(131a) A Novel Approach to Crystallizing the Desired Form Through Solid-State Solvent Exchange

Discovering novel crystalline forms can be a very challenging task in the generic industry, with the search often resulting in solvates that are not pharmaceutically viable. In the case of Compound X, this task was particularly challenging as the innovator had claimed more than eight forms and other generic players had claimed several more including amorphous form. However, through determined pursuit, a novel crystalline form was discovered, but unfortunately this form contained about 5 % methanol. Not only was this form unstable, but removal of the methanol by conventional drying techniques resulted in conversion to amorphous. To achieve the ICH limit for methanol, a novel process was developed to reduce the methanol content in the solid state by solvent exchange with water without transformation of the crystal lattice arrangement, resulting in a pharmaceutically acceptable and stable form. It was found that the extent and kinetics of solvent exchange were dependent on both the crystallization and humidification conditions.  The impact of various crystallization parameters such as temperature, mixing, anti-solvent addition rate etc. were studied through a systematic design of experiments (DOE), which revealed the interaction of parameters,  their effect on the crystal morphology and its correlation to the solvent exchange dynamics. In addition, it was required to improve the bulk density and flowability of the API for formulation processing due to a very high drug loading. The process was tailored to achieve this by engineering the formation of spherical agglomerates. This talk will present a case study on how an unconventional crystallization process was developed to effectively transform the polymorph in the solid state with desired powder properties, and the challenges to scale-up and validate this process in manufacturing.

(Dr.Reddy's Laboratories Communication number: IPDO IPM - 00252)