Lehrstuhl Feststoffverfahrenstechnik

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http://hdl.handle.net/2003/33893

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Predictive modeling of drug product stability in pharmaceutical blister packs
(2025-09-22) Pech, Jan; Kaminski, Christoph; Markus, Matthias; Hoheisel, Werner; Heumann, Roman; Winck, Judith; Thommes, Markus
Background/Objectives: The principal function of pharmaceutical blister packaging is to provide protection for the drug product. Moisture is regarded as a critical factor in the physical and chemical aging of drug products. The present work proposes a modeling framework to predict the performance of tablet blister materials based on the moisture uptake profile of the drug product as well as degradation characteristics of the drug substance, while the consumption of water due to degradation is included. Methods: The model incorporates three kinetic superimposed processes that define moisture uptake and drug stability. The processes of permeation, sorption and degradation are each described with a rate constant. Based on a mass balance, these rate processes are interconnected and the relative humidity in the blister cavity is predicted. Results: In a case study, the model was applied to demonstrate the feasibility of predicting the stability of blistered tablets. By establishing a correlation between the moisture uptake of the tablet and the drug stability demonstrated in the model, it was feasible to predict the drug content over shelf life. Conclusions: Modeling of the drug stability of blister-packed products enables a rational packaging which offers novel possibilities for reducing material in order to avoid overpackaging of pharmaceutical products. As some of the commonly used barrier materials are considered to not be sustainable, this model can be used to consider a rationally justified reduction or even abandonment of the barrier materials.
Characterization of different copovidone grades as carrier materials in hot melt extrusion of amorphous solid dispersions
(2025-08-30) Daalmann, Marvin; Kimmel, Vincent; Muehlenfeld, Christian; Thommes, Markus; Winck, Judith
Background/Objectives: Copovidone (polyvinylpyrrolidone-vinyl acetate copolymer, PVP/VA) is a widely used pharmaceutical excipient with various applications in drug formulation. In hot melt extrusion (HME), PVP/VA is an approved carrier material for the production of amorphous solid dispersions (ASDs) by embedding drugs on a molecular level. This study investigates the properties and processability of two copovidone grades—Plasdone™ S-630 (PS-630) and the novel Plasdone™ S-630 Ultra (PS-630U)—to assess their suitability as ASD carrier materials. Methods: The thermal and physicochemical characteristics of both polymers were evaluated, focusing on glass transition temperature and polymer melt rheology. The process performance in HME was investigated on small-scale as well as in production-scale extrusion. The two model drugs itraconazole and griseofulvin were used to examine drug dissolution and degradation during HME via in-line UV-vis spectroscopy. Results: When comparing both polymers, PS-630U offers various advantages due to the improved powder feeding behavior and reduced yellowing of extruded products while maintaining similar melt properties and drug compatibility compared to PS-630. Conclusions: These findings support the use of PS-630U as an optimized copovidone grade for ASD manufacturing, facilitating improved processing characteristics and best product qualities without the requirement of significant formulation adjustments.
A Monte Carlo simulation of tracer diffusion in amorphous polymers
(2024-07-24) Mansuri, Ali; Vora, Paras; Feuerbach, Tim; Winck, Judith; Vermeer, A. W. P.; Hoheisel, Werner; Kierfeld, Jan; Thommes, Markus
Tracer diffusion in amorphous polymers is a sought-after quantity for a range of technological applications. In this regard, a quantitative description of the so-called decoupling from the reverse proportionality between viscosity and diffusion coefficient into a fractional one remains a challenge requiring a deeper insight. This work employs a Monte Carlo simulation framework in 3 dimensions to investigate the consequences of different scenarios for estimating this fractional exponent on the diffusion coefficient of tracers in polymers near glass transition. To this end, we adopted a continuous-time random walk model for tracer diffusion in the supercooled liquid state. The waiting time distribution of the diffusants was computed based on the rotational correlation times of the polymer. This proposed procedure is of particular interest because it brings the quantity of waiting time (and its statistics) in connection with the measurable observable of rotational times. In the framework of our simulations the aforementioned fractional exponent appears in the relation between the diffusant's waiting time and the rotational time of the diffusion medium. A limited comparison with experimental diffusivities from the literature revealed a reasonable agreement with a fractional exponent on the basis of the molar volumes of the diffusant and the monomeric unit. Finally, an analysis of time-averaged mean squared displacement pointed to normal Brownian dynamics for tracer diffusion in polymers above the glass transition temperature.
Experimental and numerical characterization of screw elements used in twin-screw extrusion
(2024-07-16) Düphans, Vanessa; Kimmel, Vincent; Messing, Lukas; Schaldach, Gerhard; Thommes, Markus
Hot melt extrusion by a co-rotating twin screw extruder is an important process in the pharmaceutical industry. Especially for quality by design aspects, a comprehensive process understanding is indispensable. The performance of conveying elements was determined as critical process parameter, and therefore an experimental and numerical framework was developed to analyze and compare variations. A test rig capable of measuring volume flow, pressure and torque with high accuracy and precision was designed and built. The 3D simulation was performed using computational fluid dynamics (CFD). A stationary model with impulse transmission and an apparent motion of the screws was applied. The experimental data were fitted to the model of Pawlowski, and parameters for the pressure (A1, A2) and power characteristics (B1, B2) were determined. Good agreement between experimental data and the model was observed. The simulation was significantly faster compared to common methods, and the results were consistent with the literature. Systematic investigations of a native and worn screw were performed with CFD resulting in a transport capacity increase and a pressure build up decrease for all tested screw elements. An experimental and simulation setup was generated to assess the performance of co-rotating twin screw elements. The experiments provided high-quality data, and the simulations exhibited high flexibility with low computational effort.
Intrinsic dissolution rate modeling for the pharmacopoeia apparatus rotating disk compared to flow channel method
(2024-03-19) Mattusch, Amelie M.; Schaldach, Gerhard; Bartsch, Jens; Thommes, Markus
For a solid understanding of drug characteristics, in vitro measurement of the intrinsic dissolution rate is important. Hydrodynamics are often emphasized as the decisive parameter influencing the dissolution. In this study, experiments and computational fluid dynamic (CFD) simulations showed that the mixing behavior in the rotating disc apparatus causes an inhomogeneous flow field and a systematic error in the calculation of the intrinsic dissolution rate. This error is affected by both the experimental time and the velocity. Due to the rotational movement around the tablet center, commonly utilized in pharmacopeia methods, a broad variance is present with regard to the impact of fluid velocity on individual particles of the specimen surface. As this is significantly reduced in the case of uniform overflow, the flow channel is recommended for investigating the dissolution behavior. It is shown that rotating disc measurements can be compared with flow channel measurements after adjusting the measured data for the rotating disc based on a proposed, representative Reynolds number and a suggested apparatus-dependent correction factor. Additionally, modeling the apparatus-independent intrinsic dissolution rate for different temperatures in the rotating disc apparatus is possible using the adapted Levich’s equation.
Modeling Shear-Thinning Flow in Twin-Screw Extrusion Processes
(2025-03-09) Kimmel, Vincent; Gräfe, Lorena; Grieser, Luca; Lips, Alexey; Henning, Robert; Winck, Judith; Thommes, Markus
Background/Objective: Hot-melt extrusion has been established as a formulation strategy for various pharmaceutical applications. However, tailoring the screw configuration is a major challenge where 1D modeling is utilized. This usually requires specific screw parameters, which are rarely noted in the literature, especially when dealing with shear-thinning formulations. Methods: Therefore, a custom-made test rig was used to assess the behavior of various conveying and kneading elements using Newtonian silicon oil and shear-thinning silicon rubber. The pressure and the power were measured as a function of volume flow. A model was proposed characterizing the screw element behavior by six individual parameters (A1, A2, A3, B1, B2, B3). Results: The experimental results regarding the behavior with respect to Newtonian fluids were in good agreement with the literature and were modeled in accordance with the Pawlowski approach. In terms of shear-thinning fluids, the influence of screw speed on pressure and power was quantified. An evaluation framework was proposed to assess this effect using two additional parameters. Based on a high number of repetitive measurements, a confidence interval for the individual screw parameters was determined that is suitable to highlight the differences between element types. Conclusions: Finally, geometrical screw parameters for Newtonian and shear-thinning flow were assessed and modeled, with three conveying and three kneading elements characterized.
A step towards real-time release testing of pharmaceutical tablets: utilization of CIELAB color space
(2025-02-28) Brands, René; Le, Trieu Nam; Bartsch, Jens; Thommes, Markus
Background: The pharmaceutical industry is shifting from end-product testing towards real-time release testing. This approach is based on the continuous collection of process data and product information, which is finally utilized for the release decision. For continuous direct compression, spectroscopic technologies are preferred due to their short acquisition time and non-destructive nature. Methods: Here, the feasibility of the CIELAB color space was demonstrated for porosity and tensile strength. Five different formulations were processed, varying in particle size and deformation behavior. The compression forces were varied from 3 to 18 kN and the CIELAB color space was measured in-line using a UV/Vis probe implemented in the ejection position of the tablet machine. Results: Increasing the main compression force during tableting decreases the tablet surface roughness and porosity. In addition, the tablet tensile strength increases. These changes affected the reflection behavior of radiation on the tablet surface, resulting in a change in the chroma value C*. These dependencies were utilized for the in-line monitoring of porosity and tensile strength. Linear relations were observed for all formulations as exemplary, indicated by sufficient coefficients of determination and verification runs. Conclusions: Finally, UV/Vis diffuse reflectance spectroscopy in combination with a CIELAB color space transformation was demonstrated to be a suitable real-time release tool.
Intrinsic dissolution modeling: interdependence between dissolution rate, solubility, and boundary layer thickness
(2025-04-25) Mattusch, Amelie Marie; Schaldach, Gerhard; Bartsch, Jens; Thommes, Markus
Background/Objectives: In the past, many drug release models have been presented which attempt to describe the interaction of drugs and excipients in a formulation. Nevertheless, modeling the intrinsic dissolution behavior is essential for understanding the fundamental dissolution mechanisms of drugs and for enhancing the quality of computational approaches in the long term. Methods: In this study, the intrinsic dissolution of various pharmaceutical model substances (benzocaine, carbamazepine, griseofulvin, ibuprofen, naproxen, phenytoin, theophylline monohydrate, and trimethoprim) was investigated in dissolution experiments, taking into account the flow conditions in a dissolution channel apparatus. A practicable and generally valid representation was identified to describe the diffusion properties of the drugs in terms of the boundary layer thickness without considering the particle size distribution, physical state, or viscoelastic properties. This representation was supported by numerical simulations using a high-resolution mesh. The influence of the topography on the modeling was also examined. Results: Besides the prediction of the influence of a surface reaction limitation or the solubility of a diffusion controlled drug, the boundary layer thickness at the tablet surface is modellable in terms of a freely selectable length and as a function of the diffusion coefficient, drug solubility, and the flow velocity of the dissolution medium. Conclusions: Using different methods and a large dataset, this study presents a modeling approach that can contribute to a deeper understanding of intrinsic dissolution behavior.
Characterization of sprays generated by the expansion of emulsions with liquid carbon dioxide
(2023-09-26) Lauscher, Clara; Licau, Alexander; Schaldach, Gerhard; Thommes, Markus
Expanding emulsions with liquid CO2 facilitates the creation of aerosols with an average droplet diameter in the low micrometer size range, which is challenging with conventional atomizers. The droplet formation process of the expansion of high-pressure emulsions was investigated using a plain-orifice atomizer and different swirl nozzles. The local droplet size and droplet velocities were measured and used to estimate the local Weber number and thus infer the droplet size reduction. Measurements of the local mass concentration in the aerosol showed that, for the swirl nozzle, the highest concentration was found outside of the central axis, indicating radial momentum generated by the swirl nozzle. Furthermore, it was shown that the type of expansion nozzle used has an influence on the resulting median droplet size in the aerosol. For a water mass load of 0.01, the median droplet diameter was reduced from 8 to 3 μm by increasing the swirl number from 0.01 to 0.1.
Insights into the mechanism of enhanced dissolution in solid crystalline formulations
(2024-04-07) Justen, Anna; Schaldach, Gerhard; Thommes, Markus
Solid dispersions are a promising approach to enhance the dissolution of poorly water-soluble drugs. Solid crystalline formulations show a fast drug dissolution and a high thermodynamic stability. To understand the mechanisms leading to the faster dissolution of solid crystalline formulations, physical mixtures of the poorly soluble drugs celecoxib, naproxen and phenytoin were investigated in the flow through cell (apparatus 4). The effect of drug load, hydrodynamics in the flow through cell and particle size reduction in co-milled physical mixtures were studied. A carrier-and drug-enabled dissolution could be distinguished. Below a certain drug load, the limit of drug load, carrier-enabled dissolution occurred, and above this value, the drug defined the dissolution rate. For a carrier-enabled behavior, the dissolution kinetics can be divided into a first fast phase, a second slow phase and a transition phase in between. This study contributes to the understanding of the dissolution mechanism in solid crystalline formulations and is thereby valuable for the process and formulation development.
Simulation of powder flow behavior in an artificial feed frame using an Euler‐Euler model
(2022-03-01) Zimmermann, Maren; Raffel, Carola; Bartsch, Jens; Thommes, Markus
The Eulerian approach is an alternative numerical method to the traditionally used discreet particle techniques for modeling powder flow, avoiding limitations on particle number and diameter. The feasibility of an Euler-Euler simulation in a pharmaceutical application was investigated. In two- and three-dimensional flow simulations, computational fluid dynamics models and parameters were determined and verified based on comparison with experiments. Residence time distributions were calculated to show the applicability of the Eulerian model with two granular phases under the constraint of a continuous setup. Finally, this model was implemented to improve the process understanding of the powder flow in an artificial feed frame of a rotary tablet press.
Measuring and modeling of melt viscosity for drug polymer mixtures
(2024-02-21) Kimmel, Vincent; Ercolin, Enrico; Zimmer, Robin; Yörük, Muhammet; Winck, Judith; Thommes, Markus
Melt viscosity is an essential property in pharmaceutical processes such as mixing, extrusion, fused deposition modeling, and melt coating. Measuring and modeling of the melt viscosity for drug/polymer mixtures is essential for optimization of the manufacturing process. In this work, the melt viscosity of nine formulations containing the drug substances acetaminophen, itraconazole, and griseofulvin, as well as the pharmaceutical polymers Eudragit EPO, Soluplus, and Plasdone S-630, were analyzed with a rotational and oscillatory rheometer. The shear rate, temperature, and drug fraction were varied systematically to investigate their influence on viscosity. The results for the pure polymers showed typical shear-thinning behavior and are fundamental for modeling with the Carreau and Arrhenius approaches. The investigations of the viscosity of the drug/polymer mixtures resulted in a plasticizing or a filler effect, depending on the type of drug and the phase behavior. A drug shift factor was proposed to model the change in viscosity as a function of the drug fraction. On this basis, a universal model to describe the melt viscosity of drug/polymer mixtures was developed, considering shear rate, temperature, and drug fraction.
Design and characterization of a melt electrostatic precipitator for advanced drug formulations
(2024-01-01) Justen, Anna; Weltersbach, Alina Faye; Schaldach, Gerhard; Thommes, Markus
Electrostatic precipitators (ESP) are especially known for the efficient separation of micron and submicron particles from aerosols. Wet electrostatic precipitators are particularly suitable for highly resistive materials. Using these, particles can be directly transferred into a liquid for further processing or safer handling, which is advantageous for either hazardous or valuable materials. In this work, a wet ESP, which enables the separation of highly resistive particles into a heated liquid, was designed and investigated. To do this, spray-dried drug particles were embedded in a molten sugar alcohol to enhance the drug dissolution rate. After cooling, the solidified product showed advantageous properties such as a high drug dissolution rate and easy handling for further processing. For the design of the wet ESP, different discharge electrode configurations were tested. A wall film served as the collection electrode, which was generated by a specially designed distributer die. A laminar flow regime was achieved with a homogeneous film serving as the collection electrode, which is particularly important for a high separation efficiency. A prototype was designed and constructed in this respect. The particle separation into hot liquids or onto hot surfaces is challenging due to thermal effects in ESPs. The influence of thermophoresis and drag force on the particle transport was investigated, and optimum operation parameters were found for the present ESP. A broad field of applications can be covered with the presented device, where particles are embedded in even hot liquids to form liquid suspensions or, as it is presented here, solid dispersions. The dissolution of the drug-containing solid dispersion was studied in vitro. A remarkably faster drug dissolution was observed from the solid dispersion, as compared to a powder mixture of the drug and xylitol.
Particle generation with liquid carbon dioxide emulsions
(2022-07-28) Lauscher, Clara; Schaldach, Gerhard; Thommes, Markus
Spray drying is a common technique for particle generation. However, due to limitations in the droplet size, the production of solid submicron particles using conventional atomizers has proven to be challenging. With the aim of overcoming this limitation, the generation and expansion of emulsions of an aqueous solution and liquid carbon dioxide with a subsequent drying step was investigated. Potassium chloride concentrations in the solution between 0.1 and 10 wt. % and mass loads of the aqueous disperse phase between 0.01 and 0.09 were used in order to study their impact on the droplet and particle size. For the lowest potassium chloride concentration, median particle diameters in the submicron size range were measured for all mass loads of the disperse phase.
Composition dependency of the Flory–Huggins interaction parameter in drug–polymer phase behavior
(2023-11-21) Klüppelberg, Jana; Handge, Ulrich A.; Thommes, Markus; Winck, Judith
An innovative strategy to address recent challenges in the oral administration of poorly soluble drugs is the formulation of amorphous solid dispersions (ASDs), where the drug is dissolved in a highly soluble carrier polymer. Therefore, special knowledge of the drug–polymer phase behavior is essential for an effective product and process design, accelerating the introduction of novel efficacious ASD products. Flory–Huggins theory can be applied to model solubility temperatures of crystalline drugs in carrier polymers over the drug fraction. However, predicted solubility temperatures lack accuracy in cases of strong drug/polymer interactions that are not represented in the Flory–Huggins lattice model. Within this study, a modeling strategy is proposed to improve the predictive power through an extension of the Flory–Huggins interaction parameter by a correlation with the drug fraction. Therefore, the composition dependency of the Flory–Huggins interaction parameter was evaluated experimentally for various drug–polymer formulations that cover a wide variety of drug and polymer characteristics regarding molecular weights, glass transition temperatures and melting temperatures, as well as drug–polymer interactions of different strengths and effects. The extended model was successfully approved for nine exemplary ASD formulations containing the drugs acetaminophen, itraconazole, and griseofulvine, as well as the following polymers: basic butylated methacrylate copolymer, Soluplus®, and vinylpyrrolidone/vinyl acetate copolymer. A high correlation between the predicted solubility temperatures and experimental and literature data was found, particularly at low drug fractions, since the model accounts for composition dependent drug–polymer interactions.
Categorization of sprays by image analysis with convolutional neuronal networks
(2022-11-04) Pieloth, Damian; Rodeck, Matthias; Schaldach, Gerhard; Thommes, Markus
Spray characterization has been an issue for process and product characterization for decades. Because of this, a convolutional neuronal network was developed to determine the droplet size from spray images. The images were taken using a digital camera, a light source, and a dark room. These were subsequently employed to design and train a convolutional neuronal network using open-source software packages and a desktop computer. The accuracy of the network droplet size determinations was checked with additional, independent images. The median drop size was assessed with a high accuracy of more than 99.8 % as the mean spray performance indicator. Additionally, the droplet size distribution measurements from the neural network method deviated from those from the reference method (laser diffraction) by less than 1.5 %. Convolutional neuronal networks can be applied to determine the spray performance using spray cone images. This approach could be useful for multiple applications.
Preparation of micron and submicron particles via spray drying and electrostatic precipitation
(2022-11-10) Justen, Anna; Kurth, Christopher; Schaldach, Gerhard; Thommes, Markus
Small particles are of great interest in a variety of applications. Spray drying is a common technique for particle synthesis, but it is limited with respect to sizes below 10 μm. Therefore, a new laboratory-scale spray dryer was designed to address this issue. A novel aerosol generator consisting of a piezo crystal in a swirl chamber was designed to obtain droplets in the low micrometer range. After drying and cooling, particles were deposited in a molten carrier, using melt electrostatic precipitation. The median particle size of three pharmaceutical drug substances was 2 μm. The size distribution was particularly narrow, with span values of about 1.1. Spray drying is a sufficient technique to produce small drug particles below 5 μm with ultrasonic atomization at high frequencies. Electrostatic precipitation in a molten carrier is a suitable method to capture these particles.
Material transport characteristics in planetary roller melt granulation
(2023-07-28) Lang, Tom; Bramböck, Andreas; Thommes, Markus; Bartsch, Jens
Melt granulation for improving material handling by modifying particle size distribution offers significant advantages compared to the standard methods of dry and wet granulation in dust reduction, obviating a subsequent drying step. Furthermore, current research in pharmaceutical technology aims for continuous methods, as these have an enhanced potential to reduce product quality fluctuations. Concerning both aspects, the use of a planetary roller granulator is consequential. The process control with these machines benefits from the enhanced ratio of heated surface to processed volume, compared to the usually-applied twin-screw systems. This is related to the unique concept of planetary spindles flowing around a central spindle in a roller cylinder. Herein, the movement pattern defines the transport characteristics, which determine the energy input and overall processing conditions. The aim of this study is to investigate the residence time distribution in planetary roller melt granulation (PRMG) as an indicator for the material transport. By altering feed rate and rotation speed, the fill level in the granulator is adjusted, which directly affects the average transport velocity and mixing volume. The two-compartment model was utilized to reflect these coherences, as the model parameters symbolize the sub-processes of axial material transport and mixing.
Predicting residence time and melt temperature in pharmaceutical hot melt extrusion
(2023-05-06) Winck, Judith; Gottschalk, Tobias; Thommes, Markus
Hot-melt extrusion is increasingly applied in the pharmaceutical area as a continuous processing technology, used to design custom products by co-processing drugs together with functional excipients. In this context, the residence time and processing temperature during extrusion are critical process parameters for ensuring the highest product qualities, particularly of thermosensitive materials. Within this study, a novel strategy is proposed to predict the residence time distribution and melt temperature during pharmaceutical hot-melt extrusion processes based on experimental data. To do this, an autogenic extrusion mode without external heating and cooling was applied to process three polymers (Plasdone S-630, Soluplus and Eudragit EPO) at different specific feed loads, which were set by the screw speed and the throughput. The residence time distributions were modeled based on a two-compartment approach that couples the behavior of a pipe and a stirred tank. The throughput showed a substantial effect on the residence time, whereas the influence of the screw speed was minor. On the other hand, the melt temperatures during extrusion were mainly affected by the screw speed compared to the influence of the throughput. Finally, the compilation of model parameters for the residence time and the melt temperature within design spaces serve as the basis for an optimized prediction of pharmaceutical hot-melt extrusion processes.
Determination of inherent dissolution performance of drug substances
(2021-01-22) Sleziona, Dominik; Mattusch, Amelie; Schaldach, Gerhard; Ely, David R.; Sadowski, Gabriele; Thommes, Markus
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.

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