Crystallization Process Development of an Active Pharmaceutical Ingredient and Particle Engineering via the Use of Ultrasonics and Temperature Cycling

Abstract

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 multikilogram-scale GMP batches.

From form to function: Crystallization of active pharmaceutical ingredients

“…One emerging technology in the ''wet-milling'' arena is sonication, generally applying ultrasound frequencies in the 20-50 kHz range in order to break particles and reduce crystal aspect ratio. Several cases of this application are reported in the literature, including an article by researchers at Bristol-Myers Squibb Company 26 who report that such an approach has been used to reduce the size of API particles from an initial size of 100-200 microns to particles smaller than 20 microns.…”

The Effect of Ultrasound on the Crystallisation of Paracetamol in the Presence of Structurally Similar Impurities

“…Ultrasound has been widely reported to influence the primary nucleation process accelerating nucleation kinetics, this is typically expressed in terms of reducing the induction time and MSZW [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Ultrasound can also increase the rate of secondary nucleation, this is manifested as a reduction on the product crystal size distribution [20,22,24,31,32,[34][35][36][37][38][39][40][41][42][43]. Ultrasound can also influence crystal growth [20,25,26,36,40,[44][45][46] although the effect on crystal growth is not as dramatic as on nucleation and arises largely from enhanced mass transfer [46] and can influence crystal morphology.…”

Recrystallization of Active Pharmaceutical Ingredients

“…Small particles and rough edges of larger particles dissolve faster during heating periods, followed by their recrystallization onto the existing crystals during cooling. The overall effect is more uniformly shaped particles and a narrower particle size distribution range (Kim et al, 2003;Mullin, 2001). …”

“…Sonic waves give rise to a phenomenon called cavitation -the formation of bubbles that decrease in size until a critical size is reached, leading to collapse and the formation of cavities. Cavitation provides energy that accelerates the nucleation process (Banga et al, 2004;Kim et al, 2003).…”