A novel continuous crystallizer design is described with the potential to provide improved control of crystal properties, improved process reproducibility, and reduced scale-up risk. Liquid and gas are introduced into one end of the tube at flow rates selected to spontaneously generate alternating slugs of liquid and gas that remain stable while cooling crystallization occurs in each liquid slug. Mixing within each stable self-circulating slug is maximized by controlling the slug aspect ratio through specification of liquid and gas flow rates. The crystallizer is designed so that nucleation and growth processes are decoupled to enhance the individual control of each phenomenon. Coaxial or radial mixers combine liquid streams to generate seed crystals immediately upstream of the growth zone where nucleation is minimized, and crystal growth is controlled by the varying temperature profile along the length of the tube. The slug-flow crystallizer design is experimentally demonstrated to generate large uniform crystals of L-asparagine monohydrate in less than 5 min.

Continuous-flow solution crystallization is an approach to manufacture pharmaceutical crystals with improved control of product characteristics, simplified post-crystallization operations, higher production rate flexibility, and reduced capital costs and footprint. An indirect ultrasonication-assisted nucleation process is designed to vary seed generation rate during operation independent of mass flow rate, by varying the ultrasonication power. The ultrasonication probe is pressed against a tube to generate a spatially localized zone within the tube inside of a temperature bath for the generation of crystal nuclei without heating or contaminating the supersaturated solution. This nucleation design is integrated into a continuous slug-flow crystallization process to generate uniform-sized product crystals within each slug at a high supersaturation level and a short residence time of ~8.5 min, without inducing significant secondary nucleation. By increasing size uniformity, the indirect ultrasonication-assisted slug-flow crystallizer has potential as a final crystallization step to produce crystals for direct compression tableting without having any possibility of metal contamination.

A revised crystallization process for TAK-117, a selective PI3Kα inhibitor currently in Phase 1b clinical trials, was developed that greatly improved the overall purity, recovery, and physiochemical and bulk powder properties of the isolated product. The original process afforded material that was prone to agglomeration during drying, resulting in significant product losses during sieving as well as issues with drug product manufacturability. Opportunities to explore a wide array of possible crystallization routes and solvent options were limited because TAK-117 is only sparingly soluble in most commonly used organic solvents apart from dimethyl sulfoxide (DMSO) and acidic systems. However, reasonable productivities were achieved using DMSO at elevated temperatures (100 °C), and the optimized process leveraged thermal cycling to improve the aspect ratio of the isolated crystals, minimize agglomeration during drying, and improve the powder’s bulk properties. The revised process was found to produce material of acceptable quality across a total of six batches at 15 and 30 kg scales.

A simple screening protocol has been developed for assessing the agglomeration potential of active pharmaceutical ingredients (APIs) using resonant acoustic mixing that minimizes the quantity of API used. This methodology improves upon existing ones as it allows for multiple conditions to be screened in parallel, saving time and allowing for the study of agglomeration and optimization of the drying unit operation to take place early in development. In addition to a qualitative (visual) assessment, quantitative data can be obtained after the material has been dried therefore accounting for a measure of cake hardening. This methodology was also extended to assess the friability of the generated agglomerates and was validated using a scaled-down agitated filter dryer (AFD). The impact of particle size, particle size distribution, solvent selection, and solvent loading on the agglomeration potential for a Takeda API is also discussed which allowed for the development of an improved drying process that was successfully scaled-up in the pilot plant.