Crystallization process development of an active pharmaceutical ingredient and particle engineering via the use of ultrasonics and temperature cycling

Process development of a Bristol-Myers Squibb drug substance candidate involved the development of crystallization and particle engineering protocols to address polymorphism, oiling out, and particle size control issues. Two monotropic polymorphs were evaluated, and one was determined to be thermodynamically more stable. The oiling problem was solved by adjusting the polarity of the solvent system and conducting controlled nucleation at low supersaturation. Two protocols were developed to produce the desired form consistently in high quality and yield with a short processing time. Slow crystallization was required to ensure product quality since the final crystallization served as an important purification step, but slower crystallization led to larger crystals. To avoid dry milling, ultrasound was used for particle size reduction in the crystal slurry post-crystallization. Temperature cycling followed for particle size uniformity. The scale-up involved use of an ultrasonic tube through which the crystal slurry was passed continuously. The protocol was successfully executed in multi-kilogram-scale GMP batches.