Development of a Process for Crystallizing the Desired Crystal Form of An API

During scale up of a generic drug preparation process that involves crystallization of an API from a solvent, some of the production batches had exceptionally small particle size and high residual solvent levels after drying. The problem was traced to the formation of solvate crystals, which lose the solvent during drying and rapidly transform to very small crystals of the anhydrous form. Therefore, it is desirable to define the best operational parameters, such as temperature, cooling rate, and solvent ratio to directly obtain anhydrous crystals by crystallization from the solvent, without the contamination of other polymorphs and/or impurities.

Based on the notion that understanding the fundamentals is the key in developing a stable and reproducible process, an integrative approach that combines experimental observations, physical insights, and modeling has been applied to analyze the available data and suggest a suitable recipe for crystallizing the desirable anhydrous form of the API. The approach includes consideration of both solid-liquid equilibrium phase behavior of the system and kinetic effects. The relevant SLE phase behavior is studied, and used to explain the findings of the previous experiments. An initial recipe for obtaining the desired product form is developed and validated in a trial run.