Lehrstuhl Feststoffverfahrenstechnik

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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.
Inline determination of residence time distribution in hot-melt-extrusion
(2018-04-15) Wesholowski, Jens; Berghaus, Andreas; Thommes, Markus
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).
Investigations concerning the residence time distribution of twin-screw-extrusion processes as indicator for inherent mixing
(2018-10-26) Wesholowski, Jens; Berghaus, Andreas; Thommes, Markus
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.
Electrostatic precipitation of submicron particles in a molten carrier
(2019-06-13) Dobrowolski, Adrian; Pieloth, Damian; Wiggers, Helmut; Thommes, Markus
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.

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