Robust Particle Size Control During API Crystallization

A robust process offers flexibility to large scale manufacturing by permitting execution within broad parameter ranges without impact to product quality. In this paper the development of a controlled API batch crystallization will be described which delivers both a highly reproducible and predictable particle size specification. The process includes simultaneous cooling and wet milling that favors secondary nucleation over growth under low supersaturation conditions. Investigation includes a fractional factorial design of experiments (DoE) approach studied on a greater than 100 kg pilot plant scale. This DoE enabled identification of key process parameters using an equipment train nearly equivalent to commercial manufacturing. Collected data served as the basis for an empirical model used to estimate particle size and establish a demonstrable design space for the crystallization process. Comparison with similarly executed batches showed that the model may be used to accurately predict future performance. The described crystallization procedure was superior to conventional wet milling in producing unimodal particle size distribution in the isolated product.