(149d) Process Enhancements for a pH Sensitive Crystallization

A monomodal agglomerate particle size distribution and the desired morphology were achieved for an API crystallization that was pH sensitive, leading to a robust, efficient crystallization process.  Irregular crystals were formed during growth in a variable pH environment.  Switching from a simultaneous dual fed batch addition to a single feed addition, together with characterization/optimization of crystallizer mixing and pH enabled reduction of pH gradients.  Statistically designed experiments were employed to demonstrate achievement of the desired particle size and morphology over a wide operating range.  Benefits included higher crystallization yield, a 3x increase in agglomerate size, a reduction of the seed charge from 11% to 3%, widening of the design space for the range of seed particle sizes (eliminating the need for special seed milling), and reducing feed charge time by half.  The process was successfully scaled up 100-fold to the commercial reactor.