviour. Based on the DEM collision data, the changing particle shape was described in the PSE model by applying the proposed submodels for the different formation mechanisms. The resulting particle shapes obtained with this simulation framework are in a good agreement with experimental data. © 2020
    view abstract10.1016/j.powtec.2020.09.013
  • Melt milling as manufacturing method for solid crystalline suspensions
    da Igreja, P. and Erve, A. and Thommes, M.
    European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 158 (2021)
    Production of submicron particles (0.1-1 μm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long-term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility. Copyright © 2020. Published by Elsevier B.V.
    view abstract10.1016/j.ejpb.2020.11.020
  • Residence time and mixing capacity of a rotary tablet press feed frame
    Zimmermann, M. and Thommes, M.
    Drug Development and Industrial Pharmacy 47 (2021)
    Purpose: Most rotary tablet presses contain a feed frame to provide a continuous powder flow and to feed powder into the dies. The wide residence time distribution (RTD) of these feed frames is problematic, because it negatively affects material traceability in continuous manufacturing. In a rotary tablet press, different machine settings influence the RTD, which is characterized by the mean and the width of the distribution. This study focused on the effects of the rotational speed of the feed frame paddles and the rotary tablet press throughput on the RTD. Methods: An in-line UV/Vis measurement method was developed for determining the RTD in the feed frame. A model based on a plug flow and a continuous stirred tank reactor was adapted to model the experimentally determined RTDs. Finally, the mixing capacity of a feed frame was evaluated and correlated with a model parameter of the RTD. Results: Overall, the developed UV/Vis measurement method was suitable and could be used to obtain process information regarding content uniformity in real time. The experimentally-determined RTDs were described well by fitting an inverse mixing and a transport time. In addition, a correlation between the location and the shape of measured RTDs and tablet press throughput was found. In contrast, rotational feed frame paddle speed did not affect the RTDs. Split-feeding experiments indicated the mixing capacity of the rotary tablet press feed frame. Conclusion: The inverse mixing time can be used as an initial indicator for estimating the mixing capacity. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
    view abstract10.1080/03639045.2021.1934871
  • Contact Behavior of Microcrystalline Cellulose Pellets Depending on their Water Content
    Grohn, P. and Weis, D. and Thommes, M. and Heinrich, S. and Antonyuk, S.
    Chemical Engineering and Technology 43 (2020)
    Microcrystalline cellulose pellets for oral drug delivery are often produced by a combined wet extrusion-spheronization process. During the entire process, the cylindrical as well as the spherical pellets are exposed to various stresses resulting in a change of their shape and size due to plastic deformation and breakage. In this work, the effect of moisture content of pellets on their mechanical behavior is studied. In static compression tests, the strong influence of water content on deformation behavior of pellets is confirmed. Moreover, impact tests are performed using a setup consisting of three high-speed cameras to record pellet-wall collisions. Material properties, such as stiffness, restitution coefficient, breakage force, and displacement, were analyzed depending on the water content. © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
    view abstract10.1002/ceat.201900517
  • Evaluation of spray impact on a sphere with a two-fluid nozzle
    Strob, R. and Babaria, T. and Rodeck, M. and Schaldach, G. and Walzel, P. and Thommes, M.
    Journal of Aerosol Science 140 (2020)
    The generation of a secondary aerosol after impact, consisting of smaller droplets at a given velocity and mass flow, is relevant for various applications. Thus far, the investigations and modelling approaches on spray impact are based on extrapolation of the single-droplet impingement or empirical correlations. The validity of the models presented is limited to the given experimental setup and conditions such as initial droplet size, velocity and the impact surface characteristics. The aim of this work was to empirically evaluate the spray impact of a two-fluid nozzle on a sphere. A small-scale nozzle was used, which produced a primary aerosol with a mass median diameter of about 12μm (liquid-to-gas mass flow ratio = 1, gas pressure: ΔpG = 5 bar). After impact on a sphere, a multimodal distribution was observed and a higher mass flowrate of droplets in the small micrometer range (2 and 3μm) was produced for a liquid mass flow rate in the range of 1.2–6 kg/h and an atomizing gas mass flow rate of 1–4 kg/h. For easier observation, a geometrically similar, larger nozzle was used, which produced an aerosol with a mass median diameter of about 80μm (liquid-to-gas mass flow ratio = 4, gas pressure: ΔpG = 1 bar). The measured droplet size after impact is smaller for a lower liquid-to-gas mass flow ratio and increased atomizing gas inlet pressure. Droplet formation mechanisms such as splashing, crown formation and spreading on the sphere surface were observed. A characteristic film with large variations in thickness was generated. © 2019 Elsevier Ltd
    view abstract10.1016/j.jaerosci.2019.105483
  • Impact of structural relaxation on mechanical properties of amorphous polymers
    Flügel, K. and Hennig, R. and Thommes, M.
    European Journal of Pharmaceutics and Biopharmaceutics 154 (2020)
    Fusion based methods, such as hot-melt extrusion, are a common way of preparing amorphous solid dispersions. Since the amorphous glass, however, is not in a configurational equilibrium, the molecular arrangement of the obtained material can differ in dependence of the preparation conditions. Although the changes in the configuration of an amorphous material, which are commonly referred to as structural relaxation or physical aging, are well investigated, the impact on mechanical properties of amorphous solid dispersions have widely been neglected so far. The presented study investigated copovidone as a model polymer commonly used in amorphous solid dispersions and revealed that structural relaxation was already introduced into the polymer during hot-melt extrusion while its degree was cooling rate dependent. The degree of structural relaxation significantly affected the mechanical properties of copovidone as assessed by diametral compression tests, macroindentation and nanoindentation. An increase in Young's modulus and indentation hardness was observable with a higher degree of structural relaxation, which, during tablet compression, translated into tablets with significantly lower tensile strength. Furthermore, evaluation of the force-displacement curves during tablet compression revealed a decreased proportion of irreversible deformation with higher degree of structural relaxation correlating well with the increased indentation hardness during macroindentation. Thus, understanding structural relaxation and its impact on material properties is of utmost importance to assess the processability and compaction performance of amorphous solid dispersions in dependence of their preparation conditions and thermal history. © 2020 Elsevier B.V.
    view abstract10.1016/j.ejpb.2020.07.016
  • Modeling the separation performance of depth filter considering tomographic data
    Hoppe, K. and Maricanov, M. and Schaldach, G. and Zielke, R. and Renschen, D. and Tillmann, W. and Thommes, M. and Pieloth, D.
    Environmental Progress and Sustainable Energy 39 (2020)
    Fibrous depth filters are frequently used for the purification of gas streams with low dust loadings, as well as processes where a high initial filtration efficiency is required (e.g., clean rooms for aseptic production). One tool suitable for supporting the development of optimized filter media is the use of numerical simulations. The drawback of this technique is the high computational resources required. In this work, a new and fast approach based on a one-dimensional model was applied. Structural characteristics (e.g., porosity distribution and fiber diameter) of two different filter media were successfully determined using a novel X-ray microscope. These characteristics were incorporated in the filtration model, and their influence on the calculations was evaluated. It was found that the porosity distribution does have an impact on local (microscopic) deposition rates, but only a minor influence on the macroscopic filtration efficiency (around 3%). Benefits of the model are the application of measured structural data and the low computational expense. Compared to experimental data (VDI 3926 / ISO 11057), the prediction of the filtration efficiency can be improved by incorporating the structural data in the model. © 2020 The Authors. Environmental Progress & Sustainable Energy published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers.
    view abstract10.1002/ep.13423
  • Slicing parameter optimization for 3D printing of biodegradable drug-eluting tracheal stents
    Feuerbach, T. and Kock, S. and Thommes, M.
    Pharmaceutical Development and Technology 25 (2020)
    In 3D printing, the schematic representation of an object must be converted into machine commands. This process is called slicing. Depending on the slicing parameters, products with different properties are obtained. In this work, biodegradable drug-eluting tracheal stents consisting of a medical grade poly(lactic-co-glycolic acid) and a drug were printed by fused deposition modeling. A slicing parameter optimization method was proposed with the aim of obtaining a particularly low stent porosity and high mechanical strength while maintaining the stent dimensions, which is essential regarding patient-tailored implants. Depending on the three slicing parameters printing pattern, lateral strand distance and spatial fill, porosities of approximately 2–5% were obtained. The tensile strength was used as a measure for the mechanical strength of the implants and was found to be dependent on the porosity as well as the strand orientation relative to the load direction. Strand orientations in load direction yielded the highest tensile strengths of 40–46 MPa and the bonding between individual layers yielded the lowest tensile strengths of 20–24 MPa. In vitro dissolution tests of successfully printed stents were used to predict sustained release of the drug over several months. © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
    view abstract10.1080/10837450.2020.1727921
  • 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
  • A contact model for the deformation behaviour of pharmaceutical pellets under cyclic loading
    Weis, D. and Krull, F. and Mathy, J. and Evers, M. and Thommes, M. and Antonyuk, S.
    Advanced Powder Technology 30 (2019)
    Spherical pharmaceutical pellets are commonly produced by an extrusion-spheronization process. In the spheronizer, the wet cylindrical extrudates are rounded into spheres due to multiple collisions. In order to model this rounding, a suitable contact model, which can predict the dominantly plastic deformation behaviour, is necessary. In this study, a novel cyclic model for wet and dry pellets was developed. Various single particle compression and impact tests with pellets produced from microcrystalline cellulose (MCC) and lactose were conducted to calibrate and validate this model. It was found that the model is able to predict the energy dissipation as well as the deformation during pellet impact in the velocity range which is relevant for the spheronization process. Since the pellets are loaded multiple times during this process, the model was designed in order to account for the increasing flattening and hardening in the contact area as a function of the number of loading cycles. Therefore, the presented model allows the description of the pellet deformation by repeated stressing. © 2019 The Society of Powder Technology Japan
    view abstract10.1016/j.apt.2019.07.026
  • Comparison of residence time models for pharmaceutical twin-screw-extrusion processes
    Wesholowski, J. and Podhaisky, H. and Thommes, M.
    Powder Technology 341 (2019)
    Twin-Screw-Extrusion is an emerging and focused method with several applications in the pharmaceutical field. With respect to the desired process conditions, three different types of extrusion can be utilized such as Hot-Melt-, Wet- or Cold-Extrusion. For all of them the residence time and the residence time distribution are crucial process parameters determining the duration of thermal and mechanical stress to the processed material. Several approaches describing the residence time of extrusion processes are known and the most commonly applied models (Axial-Dispersion-, Tanks-in-Series- and Two-Compartment-Model) and functions (Zusatz-Function) were investigated. Therefore, experimental data representing different process conditions was applied from literature. The residence time distribution models were implemented and the least squares method was used to obtain the characteristic model parameters. The numerically calculated results were compared and evaluated based on the deviations to the experimental data overall, in crucial sections of the residence time plots and the comprehensibility of the model variables with respect to the interpretation for a process optimization. Moreover, the correlations between the characteristic parameters to those parameters of the different other tested models as well as their physical meaning have been revealed. Based on the results, a new model explicitly for twin-screw-extrusion was developed. This Twin-Dispersion-Model respects two independent mixing processes. Regarding to the parameters' comprehensibility and insight in process condition changes as well as deviations of the model fit to the experimental data, it was superior to all other tested models. © 2018 Elsevier B.V.
    view abstract10.1016/j.powtec.2018.02.054
  • Determination of the Structural Relaxation Enthalpy Using a Mathematical Approach
    Flügel, K. and Hennig, R. and Thommes, M.
    Journal of Pharmaceutical Sciences 108 (2019)
    Structural relaxation is a well-known phenomenon in amorphous materials such as amorphous solid dispersions. It is generally understood as a measure for molecular mobility and has been shown to impact certain material properties such as the dissolution rate. Several quantification methods to evaluate structural relaxation using differential scanning calorimetry have been proposed in the past, but all approaches exhibit disadvantages. In this work, a mathematical model was developed and fitted to calorimetric data enabling the analysis of the structural relaxation enthalpy by separating the structural relaxation peak from the underlying glass transition. The proposed method was validated using a parameter sensitivity analysis. Differently stressed amorphous samples were analyzed applying the new model and the results were compared to commonly applied quantification methods in literature. The proposed method showed high robustness and accuracy and overcame the observed disadvantages of the established methods. The heating rate dependence of the calculated structural relaxation enthalpy was in accordance with theoretical considerations of previous studies, supporting the validity of the results. Thus, the proposed model is suitable to accurately quantify the degree of structural relaxation and should be a valuable tool for further investigations regarding the impact of structural relaxation on material properties. © 2019 American Pharmacists Association®
    view abstract10.1016/j.xphs.2019.08.013
  • Development of filaments for fused deposition modeling 3D printing with medical grade poly(lactic-co-glycolic acid) copolymers
    Feuerbach, T. and Callau-Mendoza, S. and Thommes, M.
    Pharmaceutical Development and Technology 24 (2019)
    The manufacturing of custom implants and patient-tailored drug dosage forms with fused deposition modeling (FDM) three-dimensional (3D) printing is currently considered to be very promising. Most FDM printers are designed as an open filament system, for which filaments with a defined size are required. In addition to this processing requirement, the filament material must be of medical or pharmaceutical quality, in order to be suitable in these applications. In this work, filaments with nominal diameters of 1.75 mm and diameter tolerances of ±0.05 mm or lower were developed in a continuous extrusion process. The filaments were made from different medical grade poly(lactic-co-glycolic acid) (PLGA) copolymers. Thermal characterization of the material with differential scanning calorimetry (DSC) showed increased material degradation with increasing hydrophilicity. Mechanical characterization of the filaments showed tensile strengths in the range of 41–48 MPa and Young’s moduli in the range of 2055–2099 MPa. Stress relaxation tests showed no irreversible change in filament diameter under processing conditions similar to the utilized 3D printer. Due to unexpected differences in processability in the 3D printer, the molecular weight of the materials was identified as an additional relevant parameter. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
    view abstract10.1080/10837450.2018.1514522
  • Electrostatic precipitation of submicron particles in a molten carrier
    Dobrowolski, A. and Pieloth, D. and Wiggers, H. and Thommes, M.
    Pharmaceutics 11 (2019)
    Recently, submicron particles have been discussed as a means to increase the bioavailability of poorly water-soluble drugs. Separation of these small particles is done with both fibre and membrane filters, as well as electrostatic precipitators. A major disadvantage of an electrostatic precipitator (ESP) is the agglomerate formation on the precipitation electrode. These agglomerates frequently show low bioavailability, due to the decreased specific surface area and poor wettability. In this work, a new melt electrostatic precipitator was developed and tested to convert submicron particles into a solid dispersion in order to increase the bioavailability of active pharmaceutical ingredients. The submicron particles were generated by spray drying and transferred to the ESP, where the collection electrode is covered with a melt, which served as matrix after solidification. The newly developed melt electrostatic precipitator was able to collect isolated naproxen particles in a molten carrier. A solid naproxen xylitol dispersion was prepared, which showed a reduction of the dissolution time by 82%, and a release of 80% of the total drug, compared to the physical mixture. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
    view abstract10.3390/pharmaceutics11060276
  • Preparation of submicron drug particles via spray drying from organic solvents
    Dobrowolski, A. and Strob, R. and Dräger-Gillessen, J.F. and Pieloth, D. and Schaldach, G. and Wiggers, H. and Thommes, M.
    International Journal of Pharmaceutics 567 (2019)
    Manufacturing poorly water-soluble active pharmaceutical ingredients (API) with sufficient bioavailability is a significant challenge in pharmaceutical research. A higher bioavailability can reduce both the applied dosage and the side effects for the patient. One method of increasing the bioavailability is to reduce the particle size of the drug down to the nanoscale. An innovative procedure for the preparation of particles in the submicron size range is spray drying with aerosol conditioning, followed by subsequent separation of the particles in an electrostatic precipitator (ESP). This process has been tested before in an earlier work with aqueous model substances at high production rates (1 g/h) and narrow particle-size distributions (mannitol: d50,0 = 455 nm, span = 0,8) in the submicron range. Spray drying from an aqueous solution with low drug concentrations (<1 wt-%) leads to particles in the lower nanosize range, but the low concentrations make this process inefficient. A custom-made plant was modified in order to handle the organic spray-drying process. In addition, explosion protection had to be considered. This work focuses on the spray drying of submicron particles from organic solvents for the purpose of increasing the dissolution rate of the API griseofulvin. API particles were successfully produced in the submicron size-range, characterized and the dissolution behavior was investigated. The dissolution time to dissolve 80% of the drug, t80, was reduced from 21.5 min for the micronized grade API to 8.5 min for the submicron product. © 2019 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2019.118501
  • Scale-Up of pharmaceutical Hot-Melt-Extrusion: Process optimization and transfer
    Wesholowski, J. and Hoppe, K. and Nickel, K. and Muehlenfeld, C. and Thommes, M.
    European Journal of Pharmaceutics and Biopharmaceutics 142 (2019)
    Hot-Melt-Extrusion on Twin-Screw-Extruders has been established as a standard processing technique for pharmaceutical products. A major challenge is the transfer from a lab to a production level, since the combination of several unit operations within one apparatus leads to complex conditions for such a continuous manufacturing process. Here the residence time distribution is a crucial measure, which reflects the different mechanisms, e.g. dissolution, mixing or degradation, during processing. In the first part of a Scale-Up study, a methodology for the optimization of an extrusion process with respect to the load and throughput is presented. The developed concept was applied for different extruder scales in order to compare the identified processing windows. A deviation of the dominant material heating mechanisms was observed for the different scales, while the constraints for the transfer of a process to a different scale by the developed optimization concept is demonstrated. Finally, a sufficient operating point on a reference extruder is identified and in the second part of this study, different concepts from literature are applied for the transfer of this Hot-Melt-Extrusion process to two larger scales. The focus of the investigations was on the impact of the different approaches on the residence time distribution and the comparison. The determined results revealed a change of the most sufficient approach for the two different extruder sizes. The impact on the location in the time domain and form of the distribution are discussed and additionally evaluated by the fit to a RTD-model. In conclusion, the ratio of the applied energy for transport to mixing is identified as valuable addition in this context. © 2019 Elsevier B.V.
    view abstract10.1016/j.ejpb.2019.07.009
  • Scale-up of the rounding process in pelletization by extrusion-spheronization
    Evers, M. and Weis, D. and Antonyuk, S. and Thommes, M.
    Pharmaceutical Development and Technology 24 (2019)
    Previously described scaling models for the spheronization process of wet extrudates are incomplete, often concluding with an adjustment of the plate speed according to the spheronizer diameter, but neglecting to give guidelines on the adjustment of the load or the process duration. In this work, existing scaling models were extended to include the load and the process time. By analyzing the final particle size and shape distributions as well as the rounding kinetics for various loads and plate speeds in spheronizers with plate diameters of 0.12 m, 0.25 m and 0.38 m, the found scaling model was validated. The peripheral speed was found to be the main influence on the rounding kinetic, while the load and the plate diameter only showed minor influence. Higher peripheral speeds, higher loads and a larger spheronizer diameter led to an increase in rounding kinetic, allowing for shorter residence times and increased throughput. However, lower peripheral speed, lower loads and lower plate diameters led to particles of increased sphericity. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.
    view abstract10.1080/10837450.2019.1621900
  • Characterisation of fused deposition modeling 3D printers for pharmaceutical and medical applications
    Feuerbach, T. and Kock, S. and Thommes, M.
    Pharmaceutical Development and Technology 23 (2018)
    Fused deposition modeling (FDM) is a promising 3D printing technique for the fabrication of personalized drug dosage forms and patient-specific implants. However, there are no market products produced by FDM available at this time. One of the reasons is the lack of a consistent and harmonized approval procedure. In this study, three FDM printers have been characterised with respect to printing parameters relevant for pharmaceutical and medical applications, namely the positioning, hot-end temperature, material residence time, printing velocity and volumetric material flow. The printers are the Ultimaker 2 (UM2), the PRotos v3 (PR3) as well as an in-house developed printer (IDP). The positioning results showed discrepancies between the printers, which are mainly based on different types of drive systems. Due to comparable utilised hot-ends and nozzle geometries, the results for the temperature and residence time distribution measurements were quite similar. The IDP has a high positioning accuracy but is limited with respect to printing velocity, while the achievable material volume flows were different for all printers. The presented characterisation method aims to contribute to the development of a harmonized equipment qualification framework for FDM printers, which could lead to an acceleration and facilitation of an approval procedure for 3D printed products. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
    view abstract10.1080/10837450.2018.1492618
  • DEM simulation of the mixing behavior in a spheronization process
    Weis, D. and Evers, M. and Thommes, M. and Antonyuk, S.
    Chemical Engineering Science 192 (2018)
    Spherical pellets for pharmaceutical applications are widely produced by an extrusion-spheronization process. To achieve an equal, spherical pellet shape with a spheronization process, it is crucial that all pellets are exposed to similar stress conditions. However, in a spheronizer the pellets close to the friction plate are subjected to much higher stresses than pellets at the top of the torus, resulting in a strongly inhomogeneous stress distribution within the particle bed. Therefore, the product quality depends in particular on the mixing process in the spheronizer. In this study, the mixing behavior in a spheronization process is analyzed using DEM simulations. The real geometry and realistic process parameters of a lab scale spheronizer were investigated. To determine the mechanical properties of the wet pellets for the contact model, various single particle experiments were conducted with MCC-based pellets produced by extrusion-spheronization. The spatial mixing was characterized in different ways. Besides the determination of the degree of mixing based on statistical analysis, the Fokker-Planck equation was utilized. In this way the spatial distribution of the degree of mixing over the time was obtained. By using the poloidal distribution of the transport and dispersion coefficients of the Fokker-Planck equation the course of the degree of mixing in the different zones of the spheronizer was clarified. © 2018 Elsevier Ltd
    view abstract10.1016/j.ces.2018.07.057
  • Effect of Coandǎ-deflection-openings on the spray behavior of pressure swirl nozzles
    Kamplade, J. and Hohlfeld, I. and Kelz, M. and Thommes, M. and Walzel, P.
    Atomization and Sprays 28 (2018)
    Pressure swirl nozzles equipped with a convex deflection orifice are used for enlargement of the spray angle up to 180° and smaller drop sizes are expected from that operation. The sheet deflection behavior is investigated quantitatively by spray angle measurements for a wide range of operating conditions and nozzles geometries. To achieve proper deflection, the radius of the trumpet contour has to be adapted to the flow conditions generated upstream. Besides the spray angle, the sheet velocity is also known to have a major influence on the drop size and has been measured as compared to common nozzle types. For the deflected sheet, the velocity coefficient may go down to φ ≈ 0.7 compared to plain orifice geometries with φ > 0.9 depending on swirl ratio and viscosity. Finally, the drop size depending on the deflection geometry is measured by laser diffraction and opposed results were found depending on the operating conditions, especially on the viscosity. For low viscosity disturbances were amplified by the deflection orifice and lead to considerably lower breakup length. © 2018 by Begell House, Inc.
    view abstract10.1615/AtomizSpr.2018025126
  • Inline determination of residence time distribution in hot-melt-extrusion
    Wesholowski, J. and Berghaus, A. and Thommes, M.
    Pharmaceutics 10 (2018)
    In the framework of Quality-by-Design (QbD), the inline determination of process parameters or quality attributes of a product using sufficient process analytical technology (PAT) is a center piece for the establishment of continuous processes as a standard pharmaceutical technology. In this context, Twin-Screw-Extrusion (TSE) processes, such as Hot-Melt-Extrusion (HME), are one key aspect of current research. The main benefit of this process technology is the combination of different unit operations. Several of these sub-processes are linked to the Residence Time Distribution (RTD) of the material within the apparatus. In this study a UV/Vis spectrophotometer from ColVisTec was tested regarding the suitability for the inline determination of the RTD of an HME process. Two different measuring positions within a co-rotating Twin-Screw-Extruder were compared to an offline HPLC–UV as reference method. The obtained results were overall in good agreement and therefore the inline UV/Vis spectrophotometer is suitable for the determination of the RTD in TSE. An influence of the measuring position on repeatability was found and has to be taken into consideration for the implementation of PATs. An effect of the required amount of marker on process rheology is not likely due to the low Limit-of-Quantification (LoQ). © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
    view abstract10.3390/pharmaceutics10020049
  • Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion
    Wesholowski, J. and Prill, S. and Berghaus, A. and Thommes, M.
    Drug Delivery and Translational Research 8 (2018)
    Hot-melt extrusion on co-rotating twin screw extruders is a focused technology for the production of pharmaceuticals in the context of Quality by Design. Since it is a continuous process, the potential for minimizing product quality fluctuation is enhanced. A typical application of hot-melt extrusion is the production of solid dispersions, where an active pharmaceutical ingredient (API) is distributed within a polymer matrix carrier. For this dosage form, the product quality is related amongst others to the drug content. This can be monitored on- or inline as critical quality attribute by a process analytical technology (PAT) in order to meet the specific requirements of Quality by Design. In this study, an inline UV/Vis spectrometer from ColVisTec was implemented in an early development twin screw extruder and the performance tested in accordance to the ICH Q2 guideline. Therefore, two API (carbamazepine and theophylline) and one polymer matrix (copovidone) were considered with the main focus on the quantification of the drug load. The obtained results revealed the suitability of the implemented PAT tool to quantify the drug load in a typical range for pharmaceutical applications. The effort for data evaluation was minimal due to univariate data analysis, and in combination with a measurement frequency of 1 Hz, the system is sufficient for real-time data acquisition. © 2018, Controlled Release Society.
    view abstract10.1007/s13346-017-0465-5
  • Investigations concerning the residence time distribution of twin-screw-extrusion processes as indicator for inherent mixing
    Wesholowski, J. and Berghaus, A. and Thommes, M.
    Pharmaceutics 10 (2018)
    Over recent years Twin-Screw-Extrusion (TSE) has been established as a platform technology for pharmaceutical manufacturing. Compared to other continuous operation, one of the major benefits of this method is the combination of several unit operations within one apparatus. Several of these are linked to the Residence Time Distribution (RTD), which is typically expressed by the residence time density function. One relevant aspect for pharmaceutical processes is the mixing capacity, which is represented by the width of this distribution. In the frame of this study the influence of the mass flow, the temperature and the screw-barrel clearance were investigated for a constant barrel load (specific feed load, SFL). While the total mass flow as well as the external screw diameter affected the mixing performance, the barrel temperature had no influence for the investigated range. The determined results were additionally evaluated with respect to a fit to the Twin-Dispersion-Model (TDM). This model is based on the superimposition of two mixing functions. The correlations between varied process parameters and the obtained characteristic model parameters proved this general physical view on extrusion. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
    view abstract10.3390/pharmaceutics10040207
  • Optimization of pellets manufacturing process using rough set theory
    Pałkowski, Ł. and Karolak, M. and Kubiak, B. and Błaszczyński, J. and Słowiński, R. and Thommes, M. and Kleinebudde, P. and Krysiński, J.
    European Journal of Pharmaceutical Sciences 124 (2018)
    Pharmaceutical pellets are spherical agglomerates manufactured in extrusion/spheronization process. The composition of the pellets, the amount of active pharmaceutical ingredient (API) and the type of used excipients have an influence on the shape and quality of dosage form. A proper quality of the pellets can also be achieved by identifying the most important technological process parameters. In this paper, a knowledge discovery method, called dominance-based rough set approach (DRSA) has been applied to evaluate critical process parameters in pellets manufacturing. For this purpose, a set of condition attributes (amount of API; type and amount of excipient used; process parameters such as screw and rotation speed, time and temperature of spheronization) and a decision attribute (quality of the pellets defined by the aspect ratio) were used to set up an information system. The DRSA analysis allowed to induce decision rules containing information about process parameters which have a significant impact on the quality of manufactured pellets. Those rules can be used to optimize the process of pellets manufacturing. © 2018 Elsevier B.V.
    view abstract10.1016/j.ejps.2018.08.027
  • Preparation and characterization of spray-dried submicron particles for pharmaceutical application
    Strob, R. and Dobrowolski, A. and Pieloth, D. and Schaldach, G. and Wiggers, H. and Walzel, P. and Thommes, M.
    Advanced Powder Technology 29 (2018)
    The versatile use of submicron-sized particles (0.1–1 μm) requires new manufacturing methods. One possibility for the preparation of submicron-sized particles is spray drying. However, the generation of small droplets at a high production rate and the precipitation of submicron particles are quite challenging. In order to produce a sufficient amount of fine and uniform droplets, a two-fluid nozzle with internal mixing was combined with a cyclone droplet separator. The precipitation of particles was realized with an electrostatic precipitator. Considering the difficulty of electrostatic precipitation concerning explosion risks and to make it capable using organic solvents, the spray dryer was integrated in a pressure resistant vessel. Based on previous experiments, the now presented design is compact and the electrostatic precipitator is shortened. In addition, enhanced drying conditions ensured a controlled and reproducible preparation of submicron-sized particles. Thus, high separation efficiencies were shown. Spray-drying experiments were conducted with the model substance mannitol. With the cyclone droplet separator, a fine and uniform spray with a droplet size smaller 2 μm was produced. This robust atomizing technique is capable for high concentrations. For a 10 wt% mannitol solution, particles in the submicron range d50,3 = 0.7 μm were produced. © 2018 The Society of Powder Technology Japan
    view abstract10.1016/j.apt.2018.09.016
  • Preparation of spray dried submicron particles: Part A – Particle generation by aerosol conditioning
    Strob, R. and Dobrowolski, A. and Schaldach, G. and Walzel, P. and Thommes, M.
    International Journal of Pharmaceutics 548 (2018)
    The preparation of submicron-sized particles is relevant in chemical, food and pharmaceutical applications. In pharmaceutics, spray dried submicron-sized particles (0.1–1 µm) can increase the dissolution rate as well as the solubility of poorly water-soluble drugs. Since the particle size during spray drying is mainly influenced by the droplet size, the preparation of uniform droplets smaller than 3 µm is of particular interest. In this work, a two-fluid nozzle was combined with a cyclone droplet separator. Droplets larger than the cut-off size were separated with a cyclone droplet separator and returned to the liquid feed. The aerosol at the outlet of the droplet separator was subsequently dried. The drop size of the conditioned aerosol was small, d50,3=2 µm, and independent of the liquid-to-gas mass flow ratio and the viscosity of the liquid feed. Thus it only depended on the characteristics of the separator. Finally, the dried particles were spherical in shape and in the submicron-sized range. © 2018 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2018.06.067
  • Preparation of spray dried submicron particles: Part B – Particle recovery by electrostatic precipitation
    Dobrowolski, A. and Strob, R. and Nietfeld, J. and Pieloth, D. and Wiggers, H. and Thommes, M.
    International Journal of Pharmaceutics 548 (2018)
    The low bioavailability of poorly water-soluble drugs is currently one of the major focuses of pharmaceutical research. One strategy currently being investigated to overcome this limitation is to decrease the particle size of the active pharmaceutical ingredients (API). An innovative process for this is spray drying with spray conditioning, which can produce submicron particles. One challenge resulting from this process is the recovery of these dispersed particles from a gas flow. Electrostatic precipitation is a common technique for air purification purposes, but an adapted electrostatic precipitator (ESP) design is necessary to achieve high collection efficiencies. The ESP design in this work uses the precipitation method of Penney filters which separates charging and collection into two stages. The ESP dimensions depend on various assumptions and simplifications. Several experiments were conducted to assess the performance of the ESP and characterize its behaviour in long-term tests. The crucial parameters in the charging process are the residence time as well as the operating voltage. These constraints were examined to enhance the collection efficiency. Based on these tests it was possible to determine a suitable charging length as well as the dimensions of the collection stage. In conclusion, an ESP customized for collecting particles in the range of 0.1–1 µm was designed, built and tested, and collection efficiencies higher than 99% were achieved for submicron particle size distributions. For a robust process continuous cleaning of the charging stage is necessary. © 2018 Elsevier B.V.
    view abstract10.1016/j.ijpharm.2018.06.069
  • Corrigendum to: Partikelkinematik in der Sphäronisation pharmazeutischer Pellets (Chemie Ingenieur Technik, (2017), 89, 9, (1107), 10.1002/cite.201770905)
    Weis, D. and Niesing, M. and Thommes, M. and Antonyuk, S.
    Chemie-Ingenieur-Technik 89 (2017)
    view abstract10.1002/cite.201770905
  • Effect of the particle shape on the particle dynamics in a spheronization process
    Weis, D. and Niesing, M. and Thommes, M. and Antonyuk, S.
    EPJ Web of Conferences 140 (2017)
    Spherical granules with a narrow size distribution are widely used in many pharmaceutical applications. Extrusion-spheronization is a well-established process to produce such pharmaceutical pellets. The cylindrical extrudates from the extrusion step are rounded in the spheronizer. The formation mechanisms inside of a spheronizer depend strongly on the particle dynamics. To describe the complex particle flow and interactions, the Discrete Element Method can be used. In our previous works the spherical particles during the last part of the spheronization process were studied. Since the pellets have a cylindrical shape at the beginning and undergo different stages of deformation during the rounding process, the objective of this study was the description of the influence of the particle shape on the particle dynamics. To predict the interactions of the pellets, their dominant plastic behaviour was described with an appropriate contact model and the material parameters were calibrated with compression and impact tests. © The Authors, published by EDP Sciences, 2017.
    view abstract10.1051/epjconf/201714015005
  • Particle Kinematics in Spheronization of Pharmaceutical Pellets
    Weis, D. and Niesing, M. and Thommes, M. and Antonyuk, S.
    Chemie-Ingenieur-Technik 89 (2017)
    For the production of pharmaceutical pellets, a combined extrusion and spheronization process is widely used, where the particle kinematics strongly influences the rounding in the spheronizer. In this study, the particle kinematics of the actual pharmaceutical pellets was analyzed. For this purpose, material parameters, such as coefficient of restitution and rigidity while loading and unloading, were determined by pressure and impact tests. Based on these parameters, a contact model for the simulation of the particle movement was developed. The simulation results were validated with experimental investigations. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
    view abstract10.1002/cite.201600154
  • Preparation and physicochemical characterization of matrix pellets containing APIs with different solubility via extrusion process
    Hegyesi, D. and Thommes, M. and Kleinebudde, P. and Sovány, T. and Kása, P., Jr. and Kelemen, A. and Pintye-Hódi, K. and Regdon, G., Jr.
    Drug Development and Industrial Pharmacy 43 (2017)
    In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process. © 2016 Informa UK Limited, trading as Taylor & Francis Group.
    view abstract10.1080/03639045.2016.1261150
  • Granule size distributions after twin-screw granulation – Do not forget the feeding systems
    Meier, R. and Thommes, M. and Rasenack, N. and Moll, K.-P. and Krumme, M. and Kleinebudde, P.
    European Journal of Pharmaceutics and Biopharmaceutics 106 (2016)
    The aim of this study was to investigate the influence of qualitatively different powder feeder performances on resulting granule size distributions after twin-screw granulation of a highly drug loaded, hydrophobic mixture and a mannitol powder. It was shown that powder feeder related problems usually cannot be identified by trusting in the values given by the feeder. Therefore, a newly developed model for the evaluation of the performance of powder feeders was introduced and it was tried to connect this model to residence time distributions in twin-screw granulation processes. The influence of feeder performances on resulting granule size distributions varied, depending on the applied screw configuration and the used powder. Regarding the hydrophobic and highly drug loaded formulation, which was granulated at an L/S-ratio of 0.5, a pure conveying screw and a medium kneading configuration, consisting of 60° kneading blocks were negatively influenced by poor feeder settings. For optimal settings more narrow distributions could be obtained. For an extensive kneading configuration good and poor settings resulted in mono-modal granule size distributions but were differing in the overall size. Mannitol, a model substance for a liquid sensitive formulation was granulated at an L/S-ratio of 0.075. It was even more important to maintain optimal feeding as mannitol was highly affected by poor feeder performances. Even an extensive kneading configuration could not level the errors in powder feeder performance, resulting in qualitatively different granule size distributions. The results of this study demonstrate the importance of detailed knowledge about applied feeding systems to gain optimal performance in twin-screw granulation. © 2016 Elsevier B.V.
    view abstract10.1016/j.ejpb.2016.05.011
  • Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen
    Laukamp, E.J. and Knop, K. and Thommes, M. and Breitkreutz, J.
    International Journal of Pharmaceutics 499 (2016)
    Individual dosing of medicines is relevant for paediatrics, geriatrics and personalised medicine. The Solid Dosage Pen (SDP) allows for individual dosing by cutting monolithic, tablet-like drug carriers of pre-defined heights. The aim of the present study was to develop micropellet-loaded rods (MPLRs) with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen. Therefore, micropellets were successfully layered with carbamazepine and coated with polyvinyl acetate (PVAc) and PVAc/polyvinyl alcohol-polyethylene glycol (PVA-PEG). The tensile strength of the sustained release micropellets (300-450 μm) was more than two times higher (12.6-17.1 MPa) than pressures occurring during ram-extrusion of the MPLRs (below 5.8 MPa). Due to relative crystallinities above 93% for PVAc and PVA-PEG a low solubility of the coating films within the PEG-matrix was observed. The sustained release micropellets were successfully incorporated into MPLRs. Drug release properties of the pellets maintained after embedding into the matrix. Hence, the MPLRs provided dose-independent prolonged drug liberation which was not achieved for drug-loaded rods before. The MPLRs permitted the application of the SDP with a precise drug delivery from individually cut single doses. Storage stability was proven for MPLRs containing PVAc/PVA-PEG coated pellets. In conclusion, the MPLRs combined the advantages of multiparticulate dosage forms with the SDP as a device for individual dosing. © 2016 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ijpharm.2016.01.001
  • Untersuchung des Durchmischungsverhaltens im Sphäroniser mittels DEM-Simulationen
    Weis, D. and Thommes, M. and Antonyuk, S.
    Chemie-Ingenieur-Technik 88 (2016)
    view abstract10.1002/cite.201650323
  • A data mining approach to optimize pellets manufacturing process based on a decision tree algorithm
    Ronowicz, J. and Thommes, M. and Kleinebudde, P. and Krysiński, J.
    European Journal of Pharmaceutical Sciences 73 (2015)
    The present study is focused on the thorough analysis of cause-effect relationships between pellet formulation characteristics (pellet composition as well as process parameters) and the selected quality attribute of the final product. The shape using the aspect ratio value expressed the quality of pellets. A data matrix for chemometric analysis consisted of 224 pellet formulations performed by means of eight different active pharmaceutical ingredients and several various excipients, using different extrusion/spheronization process conditions. The data set contained 14 input variables (both formulation and process variables) and one output variable (pellet aspect ratio). A tree regression algorithm consistent with the Quality by Design concept was applied to obtain deeper understanding and knowledge of formulation and process parameters affecting the final pellet sphericity. The clear interpretable set of decision rules were generated. The spehronization speed, spheronization time, number of holes and water content of extrudate have been recognized as the key factors influencing pellet aspect ratio. The most spherical pellets were achieved by using a large number of holes during extrusion, a high spheronizer speed and longer time of spheronization. The described data mining approach enhances knowledge about pelletization process and simultaneously facilitates searching for the optimal process conditions which are necessary to achieve ideal spherical pellets, resulting in good flow characteristics. This data mining approach can be taken into consideration by industrial formulation scientists to support rational decision making in the field of pellets technology. © 2015 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejps.2015.03.013
  • Development of sustained and dual drug release co-extrusion formulations for individual dosing
    Laukamp, E.J. and Vynckier, A.-K. and Voorspoels, J. and Thommes, M. and Breitkreutz, J.
    European Journal of Pharmaceutics and Biopharmaceutics 89 (2015)
    In personalized medicine and patient-centered medical treatment individual dosing of medicines is crucial. The Solid Dosage Pen (SDP) allows for an individual dosing of solid drug carriers by cutting them into tablet-like slices. The aim of the present study was the development of sustained release and dual release formulations with carbamazepine (CBZ) via hot-melt co-extrusion for the use in the SDP. The selection of appropriate coat- and core-formulations was performed by adapting the mechanical properties (like tensile strength and E-modulus) for example. By using different excipients (polyethylene glycols, poloxamers, white wax, stearic acid, and carnauba wax) and drug loadings (30-50%) tailored dissolution kinetics was achieved showing cube root or zero order release mechanisms. Besides a biphasic drug release, the dose-dependent dissolution characteristics of sustained release formulations were minimized by a co-extruded wax-coated formulation. The dissolution profiles of the co-extrudates were confirmed during short term stability study (six months at 21.0 ± 0.2 °C, 45% r.h.). Due to a good layer adhesion of core and coat and adequate mechanical properties (maximum cutting force of 35.8 ± 2.0 N and 26.4 ± 2.8 N and E-modulus of 118.1 ± 8.4 and 33.9 ± 4.5 MPa for the dual drug release and the wax-coated co-extrudates, respectively) cutting off doses via the SDP was precise. While differences of the process parameters (like the barrel temperature) between the core- and the coat-layer resulted in unsatisfying content uniformities for the wax-coated co-extrudates, the content uniformity of the dual drug release co-extrudates was found to be in compliance with pharmacopoeial specification. © 2015 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2014.12.027
  • Encapsulation of liquids using a counter rotating twin screw extruder
    Tackenberg, M.W. and Krauss, R. and Marmann, A. and Thommes, M. and Schuchmann, H.P. and Kleinebudde, P.
    European Journal of Pharmaceutics and Biopharmaceutics 89 (2015)
    Until now extrusion is not applied for pharmaceutical encapsulation processes, whereas extrusion is widely used for encapsulation of flavours within food applications. Based on previous mixing studies, a hot melt counter-rotating extrusion process for encapsulation of liquid active pharmaceutical ingredients (APIs) was investigated. The mixing ratio of maltodextrin to sucrose as matrix material was adapted in first extrusion trials. Then the number of die holes was investigated to decrease expansion and agglutination of extrudates to a minimum. At a screw speed of 180 min-1 the product temperature was decreased below 142°C, resulting in extrudates of cylindrical shape with a crystalline content of 9-16%. Volatile orange terpenes and the nonvolatile α-tocopherol were chosen as model APIs. Design of experiments were performed to investigate the influences of barrel temperature, powder feed rate, and API content on the API retentions. A maximum of 9.2% α-tocopherol was encapsulated, while the orange terpene encapsulation rate decreased to 6.0% due to evaporation after leaving the die. During 12 weeks of storage re-crystallization of sucrose occurred; however, the encapsulated orange terpene amount remained unchanged. © 2014 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2014.11.017
  • Mechanistic study of carvacrol processing and stabilization as glassy solid solution and microcapsule
    Tackenberg, M.W. and Geisthövel, C. and Marmann, A. and Schuchmann, H.P. and Kleinebudde, P. and Thommes, M.
    International Journal of Pharmaceutics 478 (2015)
    Essential oils and other liquid active pharmaceutical ingredients (APIs) are frequently microencapsulated to improve shelf life, handling, and for tailoring release. A glassy solid solution (GSS), a single-phase system, where the excipient is plasticized by the API, could be an alternative formulation system. Thus this study focuses on the investigation of two formulation strategies using carvacrol as a model compound, namely a microcapsule (MC) and a glassy solid solution (GSS). Applying the solubility parameter approach, polyvinylpyrrolidone (PVP) was chosen as a suitable matrix material for a GSS system, whereas maltodextrin and sucrose served as excipients for a microcapsule (MC) system. Differential scanning calorimetry (DSC) measurements of the excipients' glass transition temperatures and the melting point of carvacrol verified plasticizing properties of carvacrol on PVP. Batch mixing processes, as preliminary experiments for future extrusion processes, were performed to prepare GSSs and MCs with various amounts of carvacrol, followed by crushing and sieving. Maximally 4.5% carvacrol was encapsulated in the carbohydrate material, whereas up to 16.3% were stabilized as GSS, which is an outstanding amount. However, grinding of the samples led to a loss of up to 30% of carvacrol. © 2014 Published by Elsevier B.V.
    view abstract10.1016/j.ijpharm.2014.12.012
  • Orientation to determine quality attributes of flavoring excipients containing volatile molecules
    Kiene, F.E. and Pein, M. and Thommes, M.
    Journal of Pharmaceutical and Biomedical Analysis 110 (2015)
    Pharmaceutical excipients containing volatile odor-active molecules can be used in pharmaceutical development to increase patients' compliance. However, capturing the molecular composition of these odor-active substances is challenging. Therefore, guidance for the analytical investigation of these excipients should be developed. Using a model flavor, lead molecules were chosen and a gas chromatographic method was validated according to pharmaceutical guidelines. Changes during storage as well as batch homogeneity and conformity were investigated. The knowledge gained could be used to understand molecular differences between batches caused by aging. A suitable attempt to capture the volatile molecular composition of flavoring substance was presented and the found results could be used for the determination and interpretation of quality attributes. © 2015 Elsevier B.V.
    view abstract10.1016/j.jpba.2015.01.033
  • Simplified formulations with high drug loads for continuous twin-screw granulation
    Meier, R. and Thommes, M. and Rasenack, N. and Krumme, M. and Moll, K.-P. and Kleinebudde, P.
    International Journal of Pharmaceutics 496 (2015)
    As different batches of the same excipients will be intermixed during continuous processes, the traceability of batches is complicated. Simplified formulations may help to reduce problems related to batch intermixing and traceability. Twin-screw granulation with subsequent tableting was used to produce granules and tablets, containing drug, disintegrant and binder (binary and ternary mixtures), only. Drug loads up to 90% were achieved and five different disintegrants were screened for keeping their disintegration suitability after wetting. Granule size distributions were consistently mono-modal and narrow. Granule strength reached higher values, using ternary mixtures. Tablets containing croscarmellose-Na as disintegrant displayed tensile strengths up to 3.1 MPa and disintegration times from 400 to 466 s, resulting in the most robust disintegrant. Dissolution was overall complete and above 96% within 30 min. Na-starch glycolate offers tensile strengths up to 2.8 MPa at disintegration times from 25 s to 1031 s, providing the broadest application window, as it corresponds in some parts to different definitions of orodispersible tablets. Tablets containing micronized crospovidone are not suitable for immediate release, but showed possibilities to produce highly drug loaded, prolonged release tablets. Tablets and granules from simplified formulations offer great opportunities to improve continuous processes, present performances comparable to more complicated formulations and are able to correspond to requirements of the authorities. © 2015 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ijpharm.2015.05.060
  • Spheronization of solid lipid extrudates: A novel approach on controlling critical process parameters
    Petrovick, G.F. and Pein, M. and Thommes, M. and Breitkreutz, J.
    European Journal of Pharmaceutics and Biopharmaceutics 92 (2015)
    Solid lipids are non-toxic excipients, which are known to potentially enhance delivery and bioavailability of poorly water-soluble drugs and moreover to mask unpleasant tasting drugs. Multiple unit matrix dosage forms based on solid lipids, such as lipid pellets, can be obtained by solvent-free cold extrusion and spheronization. This method presents advantages in the processing of sensitive substances, such as low process temperatures, the absence of solvents and a drying step. However, the material temperature during the spheronization showed to be critical so far. The process leads to increased material temperatures, causing particle agglomeration and discontinuity of the spheronization. In the present study, extrudates of 0.5 mm in diameter containing metformin hydrochloride, and either semisynthetic hard fat (Witocan® 42/44) or different ternary mixtures based on hard fat, glyceryl trimyristate, and glyceryl distearate, were spheronized. By applying common process parameters, particle agglomeration or material stickiness on equipment walls was observed in preliminary experiments after 2-6 min, depending on the lipid composition. Therefore, an innovative instrumental setup to control the spheronization process was developed utilizing an infrared light source, which was positioned over the particle bed. The new approach enabled a spheronization process that reached the desired spheronization temperature after 2-3 min and neither particle agglomeration nor material adherence occurred even after longer process times. The different formulations, even those based on high amount of solid lipids, were successfully spheronized over 15 min, resulting in small diameter lipid pellets with smooth surface and aspect ratios below 1.3. © 2015 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2015.02.004
  • Hot-melt extruded drug-loaded rods: Evaluation of the mechanical properties for individual dosing via the Solid Dosage Pen
    Laukamp, E.J. and Thommes, M. and Breitkreutz, J.
    International Journal of Pharmaceutics 475 (2014)
    Individual dosing of peroral medicines is important for personalised medicine and patient-centred treatment, e.g., of children and the elderly. The Solid Dosage Pen (SDP) offers the opportunity to dose individually by cutting drug-loaded rods into tablet-like slices. The aim of the present study is the systematic evaluation of the mechanical properties of these drug-loaded rods prepared via hot-melt extrusion. The drug-loaded rods contain carbamazepine as a model drug, and polyethylene glycols and poloxamers as excipients. For the evaluation of the mechanical properties of the extrudates, three parameters were considered: tensile strength, E-modulus, and maximum cutting force. To examine the practicability of the device and the formulations for patient-centred treatment, the needed cutting forces were compared to literature data of the manual forces of different age groups. The maximum cutting force and the tensile strength were marginally changed over a storage period of six months (21 ± 0.2 °C, 45% r.H). A tensile strength below 9.1 ± 0.3 MPa and an E-modulus below 135.9 ± 7.2 MPa were found to be valuable thresholds for the applicability by the Solid Dosage Pen. Formulations containing PEG 1500 as additive fulfilled the pharmacopeial requirements containing the content uniformity even for the smallest dose. © 2014 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ijpharm.2014.09.001
  • Influence of storage condition on properties of MCC II-based pellets with theophylline-monohydrate
    Krueger, C. and Thommes, M. and Kleinebudde, P.
    European Journal of Pharmaceutics and Biopharmaceutics 88 (2014)
    Microcrystalline cellulose II (MCC II1) is a polymorph of commonly used MCC I; in 2010 it was introduced as new pelletization aid in wet-extrusion/spheronization leading to fast disintegrating pellets. Previous investigations suggested that the storage of the resulting pellets affect the disintegration behavior, the non-hygroscopic substance chloramphenicol that showed no polymorphism or hydrate formation due to relative humidity was used for the investigations. Therefore, theophylline-monohydrate that can dehydrate during storage, but also during manufacturing and drying was used for this study to confirm the results of the previous study and give a more detailed overview of the influence of recrystallization of theophylline monohydrate on disintegration. Storage recommendations should be derived. MCC II-based pellets were prepared of binary mixtures containing 10%, 20% or 50% MCC II as pelletization aid and theophylline-monohydrate as API. These pellets were stored at different relative humidity (0-97%rH; 20 °C); the influence on their disintegration and drug release was investigated. The storage conditions had an impact on pellet disintegration. Low relative humidities (≤40%rH) led to a conversion of the monohydrate to the anhydrous form. Newly grown crystals formed a kind of network around the pellet and inhibited the disintegration. High relative humidity (>80%rh) affected the disintegration caused by changes in the MCC II as already seen in the previous study. Due to the changed disintegration behavior also the drug release and release kinetic changed. Therefore, for theophylline containing pellets a storage humidity of 55%rH to 80%rH (20 °C) is recommended. All in all, these investigations substantiate the knowledge of MCC II-based pellets providing a better basis for adequate storage conditions of MCC II based pellets. © 2014 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2014.06.006
  • Investigation into mixing capability and solid dispersion preparation using the DSM Xplore Pharma Micro Extruder
    Sakai, T. and Thommes, M.
    Journal of Pharmacy and Pharmacology 66 (2014)
    Objectives The goal of this investigation was to qualify the DSM Xplore Pharma Micro Extruder as a formulation screening tool for early-stage hot-melt extrusion. Methods Dispersive and distributive mixing was investigated using soluplus, copovidone or basic butylated methacrylate copolymer with sodium chloride (NaCl) in a batch size of 5 g. Eleven types of solid dispersions were prepared using various drugs and carriers in batches of 5 g in accordance with the literature. Key findings The dispersive mixing was a function of screw speed and recirculation time and the particle size was remarkably reduced after 1 min of processing, regardless of the polymers. An inverse relationship between the particle size and specific mechanical energy (SME) was also found. The SME values were higher than those in large-scale extruders. After 1 min recirculation at 200 rpm, the uniformity of NaCl content met the criteria of the European Pharmacopoeia, indicating that distributive mixing was achieved in this time. For the solid dispersions preparations, the results from different scanning calorimetry, powder X-ray diffractometry and in-vitro dissolution tests confirmed that all solid-dispersion systems were successfully prepared. Conclusions These findings demonstrated that the extruder is a useful tool to screen solid-dispersion formulations and their material properties on a small scale. © 2013 Royal Pharmaceutical Society.
    view abstract10.1111/jphp.12085
  • Orange terpenes, carvacrol and α-tocopherol encapsulated in maltodextrin and sucrose matrices via batch mixing
    Tackenberg, M.W. and Marmann, A. and Thommes, M. and Schuchmann, H.P. and Kleinebudde, P.
    Journal of Food Engineering 135 (2014)
    Orange terpenes, carvacrol and tocopherol were used as model substances for flavours, essential oils and lipophilic liquid (bio)-active ingredients (AI). They were encapsulated via a batch mixing process in various carbohydrate matrices containing maltodextrin and sucrose. Plasticizing properties of the AIs, independently from their concentration (4.5-8.8%), on the matrices were not obtained. Furthermore the AIs did not affect the solid state properties, especially the crystalline content, of the carbohydrate matrix. An AI retention between 6% and 100% correlated inversely with the vapour pressure of the pure AI. At a mixing time of 5 min a vapour pressure of higher than 70 kPa led to a almost completely loss of the AI. The AI retention and the solid state of the matrices were not affected by applying different cooling conditions. These results can be used to adjust the parameters of an extrusion process to receive high AI retention. © 2014 Elsevier Ltd. All rights reserved.
    view abstract10.1016/j.jfoodeng.2014.03.010
  • Ostwald-Freundlich diffusion-limited dissolution kinetics of nanoparticles
    Ely, D.R. and Edwin García, R. and Thommes, M.
    Powder Technology 257 (2014)
    For many years, nanoparticles have garnered increasing interest in pharmaceutical investigations. It is well known that the solubility of nanoparticles increases with decreasing size due to the Gibbs-Thomson effect. However, there are currently no analytical models to describe the kinetics of nanoparticle dissolution. The purpose of this article is to provide a Thermodynamics-based description of the kinetics of nanoparticle dissolution. In particular, the Ostwald-Freundlich relation is used to correct dissolution times for small particles, which have higher solubilities than larger particles. The developed model is an extension of the Hixson-Crowell cube root law in which the total normalized dissolution time is corrected by a "solubility size factor" that approaches unity for increasing initial particle size. This model enables rapid estimation of the total dissolution time of spherical nanoparticles in a gently agitated, zero solute concentration reservoir. The total dissolution time predicted differs from Hixson-Crowell by nearly 10% for initial particle sizes fifty times larger than the characteristic particle size, and increases to more than a factor of six at the characteristic particle size. This work provides a physics-based description of the nanoparticle dissolution kinetics and details the reaches and limitations of the developed model. The theoretical framework provided herein is valid for a wide range of dissolution processes and size scales affording it a high level of practicality. © 2014 Elsevier B.V.
    view abstract10.1016/j.powtec.2014.01.095
  • Small-scale twin-screw extrusion - evaluation of continuous split feeding
    Muehlenfeld, C. and Thommes, M.
    The Journal of pharmacy and pharmacology 66 (2014)
    OBJECTIVES: The aim of this work was to evaluate a continuous, small-scale extrusion process with a particular focus on powder and liquid-feeding systems, because it is likely that uniformity issues are related to small-scale production. METHODS: The study is divided into three parts. The first part investigates the uniformity and accuracy of the powder and the liquid feeders. In the second part, a solid polymer and low amounts of liquid plasticizer were combined in hot-melt extrusion. The third part deals with wet extrusion-spheronization using water as the granulation liquid. KEY FINDINGS: The powder and the liquid feed rate were identified as crucial parameters in small-scale extrusion. With respect to powder feeding, the cohesiveness of the powder and electrostatic charging are the limitations, while liquid feeding is challenging based on particularly low feed rates. The hot-melt extrusion was performed using a powder feed rate of 2 g/min. When small quantities of plasticizer were applied to the hot melt extrusions (from 2.5% to 15% w/w), homogenous plasticizer distribution was found. In wet extrusion, larger quantities of water were used and the extrudates were investigated with respect to their spheronization behaviour. Spherical pellets were obtained at certain water contents. CONCLUSIONS: These findings demonstrated that the extruder is a useful tool to screen formulations and perform feasibility studies on a small scale in the early stages of product development. © 2014 Royal Pharmaceutical Society.
    view abstract10.1111/jphp.12301
  • Solid state of processed carbohydrate matrices from maltodextrin and sucrose
    Tackenberg, M.W. and Thommes, M. and Schuchmann, H.P. and Kleinebudde, P.
    Journal of Food Engineering 129 (2014)
    Various mixtures of maltodextrin, sucrose, and water, as typical compounds of food matrices used for flavour encapsulation via extrusion, were processed in a batch mixing process. Plasticization, melting and caramelization just as the formation of amorphous sucrose were studied. All matrices were plasticized within 2 min, resulting in a loss of crystalline sucrose. Melting occurred due to water loss higher than 55%. Caramelization could be correlated to a specific mechanical energy input higher than 300 Wh/kg. The glass transition temperature of the caramelized matrices could not be fitted with the Gordon Taylor equation, based on the used compounds. Increasing sucrose content in the preblended powder mixture combined with increasing sample water content increased the crystalline fraction within the matrix. These findings enable a systematically investigation of matrices for encapsulation of flavours within the batch mixing process, which can help to transfer the flavour encapsulation to an extrusion process. © 2014 Elsevier Ltd. All rights reserved.
    view abstract10.1016/j.jfoodeng.2014.01.003
  • Spheronization process particle kinematics determined by discrete element simulations and particle image velocimentry measurements
    Koester, M. and García, R.E. and Thommes, M.
    International Journal of Pharmaceutics 477 (2014)
    Spheronization is an important pharmaceutical manufacturing technique to produce spherical agglomerates of 0.5-2 mm diameter. These pellets have a narrow size distribution and a spherical shape. During the spheronization process, the extruded cylindrical strands break in short cylinders and evolve from a cylindrical to a spherical state by deformation and attrition/agglomeration mechanisms. Using the discrete element method, an integrated modeling-experimental framework is presented, that captures the particle motion during the spheronization process. Simulations were directly compared and validated against particle image velocimetry (PIV) experiments with monodisperse spherical and dry γ-Al2O3 particles. Result demonstrate a characteristic torus like flow pattern, with particle velocities about three times slower than the rotation speed of the friction plate. Five characteristic zones controlling the spheronization process are identified: Zone I, where particles undergo shear forces that favors attrition and contributes material to the agglomeration process; Zone II, where the static wall contributes to the mass exchange between particles; Zone III, where gravitational forces combined with particle motion induce particles to collide with the moving plate and re-enter Zone I; Zone IV, where a subpopulation of particles are ejected into the air when in contact with the friction plate structure; and Zone V where the low poloidal velocity favors a stagnant particle population and is entirely controlled by the batch size. These new insights in to the particle motion are leading to deeper process understanding, e.g., the effect of load and rotation speed to the pellet formation kinetics. This could be beneficial for the optimization of a manufacturing process as well as for the development of new formulations. © 2014 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ijpharm.2014.10.007
  • Analysis of particle kinematics in spheronization via particle image velocimetry
    Koester, M. and Thommes, M.
    European Journal of Pharmaceutics and Biopharmaceutics 83 (2013)
    Spheronization is a wide spread technique in pellet production for many pharmaceutical applications. Pellets produced by spheronization are characterized by a particularly spherical shape and narrow size distribution. The particle kinematic during spheronization is currently not well-understood. Therefore, particle image velocimetry (PIV) was implemented in the spheronization process to visualize the particle movement and to identify flow patterns, in order to explain the influence of various process parameters. The spheronization process of a common formulation was recorded with a high-speed camera, and the images were processed using particle image velocimetry software. A crosscorrelation approach was chosen to determine the particle velocity at the surface of the pellet bulk. Formulation and process parameters were varied systematically, and their influence on the particle velocity was investigated. The particle stream shows a torus-like shape with a twisted rope-like motion. It is remarkable that the overall particle velocity is approximately 10-fold lower than the tip speed of the friction plate. The velocity of the particle stream can be correlated to the water content of the pellets and the load of the spheronizer, while the rotation speed was not relevant. In conclusion, PIV was successfully applied to the spheronization process, and new insights into the particle velocity were obtained. © 2012 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2012.08.013
  • Design of biorelevant test setups for the prediction of diclofenac in vivo features after oral administration
    Guhmann, M. and Thommes, M. and Gerber, F. and Pöllinger, N. and Klein, S. and Breitkreutz, J. and Weitschies, W.
    Pharmaceutical Research 30 (2013)
    Purpose: Design of biorelevant test setups mimicking the physiological conditions experienced by drugs after oral administration along the passage through the mouth and the GI tract for the in vitro evaluation of diclofenac exhibiting multiple-peak phenomenon during absorption. Methods: The biorelevant models simulated successively saliva (SSF, pH 6.2-6.75-7.4, 5 mL, 3 min), gastric (SGF-FaSSGF, pH 1.2-1.6, 50-250 mL, 30 min) and intestinal (FaSSIF, pH 6.8, 250 mL, 60 min) fluids. Applying these models, diclofenac free acid and its sodium/potassium salt were comparatively evaluated for dissolution and further characterized by HPLC, optical morphogranulometry, DSC and PXRD to elucidate peculiar behaviors. Results: Diclofenac salts almost completely dissolved in SSF and showed a transitional dissolution pattern before complete precipitation in SGF/FaSSGF. This peculiar pattern correlated with simultaneous chemical modification and formation of agglomerates. With low dissolution in SSF and almost immediately complete precipitation, these behaviors were not observed with diclofenac free acid. Distinct diclofenac features were strongly determined by pH-modifications after oral administration. Conclusions: The multiple-peak phenomenon observed after administrating a solution, suspension or dispersible formulation of diclofenac salts are likely caused by drug precipitation and agglomeration in the stomach leading to irregular gastric-emptying. Diclofenac free acid may provide more reliable in vivo features. © 2013 Springer Science+Business Media New York.
    view abstract10.1007/s11095-013-0974-y
  • Improved group contribution parameter set for the application of solubility parameters to melt extrusion
    Just, S. and Sievert, F. and Thommes, M. and Breitkreutz, J.
    European Journal of Pharmaceutics and Biopharmaceutics 85 (2013)
    Hot-melt extrusion is gaining importance for the production of amorphous solid solutions; in parallel, predictive tools for estimating drug solubility in polymers are increasingly demanded. The Hansen solubility parameter (SP) approach is well acknowledged for its predictive power of the miscibility of liquids as well as the solubility of some amorphous solids in liquid solvents. By solely using the molecular structure, group contribution (GC) methods allow the calculation of Hansen SPs. The GC parameter sets available were derived from liquids and polymers which conflicts with the object of prediction, the solubility of solid drugs. The present study takes a step from the liquid based SPs toward their application to solid solutes. On the basis of published experimental Hansen SPs of solid drugs and excipients only, a new GC parameter set was developed. In comparison with established parameter sets by van Krevelen/Hoftyzer, Beerbower/Hansen, Breitkreutz and Stefanis/Panayiotou, the new GC parameter set provides the highest overall predictive power for solubility experiments (correlation coefficient r = -0.87 to -0.91) as well as for literature data on melt extrudates and casted films (r = -0.78 to -0.96). © 2013 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2013.04.006
  • Influence of MCC II fraction and storage conditions on pellet properties
    Krueger, C. and Thommes, M. and Kleinebudde, P.
    European Journal of Pharmaceutics and Biopharmaceutics 85 (2013)
    Microcrystalline cellulose II (MCC II) - a polymorph of commonly used MCC I - was introduced as new pelletization aid in wet-extrusion/spheronization leading to fast disintegrating pellets. Previous investigations suggested that pellet properties were influenced by the fraction of MCC II. Furthermore, it is unknown whether the storage conditions can affect the disintegration behavior. Therefore, the effects of MCC II fraction and the storage conditions on several pellet properties were investigated. MCC II-based pellets were prepared of pure MCC II or binary mixtures containing 10-50% (steps of 10%) MCC II as pelletization aid and theophylline, chloramphenicol or lactose. The pellets were characterized by their aspect ratio, equivalent diameter, water content, tensile strength, porosity as well as shrinking, and disintegration behavior and drug release according to their MCC II fraction. Furthermore, the pellets were stored at different relative humidities (0-97%rh), and the influence on their disintegration and drug release was investigated. With increasing MCC II fraction, the pellets became lager in size, decreased their porosity, and required higher water contents for spheronization. Moreover, the disintegration time increased and the disintegration itself was incomplete. Furthermore, the storage conditions had an impact on the disintegration properties of MCC II-based pellets. The disintegrating was affected irreversibly after storage at high humidity (80-97%rh) resulting in a slow drug release. Therefore, MCC II-based pellets need to be stored below 80%rh to secure a fast disintegration. A better knowledge of the properties of MCC II-based pellets was obtained providing a basis for a successful manufacturing and adequate storage of MCC II-based pellets prepared by extrusion/spheronization. © 2013 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2013.07.001
  • Lipid-based intravesical drug delivery systems with controlled release of trospium chloride for the urinary bladder
    Haupt, M. and Thommes, M. and Heidenreich, A. and Breitkreutz, J.
    Journal of Controlled Release 170 (2013)
    The overactive bladder (OAB) is a common disease with an overactivity of the detrusor muscle in the bladder wall. Besides peroral administration of anticholinergic drugs and bladder irrigations, there is a need for a sustained release formulation in the urinary bladder. In order to realise a local long-term treatment of the overactive urinary bladder, lipidic drug delivery systems were prepared. Requirements for an intravesical application are a long-term controlled release of trospium chloride, a high drug loading and small sized drug carriers to permit an insertion through the urethra into the urinary bladder. The drug delivery systems were manufactured by using compression (mini-tablets), solid lipid extrusion (extrudates) and a melting and casting technique (mini-moulds) with different amounts of trospium chloride and glyceryl tristearate as matrix former. Drug release depended on the drug loading and the preparation method. Mini-tablets and lipidic extrudates showed a drug release over five days, whereas that from mini-moulds was negligibly small. The appearance of polymorphic transformations during processing and storage was investigated by using differential scanning calorimetry and X-ray diffraction. In contrast to mini-tablets and mini-moulds, lipidic extrudates showed no polymorphic transformations. In summary, lipids are suitable matrix formers for a highly water-soluble drug, like trospium chloride. Despite a drug loading of up to 30%, it was feasible to achieve a drug release ranging from several days up to weeks. In addition, small dosage forms with a size of only a few millimetres were realised. Therefore, an insertion and excretion through the urethra is possible and the requirements for an intravesical application are fulfilled. © 2013 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.jconrel.2013.05.018
  • Multiple batch manufacturing of theophylline pellets using the wet-extrusion/spheronization process with κ-carrageenan as pelletisation aid
    Krueger, C. and Thommes, M.
    Pharmaceutical Development and Technology 18 (2013)
    κ-Carrageenan has been suggested as a pelletisation aid for wet-extrusion/spheronization processes for several years. Until now there have been no systematic investigations regarding process development and stability for long-term production. The aim of this study was to develop a high drug-loaded pellet formulation with κ-carrageenan, so that a robust process cycle occurred over the course of several hours. Binary mixtures of κ-carrageenan and theophylline monohydrate were used and the drug content was varied from 90 to 95%. A twin-screw extruder was used; the power consumption and feed rates were recorded. The pellets were characterized by aspect ratio, diameter, 10% interval, tensile strength and dissolution behavior. The process ran on two occasions for 4.5 h each time. During the extrusion process neither the power consumption nor the feed rates differed significantly, so there was no need to stop the process or change the extrusion parameters. Regarding the spheronization, a cleaning of the spheroniser friction plate was necessary every five batches due to packing of the material on this plate. Overall the resulting pellets showed reproducible and adequate qualities regarding all investigated properties. In conclusion a robust pelletisation process over several hours could be verified. It was possible to produce 42 kg of pellets with adequate properties, without any problems during the process. © 2013 Informa Healthcare USA, Inc.
    view abstract10.3109/10837450.2012.700935
  • Residence time modeling of hot melt extrusion processes
    Reitz, E. and Podhaisky, H. and Ely, D. and Thommes, M.
    European Journal of Pharmaceutics and Biopharmaceutics 85 (2013)
    The hot melt extrusion process is a widespread technique to mix viscous melts. The residence time of material in the process frequently determines the product properties. An experimental setup and a corresponding mathematical model were developed to evaluate residence time and residence time distribution in twin screw extrusion processes. The extrusion process was modeled as the convolution of a mass transport process described by a Gaussian probability function, and a mixing process represented by an exponential function. The residence time of the extrusion process was determined by introducing a tracer at the extruder inlet and measuring the tracer concentration at the die. These concentrations were fitted to the residence time model, and an adequate correlation was found. Different parameters were derived to characterize the extrusion process including the dead time, the apparent mixing volume, and a transport related axial mixing. A 23 design of experiments was performed to evaluate the effect of powder feed rate, screw speed, and melt viscosity of the material on the residence time. All three parameters affect the residence time of material in the extruder. In conclusion, a residence time model was developed to interpret experimental data and to get insights into the hot melt extrusion process. © 2013 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2013.07.019
  • Solid crystal suspensions containing griseofulvin-Preparation and bioavailability testing
    Reitz, E. and Vervaet, C. and Neubert, R.H.H. and Thommes, M.
    European Journal of Pharmaceutics and Biopharmaceutics 83 (2013)
    The improvement of the bioavailability of poorly soluble drugs has been an important issue in pharmaceutical research for many years. Despite the suggestion of several other technologies in the past, drug particle size reduction is still an appropriate strategy to guarantee high bioavailability of various drugs. A few years ago, the Solid Crystal Suspension (SCS) technology was suggested, in which crystalline drug particles are ground and dispersed in a highly soluble crystalline carrier by a hot melt extrusion process. The current study demonstrates the scale-up of the SCS technology to standard, lab-scale extrusion equipment - a change from previous investigations, which used small batch sizes. A twin-screw extruder was modified to account for the rapid crystallization of the carrier. The screw speed and the barrel temperature were identified as critical process parameters and were varied systematically in several experimental designs. Finally, parameters were identified that produced extrudates with rapid dissolution rates. After extrusion, the extrudates were milled to granules and then tableted. These tablets were investigated with respect to their bioavailability in beagle dogs. It was found that drug particle size reduction in the hot melt extrusion led to 3.5-fold higher bioavailability in these dogs than occurred with the physical mixture of the used substances. The solid crystal suspension formulation had a slightly higher bioavailability than the marked product. In conclusion, the SCS technology was successfully scaled up to lab-scale equipment, and the concept was confirmed by a bioavailability study. © 2012 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ejpb.2012.09.012
  • Solid dispersions prepared by continuous cogrinding in an air jet mill
    Muehlenfeld, C. and Kann, B. and Windbergs, M. and Thommes, M.
    Journal of Pharmaceutical Sciences 102 (2013)
    Embedding a poorly water-soluble drug as a solid dispersion in a hydrophilic carrier by cogrinding is a possible strategy for enhancing the drug dissolution rate. Although general interest in continuous processes for manufacturing drug formulations has increased, many publications still focus on batch processes. The jet mill used in this study is a promising tool for continuous cogrinding. Investigation of different drug-to-carrier ratios (griseofulvin/mannitol) demonstrated that a drug load of 10% is best suited to investigate the enhanced dissolution behavior. To gain deeper insight into the underlying mechanisms, the coground dispersion is compared with different physical mixtures in terms of physicochemical properties and dissolution behavior. Differential scanning calorimetry and X-ray powder diffraction were used to verify the crystalline structure of the coground formulation. On the basis of the Hixson-Crowell model, particle size reduction was ruled out as the main reason for dissolution enhancement. An increase of surface free energies because of grinding is shown with contact angle measurements. Confocal Raman microscopy investigations revealed the drug's bulk dispersity in the coground formulation as an additional factor for the increased dissolution rate. In conclusion, the continuous cogrinding approach is a promising technique to prepare the drug in a rapidly dissolving, yet crystalline, form. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.
    view abstract10.1002/jps.23731
  • Spheronisation mechanism of MCC II-based pellets
    Krueger, C. and Thommes, M. and Kleinebudde, P.
    Powder Technology 238 (2013)
    Microcrystalline cellulose II (MCC II) - a polymorph of commonly used MCC I - was introduced as new pelletisation aid in wet-extrusion/spheronisation. Preliminary investigations suggested that the spheronisation mechanism of MCC II-based pellets differs from the known mechanism of MCC I. Therefore the spheronisation mechanism of MCC II-based pellets was investigated and compared to that of MCC I.The study dealt with the effect of spheroniser load as well as spheronisation speed and time on the pellet properties of shape (aspect ratio), size (equivalent diameter), weight, porosity, size distribution (10%-interval) and yield (fine fraction) of MCC II-based formulations. The parameters were systematically varied in a 33 full factorial design; Furthermore spheronisation time experiments with spheronisation times from 10s to 15min (13 steps) were conducted. For this purpose mixtures with 20% MCC II and 80% lactose or chloramphenicol were chosen. A mixture of 20% MCC I and 80% lactose served as comparison.Regarding the MCC II-based pellets all investigated pellet properties were significantly influenced by spheronisation speed and time, spheroniser load showed nearly no influence. Aspect ratio, 10%-interval and porosity decreased continuously throughout the entire spheronisation process. After a slight decrease, pellet weight and equivalent diameter increased during spheronisation. On the contrary the fine fraction decreased during spheronisation after passing a maximum in the first minutes of spheronisation. MCC I-based pellets behaved differently during spheronisation: Pellet weight remained nearly constant during spheronisation and the equivalent diameter decreased; The fine fraction was lower compared to that of the MCC II-based pellets. The higher fine fraction of MCC II could partly explain this result as the fine fraction layered on the pellets. However, the fine fraction was too low to explain the complete weight gain. Therefore, a new spheronisation mechanism for MCC-II based pellets was proposed: It was suspected that small pellets abraded during processing and layered on the other pellets. This presumption was supported by the high increase of the 10%-interval of the MCC II-based pellets during spheronisation indicating a narrowing of the size distribution; The improvement was less pronounced for the MCC I-based pellets.MCC II behaves in a different manner than MCC I in spheronisation: A deeper insight into the spheronisation of MCC II-based pellets was obtained providing a new pelletisation mechanism that is the basis to control and influence the spheronisation process of MCC II-based pellets. © 2011 Elsevier B.V.
    view abstract10.1016/j.powtec.2011.12.052
  • Miniaturization in pharmaceutical extrusion technology: Feeding as a challenge of downscaling
    Muehlenfeld, C. and Thommes, M.
    AAPS PharmSciTech 13 (2012)
    In recent years, extrusion technology has shifted the focus of pharmaceutical research due to versatile applications like pelletization, bioavailability improvement or manipulation of solid-state properties of drugs, continuous granulation, and the development of novel solid dosage forms. Meanwhile, a major effort has been devoted to the miniaturization of equipment in pharmaceutical extrusion technology, particularly with regard to the requirements of the development of new chemical entities and formulations. In the present study, a lab-scale twin-screw extruder was investigated in order to determine the limitations imposed by the feeding systems. The wet extrusion process was considered as challenging because both a powder and a liquid feeder have to be considered. Initially, the accuracy and uniformity of the powder and liquid feeder were tested independently of the extrusion process. After modification of the powder feeder, both feeders were investigated in conjunction with extrusion. Based on this, an optimization of the liquid feeder was required and completed. Both feeder modifications reduced the variability of the moisture content in the extrudates 10-fold. This led to a reliable small-scale extrusion process. © 2011 American Association of Pharmaceutical Scientists.
    view abstract10.1208/s12249-011-9726-7
  • Quantification of mass transfer during spheronisation
    Koester, M. and Thommes, M.
    AAPS PharmSciTech 13 (2012)
    Spherical granules (pellets) are quite useful in many pharmaceutical applications. The extrusion spheronisation technique is well established as a method of producing pellets of a spherical shape and narrow size distribution. After the extrusion, the cylindrical extrudates are transformed to spherical pellets by spheronisation. The frequently used models consider deformation and breakage during this process. However, the adhesion of fine particles has been neglected as a mechanism in spheronisation for many years. This study quantifies the mass transfer between pellets during spheronisation. During the investigation, the pelletisation aids (microcrystalline cellulose and kappa-carrageenan), the drug (acetaminophen and ibuprofen) and water content were varied systematically. A novel parameter, namely, the "mass transfer fraction " (MTF), was defined to quantify the mass transfer between the pellets. All four investigated formulations had an MTF between 0.10 and 0.52 that implies that up to 50 % of the final pellet weight was involved in mass transfer. Both pelletisation aids showed similar MTF, independent of the drug used. Furthermore, an increase of the MTF, with respect to an increase of the water content, was found for microcrystalline cellulose formulations. In conclusion, the mass transfer between the pellets has to be considered as a mechanism for spheronisation. © 2012 American Association of Pharmaceutical Scientists.
    view abstract10.1208/s12249-012-9770-y
  • Systematic evaluations regarding interparticular mass transfer in spheronization
    Koester, M. and Willemsen, E. and Krueger, C. and Thommes, M.
    International Journal of Pharmaceutics 431 (2012)
    Pellets are frequently used in pharmaceutical applications. The extrusion-spheronization process is a well-established technique used to produce pellets of a spherical shape and narrow size distribution. In this process, cylindrical extrudates are transformed into spherical pellets by spheronization. Most established mechanisms consider only breakage and deformation to explain pellet formation. An interaction between the rounding extrudates via adhesion of fine particles was not considered for many years. This study deals with the evolution of pellet properties over time during the spheronization process in order to quantify the influence of pellet interactions on their properties. Therefore the most important pelletization aids (MCCI, MCCII and κ-carrageenan) were investigated using acetaminophen as a model drug and lactose as a filler. In the first seconds of the spheronization process, a high fine fraction was seen which decreased during the process. Simultaneously, the material transferred between the pellets increased. However the fine fraction is not high enough to explain the mass transfer; therefore a direct transfer between the pellets was assumed. The pelletization aid has a huge influence on the amount of mass transferred. Whereas κ-carrageenan leads to a quite low mass transfer of 15%, MCCI and MCCII show higher values up to 25%. © 2012 Elsevier B.V. All rights reserved.
    view abstract10.1016/j.ijpharm.2012.04.045
  • 800mg Darunavir tablets prepared by hot melt extrusion
    Thommes, M. and Baert, L. and Rosier, J.
    Pharmaceutical Development and Technology 16 (2011)
    Darunavir (TMC 114) is a protease inhibitor used in the therapy of HIV-1. The aim of this study was to formulate 800mg of Darunavir in a single unit dosage form, with suitable mechanical properties and dissolution behavior, using a corotating twin screw extruder. In preliminary investigations, extrudates of 1mm diameter were prepared to evaluate the extrusion and dissolution behavior of Darunavir. Two different poloxamers (188 and 407) were used to modify the dissolution properties of Darunavir, and a higher solubilization for poloxamer 188 was observed. Furthermore, a zero order drug release from pure Darunavir extrudates was found which was modulated by the extrudate diameter. Extrudates of 13mm diameter were cut into tablets containing 800mg of Darunavir. Due to the lower specific surface area in comparison to the 1mm extrudates, an addition of solubilizing agent was required to obtain the desired dissolution profiles. Therefore, the influence of Mannitol and poloxamer 188 was investigated in different formulations. The formulations exhibited acceptable extrusion behavior and dissolution properties. © 2011 Informa Healthcare USA, Inc.
    view abstract10.3109/10837450.2010.508077
  • Improvement of the dissolution rate of poorly soluble drugs by solid crystal suspensions
    Thommes, M. and Ely, D.R. and Carvajal, M.T. and Pinal, R.
    Molecular Pharmaceutics 8 (2011)
    We present a novel extrusion based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin and spironolactone) is significantly accelerated. The drug and highly soluble mannitol are coprocessed in a hot melt extrusion operation. The obtained product is an intimate mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions is over 2 orders of magnitude faster than that of the pure drug. Since the resulting product is crystalline, the accelerated dissolution rate does not bear the physical stability concerns inherent to amorphous formulations. This approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug. Being thermodynamically stable, the dissolution profile and the solid state properties of the product are maintained after storage at 40 °C, 75% RH for at least 90 days. © 2011 American Chemical Society.
    view abstract10.1021/mp1003493
  • "MCC SANAQ®burst"-a new type of cellulose and its suitability to prepare fast disintegrating pellets
    Krueger, C. and Thommes, M. and Kleinebudde, P.
    Journal of Pharmaceutical Innovation 5 (2010)
    Introduction: Microcrystalline cellulose (MCC) is the commonly used pelletization aid in wet extrusion-spheronization processes. MCC has the structure of cellulose I and is denoted as MCC I. Recently, MCC II, a different polymorphic type of MCC, became commercially available, known under the name MCC SANAQ®burst. Due to the fact, that MCC II can be used as a filler and a disintegrant in tableting, MCC SANAQ®burst was investigated as new pelletization aid with the goal to prepare disintegrating pellets. Materials: MCC II pellets were compared to the corresponding conventional pellets, manufactured on the basis of MCC I, namely Avicel® PH 102. Formulations with 10%, 20%, and 50% of either MCC I or MCC II as pelletization aids were produced. Methods: One series of binary mixtures, contained lactose monohydrate as filler and a second series chloramphenicol as model drug. All pellets were characterized by their yield, aspect ratio, equivalent diameter, water content, tensile strength, disintegration behavior and-if applicable-drug release. Results and Discussion: The production of pellets with sufficient quality properties by addition of 10%, 20%, and 50% of MCC II as pelletization aid was possible. In contrast to MCC I pellets, MCC II-based pellets showed disintegration resulting in a much faster drug release. Conclusion: MCC SANAQ®burst is a promising pelletization aid providing disintegrating and fast-dissolving pellets. © 2010 Springer Science+Business Media, LLC.
    view abstract10.1007/s12247-010-9080-4
  • Analysis of pellet properties with use of artificial neural networks
    Mendyk, A. and Kleinebudde, P. and Thommes, M. and Yoo, A. and Szlêk, J. and Jachowicz, R.
    European Journal of Pharmaceutical Sciences 41 (2010)
    The objective was to prepare neural models identifying relationships between formulation characteristics and pellet properties based on algorithmic approach of crucial variables selection and neuro-fuzzy systems application. The database consisted of information about 227 pellet formulations prepared by extrusion/spheronization method, with various model drugs and excipients. Cheminformatic description of excipients and model drugs was employed for numerical description of pellet formulations. Initial numbers of neural model inputs were up to around 3000. The inputs reduction procedure based on sensitivity analysis allowed to obtain less than 40 inputs for each model. The reduced models were subjects of fuzzy logic implementation resulting in logical rules tables providing human-readable rule sets applicable in future development of pellet formulations. Neural modeling enhanced knowledge about pelletization process and provided means for future computer-guided search for the optimal formulation. © 2010 Elsevier B.V.
    view abstract10.1016/j.ejps.2010.07.010
  • In-line dynamic torque measurement in twin-screw extrusion process
    Köster, M. and Thommes, M.
    Chemical Engineering Journal 164 (2010)
    Extrusion technology has been a focus of pharmaceutical research for many years. Extrusion processes are used for improvement of drug bioavailability, for bead manufacturing as well as for continuous granulation. Besides these, there are also several research efforts regarding the use of process understanding as a tool in quality management. Several initiatives of the Food and Drug Administration (FDA) about this issue such as Process Analytical Technology (PAT) and Quality by Design (QbD) are becoming more and more accepted.In the present study, a corotating twin-screw extruder was equipped with a torque gauge as a tool for process monitoring. The experimental setup was qualified in accordance with the ICH guidelines. The torque of extrusion correlated linearly with the water content in a wet extrusion process. Moreover, a pelletisation process was performed using different formulations in wet extrusion/spheronisation. A relationship between the torque on the screws and the shape of the pellets was found. In conclusion, the torque was found to be a suitable extrusion parameter for monitoring wet extrusion processes. © 2010 Elsevier B.V.
    view abstract10.1016/j.cej.2010.03.076
  • New insights into the pelletization mechanism by extrusion/spheronization
    Koester, M. and Thommes, M.
    AAPS PharmSciTech 11 (2010)
    Pellet manufacturing by extrusion/spheronization is quite common in the pharmaceutical field because the obtained product is characterized by a high sphericity as well as a narrow particle size distribution. The established mechanisms only consider deformation of the initially fractured particles but do not account for mass transfer between the particles as a factor in achieving spherical particles. This study dealt with the visualization of mass transfer during spheronization. Therefore, two common pelletization aids, microcrystalline cellulose and kappa-carrageenan, were used alone as well as in combination with lactose as a filler. This study proves that mass transfer between particles must be considered in addition to plastic deformation in order to capture the spheronization mechanism. Moreover, it is evident that there are regional distinctions in the amount of mass transfer at the particle surface. Therefore, the commonly espoused pelletization mechanisms need to be extended to account for material transfer between pellet particles, which has not been considered before. © 2010 American Association of Pharmaceutical Scientists.
    view abstract10.1208/s12249-010-9532-7
  • drug design

  • solubility

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