(509b) Process Development and API Attribute Control of An Amorphous API

This paper describes our efforts to develop a robust isolation process and control the attribute of an amorphous API. Its precipitation is characterized by very small induction times (< 60 ms) and is therefore mixing sensitive. The amorphous nature of the API introduced additional complications during the precipitation or subsequent processing steps such as vacuum distillation, filtration and drying. Local mixing effects and/or elevated temperatures rendered a gummy and therefore not processable API. The same physical state was also obtained when filtering at elevated pressures. In addition, we found that the particle size formed during the precipitation in combination with the operating temperature profile followed during subsequent processing had a profound effect on API attributes such as specific surface area and bulk density, which in turn, had an impact on the formulation process. A tiered approach was adopted to overcome these challenges. First, we developed a mechanistic understanding of the underlying phenomena. We found that the API physical state (gummy or particulate) is determined by the interplay between operating temperature, solvent composition and the corresponding API glass transition temperature. It was determined that the operating temperature must always be maintained below the glass transition temperature, and preferably at least 15-20oC lower to obtain a processable particulate product. Second, we developed a continuous tee mixer precipitation process to minimize the effect of mixing on particle size and surface area. The developed precipitation was transferred successfully to commercial scale. The API surface area produced ranged between 25 and 32 m2/g for 10 batches. The equivalent average particle sizes are 220 and 170 nm, values indicating the good PSD control offered by the continuous precipitation process. Third, we controlled API surface area within a narrow range to satisfy formulation requirements. This was a challenging task for two reasons. First, the API surface area changes by almost an order of magnitude from the particle formation event to the final DS powder due to agglomeration phenomena. Second, surface area change is a complex function of solvent composition (4 solvents), batch temperature, initial surface area of the particles produced from the continuous precipitation process and processing time. We achieved good batch-to-batch API surface area reproducibility by controlling the process at two different points. First, we were able to achieve consistent particle generation with the continuous precipitation process implemented. Second, we applied a vacuum distillation step following a specified solvent composition-batch temperature trajectory, which essentially "tunes" the API surface area to the desired levels. By incorporating these steps into the process we were able to achieve tight control of the API surface area (5.3-6.4 m2/g) for a total of 10 commercial scale batches. It is apparent that one can essentially dial the final API surface area value by controlling the surface area output of the precipitation process and by selecting an appropriate distillation profile.