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Drug Substance Physical Property Control in the Process of Crystallization

By Haitao Zhang, Ph.D.
Associate Research Fellow,
Sumitomo Pharma America, Inc.

The crystallization of active pharmaceutical ingredients, particularly those with multiple polymorphic forms, particle size and morphology critical properties, is a highly complex and least understood manufacturing procedure. The poor understanding or lack of control over crystallization procedures often leads to various process and product failures. Therefore, it is imperative for the pharmaceutical industry to enhance competitiveness and develop robust processes by gaining knowledge about the molecular complexity and challenges associated with solid forms. Process understanding using in-process techniques, modeling, and applicable novel techniques in development scale is a suitable way to reach the desired active ingredient requirements. This understanding is essential due to the significant impact of material properties on production efficiency and their implications for drug product formulation. In this presentation, 3 real case examples will be presented for 3 different compounds in terms of polymorphism transformation investigation with online Raman, modeling-aided PSD control, and crystal morphology manipulation with sonication/micronization and pressure crystallization. In case #1, Compound A has shown two different polymorphs in the process of crystallization. Online Raman has been employed to understand the crystal form transformation process, identify the end point form flip and set process parameters. In case #2, PSD has been identified as one of the CQAs of compound B. A crystallization kinetic model has been developed to understand the PSD fluctuation during scale-up manufacturing and identified the corresponding process parameter to ensure a robust control over PSD during scale-up manufacturing. In case #3, compound C crystallized as unfavorable long needle crystals with poor flow and low bulk density. Sonication/micronization are able to break the crystals up to block-like crystals. Pressure crystallization has been explored and it resulted in crystals with much lower aspect ratio.
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