(394d) Discovery and Development of a Novel Hydrate of An API Via Controlled Solid-State Form Transformation

Discovering novel forms can be a challenging task in the generic industry, with the search often resulting in solvates or unstable forms. This poster will present a case study wherein a stable novel form of an API was discovered by controlling the solid-state form transformation of an unstable methanolate. Compound A, which is a HCl salt, is reported to have several forms including a stable anhydrous form (Form-IV), stable mono-hydrate (Form V), mono-methanolate (Form XI), and several other solvates. While reactive crystallization of this compound in methanol lead to the reported mono-methanolate (Form XI), it was found that reducing the temperature of salt formation lead to a hitherto undiscovered form (designated as Form-P). However, Form-P, suspected to be an unstable methanolate, readily converted to a number of different forms depending on the process parameters during filtration: (i) The PXRD pattern of Form XI was obtained during filtration if the temperature increased or the wet cake was exposed to high humidity. Further investigation lead to the discovery that the Form-XI could be obtained by either formation of the mono-methanolate or by formation of a hydrate that was iso-structural with Form-XI. (ii) Interestingly, if Form-P was filtered quickly with exposure to mild humidity (40-60%RH), it converted to a second novel form, designated as Form-Q. (iii) Or, if filtered under pressure with dry nitrogen, it converted to a third novel form, Form-R.

Both Forms Q and R were found to be dihydrates, and Form-Q was selected for further development based on stability. The challenge then was to develop a robust process to control the conversion of Form-P to only Form-Q without any contamination of the other crystalline forms. This poster describes the development of a controlled solid-state transformation pathway, how challenges to scale-up the process were successfully addressed along with implementation of a QbD approach to ensure robustness.

Communication number: IPDO IPM - 00369