Producing Small Crystals of a Pharmaceutical Compound by a Continuous Polymorph Transformation Process
Bing Shiou Yang, Chenkou Wei, and San Kiang. Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, NJ 08903
This presentation illustrates a novel crystallization technique to produce small crystals of an active pharmaceutical ingredient (API). This technique involves polymorph transformation between Forms A (a kinetically favored form) and Form B (a thermodynamically more stable form) of a BMS compound, BMS-X. We demonstrate that, under high-shear conditions, needle-like Form A crystals can be transformed to small granular Form B crystals that meet the particle size specification of D90 < 50 um. A continuous process was subsequently developed to improve the scalability of the polymorph transformation crystallization. In this modified process, Form A slurry is transferred through a transit vessel maintained at elevated temperature and equipped with an overhead homogenizer that provides high shear and good mixing. A short residence time (7-10 minutes) in the transit vessel transforms the Form A crystals to small Form B ones. This process significantly shortens the processing time and is easy for scaled-up due to its continuous nature. It consistently produces crystals with the required particle size. The overall process was further simplified by telescoping with the API synthesis reaction. The telescoped process significantly shortened the processing time by eliminating the isolation of crude API and was successfully demonstrated in a 100 kg campaign in the pilot plant.