Robust Crystallization Process Development for the Metastable δ-form of Pyrazinamide

Abstract

The α-form of the first-line antituberculosis drug pyrazinamide (PZA), which is the thermodynamically stable polymorph at ambient conditions, exhibits a fine needle shape that easily forms a mesh-like structure, making it undesirable for downstream processing. This study implements the Quality by Design (QbD) approach to develop a robust design space for isolating the metastable δ-form of PZA. A solvent mixture of methanol and 1,4-dioxane is selected for the process. Five process parameters are considered in the development of the design space: cooling rate, seeding temperature, seed loading, solvent composition, and seed preparation technique. The robustness of the established design space is verified by model uncertainty evaluation and demonstrated through experiments.