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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 (A 1 , A 2 ) and power characteristics (B 1 , B 2 ) 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.

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.

The poor solubility of a large number of active pharmaceutical ingredients (APIs) is a major challenge in pharmaceutical research. Therefore, the extrusion of amorphous solid dispersions (ASDs) is one promising approach to enhance the dissolution rate by molecularly dissolving the API in an amorphous carrier polymer. During ASD extrusion, crucial parameters as the dissolution of the API in the carrier polymer need to be monitored. Within this study, a small scale twin screw extruder was coupled with special ColVisTec UV-vis probes that are characterized by their small dimensions. This setup enables a systematic formulation design and optimization based on in-line monitoring of drug dissolution using small material quantities. In fact, sample quantities of about 5 mg were evaluated for each measurement, representing 50% of the material inside the die. The amount of undissolved drug particles was determined based on the lightness of the extrudates. It was shown that the temperature has a significant effect on the drug dissolution in the polymer. Furthermore, complete drug dissolution was shifted to lower temperatures if higher residence times were applied. Based on the courses of lightness, regime maps were modeled that specify the process conditions where ASDs are successfully manufactured.

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.

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.

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.

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.

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.

Darunavir (TMC 114) is a protease inhibitor used in the therapy of HIV-1. The aim of this study was to formulate 800 mg 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 1 mm 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 13 mm diameter were cut into tablets containing 800 mg of Darunavir. Due to the lower specific surface area in comparison to the 1 mm 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.

kappa-Carrageenan is a biopolymer extracted from red seaweeds which has been in the focus of pharmaceutical development for many years. Most applications make use of the large water binding capacity of kappa-carrageenan. The primary limitation of kappa-carrageenan is the variation in the substance quality. Therefore, the water binding capacity of different kappa-carrageenan products was investigated by dynamic vapor adsorption, freezing and non-freezing bound water and water retention value. The kappa-carrageenans were observed to have a higher water binding capacity than microcrystalline cellulose (MCC) in all three methods. The amount of adsorbed water is similar for all carrageenans. Differences between the carrageenan types (kappa, iota, and lambda) were remarkable for the freezing bound water and centrifugation bound water as well as between the kappa-carrageenans of different suppliers.

kappa-Carrageenan is known as a novel pelletization aid in manufacturing of pellets by extrusion/spheronization. The implentation of kappa-carrageenan as a pelletization aid can overcome several disadvantages of commonly used microcrystalline cellulose (MCC) such as lacking disintegration and adsorption of several actives. The aim of this study was to compare different types of carrageenans from different suppliers: one iota-, five kappa-, and one lambda-carrageenan. The kappa-carrageenans had the best pelletization behavior. Four of the five tested kappa-carrageenans resulted in pellets with acceptable shapes, sizes, and size distributions using a high drug load of 80% hydrochlorothiazide. These pellets have similar properties over a wide range of water contents ranging from 90 to 105%. The filler, dicalcium phosphate, affected the pelletization process and the pellet properties of all investigated kappa-carrageenans.