Precision crystallization, spherical agglomeration and formulation of pharmaceuticals

Crystallization is a crucial purification step widely adopted in the pharmaceutical industry. The crystal shape and size distribution dictate the efficiency of downstream processing and critical quality attributes of the final drug product. The aim of this research is to improve the crystallization step with shape modification techniques such as additive addition, spherical agglomeration, and excipient formulation, by using new methodologies different process designs, and various scales. These include, a capillary microfluidic device at a working scale of 1-20 mL/min, a flat-membrane dispersion cell, with a working batch volume of 30-100 mL, a tubular oscillating membrane (volume: 150 mL) and a benchtop scale crystalliser (0.5 L) with a custom design membrane holder that were used to achieve spherical agglomeration. The microfluidic device was used to effectively test the recipes and generate experimental insights prior to the implementation of larger scales. The dispersion cell helped deliver spherical agglomerates at a lab-scale and was used as a basis for a design of the membrane holder used in the benchtop scale crystallizer that can potentially be used in vessels up to 2 L. The tubular oscillating membrane helped achieve spherical agglomerates and allowed identification of the optimum mixing conditions necessary to achieve the targeted critical quality attributes when attempting scale-up design of a spherical agglomeration process. The scale-up of the membrane dispersion cell into a crystallizer proved successful in achieving spherical agglomeration and expanded the understanding of the spherical agglomeration mechanism with the presence of process analytical technologies (PATs) including real-time particle vision measurement, focused-beam reflectance measurement for particle count monitoring and UV-vis for concentration monitoring. Finally, the microfluidic device and dispersion cell were used for the formulation of co-processed API particles with enhanced micromeritic properties such as particle size distribution, morphology and API composition. This has the aim of reducing further the necessary processing steps in the pharmaceutical process and serves as a process intensification technique where the aim is to obtain particles readily available for tableting.

Several sets of experiments were designed and carried out to explore a range of operating and design parameters (CPPs) to identify optimal recipes and process designs. The most important critical process parameter for spherical agglomeration is an optimised bridging liquid to crystal solids ratio (BSR). Other CPPs to consider when designing a spherical agglomeration process include membrane pore diameter, mixing rate and bridging liquid injection rate. It is also important to consider the crystal concentration and supersaturation during the crystallization step before the agglomeration process. The critical quality attributes (CQAs) that were investigated include mean agglomerate and crystal size distribution, agglomerate porosity, surface morphology, particle crystallinity and encapsulation efficiency. With the combination of effective control of critical process parameters and analytical techniques, it was possible to provide an insight into the agglomerate formation mechanism as a combination of the immersion and distribution mechanisms occurring simultaneously during bridging liquid droplet addition for the process of a model API compound, benzoic acid. A simple force balance was used to predict droplet size obtained in the membrane dispersion cell and was compared to the size of obtained agglomerates, accounting to a factor of 1.5-2 of a predicted droplet size compared to the obtained agglomerate size. A similar prediction and mean agglomerate size range was obtained from the lab-scale crystallizer when implementing the membrane for bridging liquid droplet formation, with agglomerates in the range of 200-600 μm. The addition of excipients was effective in decreasing the mean particle size further from an agglomerate diameter range of 300-500 μm to a range of 30-100 μm for excipient-API particle. Encapsulation efficiency for co-process API particles was obtained in the range of 75-99% for three different APIs, including benzoic acid, piroxicam and carbamazepine. The presence of API in the particles was also confirmed with powder X-ray diffraction. The oscillating membrane gave way to a porosity investigation of the spherical agglomerates obtained, when agglomerates with a visibly observed lower porosity were obtained. The porosity of particles obtained in the range 77-83% is comparable to the values reported in literature and serves as a good indicator of agglomerate flowability. Process parameter optimization was performed to establish an improved method for crystal spherical agglomeration and polymer particle formation with the implementation of membrane systems.