Excipients in Pharmaceutical Additive Manufacturing: A Comprehensive Exploration of Polymeric Material Selection for Enhanced 3D Printing.

This review provides a comprehensive overview of additive manufacturing (AM) or 3D-printing (3DP) applications in the pharmaceutical industry, with a particular focus on the critical role of polymer selection. By providing insights into how material properties influence the 3DP process and the quality of the final product, this review aims to contribute to a better understanding of the interplay between polymers and pharmaceutical 3DP. As 3DP technologies are increasingly integrated into pharmaceutical sciences, this review contributes insights into the nuanced process of polymer selection, serving mainly as a foundational guide for researchers and formulators new to the subject seeking to harness the full potential of pharmaceutical 3DP by understanding the physicochemical properties, roles, and functions of used polymers in 3D-printed dosage forms and medical devices.

Scale-Up of pharmaceutical Hot-Melt-Extrusion: Process optimization and transfer.

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.

Competing for water: A new approach to understand disintegrant performance.

The understanding of tablet disintegration is still incomplete as not all involved factors and processes are known or accounted for. E.g., the negative influence of soluble fillers, on disintegration is usually attributed to increased viscosity due to dissolved filler. When the most common filler, lactose, dissolves, the viscosity increases only slightly. The impact of binders has hardly been studied systematically. In this study, water uptake and force development as well as water sorption experiments were performed of tablets containing either a soluble or an insoluble filler, one of four different binders, and one of four different disintegrants. For both fillers, one disintegrant performed distinctly worse than the others. For the insoluble filler, dibasic calcium phosphate (DCP), sodium starch glycolate resulted in the longest disintegration, for the soluble filler, lactose, croscarmellose sodium performed worst. Based on the experimental results, the authors introduce the competition-for-water hypothesis, which takes into consideration the amount of freely available water molecules and hydration kinetics of excipients. Soluble fillers bind a large number of water molecules in hydrate shells and prevent, therefore, proper disintegrant action. Previously inconsistent observations can be approached with this hypothesis and a better understanding of the underlying processes and explanations is possible.

Small-scale twin-screw extrusion - evaluation of continuous split feeding.

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.

Solid dispersion prepared by continuous cogrinding in an air jet mill.

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.

Miniaturization in pharmaceutical extrusion technology: feeding as a challenge of downscaling.

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.