(656e) Optimizing a Distillative Crystallization and Evaluating Form Risk

Distillative crystallizations represent a class of particle formation with unique challenges in establishing control. In contrast to antisolvent addition rate-controlled or temperature ramp rate-controlled crystallizations, the evolution of supersaturation with time is both scale and equipment dependent for distillative crystallizations. Thus, controlling the nucleation and growth processes that contribute to particle size and form is more challenging. This presentation provides a case study of a distillative crystallization which exhibited poor and unreliable filtration rates upon scale up, leading to a process bottleneck. The variable nature of this unit operation also resulted in the appearance of several polymorphs. Further process understanding was needed to establish a robust process with respect to filtration rate and polymorph control to a desired form. The crystallization was characterized through monitoring trends in nucleation and growth via FBRM, evaluating particle size via photomicroscopy, and determining relative supersaturation via HPLC. Water content, temperature, and age time were identified as critical parameters in maximizing the particle size of the crystals. Competitive slurry experiments and measurement of relative solubilities were used to develop the thermodynamic phase map and establish optimized conditions to enable generation of the desired form.