(694d) Tailoring Powder Properties of Drug Substance through Polymorphic Transformation

An active pharmaceutical ingredient (API) with a propensity for forming large crystals requires stringent particle size control. Jet-milling, an intuitive top-down approach, was attempted first to meet the particle size target. The micronization process resulted in material that achieved the particle size target but powder properties such as cohesiveness and powder flow can be further optimized. There is a development opportunity which includes enhancing powder properties to enable more robust product-collecting operations and formulation process scalability. In this work, a bottom-up approach using polymorphic transformations is used to achieve targeted particle size and powder properties.

The API has a diverse form landscape of >10 polymorphs and several salts. Form III is the most thermodynamically stable form, and the target form for our process. Two routes were developed to reach Form III with tailored particle properties – one through intermediate Form I and the other through intermediate Form IX. Although Form I and Form IX are metastable polymorphs, they can be reproducibly made through breaking the sodium salt of the API. The final conversions to Form III were effective in producing particles within the size control limit. When high-shear wet milling (HSWM) was integrated into the process, it further enhanced the kinetics of the process. The benefits of this approach include inherently small and uniform crystals, well-defined shape, good flowability and minimal cohesiveness. The investigation demonstrated a bottom-up process strategy used to achieve the desired physical characteristics beyond particle size target. We believe the use of polymorphic transformation to achieve desired properties has broader applications to other pharmaceutical compounds with powder property challenges. The options created by polymorph transformation represent alternative opportunities to ensure formulation robustness and product performance.