(84f) API Crystallization Process Development for Improved Consistency, Bulk Properties, and to Enable Downstream Processing | AIChE

(84f) API Crystallization Process Development for Improved Consistency, Bulk Properties, and to Enable Downstream Processing

Authors 

Quon, J. - Presenter, Takeda Pharmaceuticals
Papageorgiou, C. D., Takeda Pharmaceuticals International Co.
Durak, L., Takeda Pharmaceutical Company Ltd
A revised crystallization process for an Active Pharmaceutical Ingredient (API) was developed to improve the physiochemical and bulk powder properties of the isolated product. The first generation process consisted of an unseeded cooling crystallization that provided material with low bulk density, a propensity to agglomerate on handling and storage, and was not amenable to formulation. Additionally, a clarifying filtration was not possible due to solubility limitations of the API at the target operating volume. Development of the crystallization process explored the use of seed crystals generated by wet-milling and jet-milling, the use of in-situ wet milling during the crystallization, and thermalcycling to improve the bulk properties of the resultant powders. Optimization of these parameters led to a second generation process that is run at a higher operating volume to accommodate a clarifying filtration, distilled to a target concentration, seeded with jet-milled seed material, and subjected to a series of thermalcycles to ripen the product crystals. The resulting API is isolated with an increased bulk density, higher aspect ratio, and improved handling during formulation. The second generation process was studied as part of a fractional factorial Design of Experiments to assess and rank the impact of all of the processing parameters on the isolated product’s quality attributes. It was determined that the physical properties of the seed crystals, the seeding point, and the temperature targets of the thermal cycling had the greatest impact on the product particle size distribution and bulk powder properties.