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

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• 作者：Martin Wijaya Hermanto ; Alvin Yeoh ; Beatrice Soh ; Pui Shan Chow ; Reginald B. H. Tan
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：December 18, 2015
• 年：2015
• 卷：19
• 期：12
• 页码：1987-1996
• 全文大小：454K
• ISSN：1520-586X

文摘

The 伪-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 未-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.