(M1230-06-34) Solid Form Screening and Crystallization Process Development of a Clinical Phase II API

Purpose: Late stage unexpected appearance of new solid forms of an API is costly and detrimental to meeting what are often tight drug development timelines. In this case study, upon manufacturing registration batches of Form 1 of a drug, inconsistency of the solid form was noted (Form 1 and other forms were produced; see image 1). Goals of this study were to characterize the newly observed form of the drug, fully map out the solid form landscape of the drug (possible new forms within the process relevant space and their relationship), and develop a robust small-scale crystallization process for reliably manufacturing the preferred form of the drug.

Methods: Polymorph screening was done by slurry, cooling and solvent/anti-solvent crystallization techniques. All new Forms were characterized by PXRD, TGA, DSC, PLM, and FTIR. Metastable Zone Widths (MSZW) were determined to narrow down the conditions for designing a robust crystallization process for the desired Form. The final scaled-up batch of the desired form was further characterized by KF, purity assays, powder flow (Carr Index) and particle size distribution (light scattering).

Results: Complete characterization of the different registration batches revealed a prior unknown Form 2 of the drug that had not been found in previous polymorph screens. In our comprehensive polymorph screen, we were able to characterize the two forms from the manufacturing campaign. Form 1 and Form 2 are enantiotropic with a transition temperature of about 100 ºC, where Form 2 is stable below 100 ºC while Form 1 is stable above 100 ºC. This relationship was suggested by DSC and true density measurements, and confirmed with competitive slurries (see image 2). In addition, a third polymorph was identified, being a less stable polymorph under all conditions. We also found conditions that favored crystallization of Form 1, 2, and 3 which is highly dependent on both crystallization rate and the dielectric constant of the solvent system. The program switched to development of Form 2 as the new preferred form of the drug (thermodynamically stable below 100 ºC). Based on this data and preferential growth of Forms in different solvents, we determined the metastable zone widths in solvent blends and designed a seeded solvent/anti-solvent crystallization process for producing Form 2 (see image 3). The reliability of the new, small-scale crystallization process was demonstrated by crystallizing Form 2 from 100 mg to 100 g scale.

Conclusion: Here we show a late stage application of solid form services for troubleshooting unexpected appearance of a previously unknown form of a drug. The new form was thoroughly characterized and its stability vs. other form(s) verified before establishing the new form (Form 2) as the one to be developed further (thermodynamically stable). We combined our understanding of metastable zone widths determined on a small scale with the observation of selective crystallization of forms dependent on dielectric constant of solvent and rate of addition of anti-solvent to design a robust crystallization process for Form 2 of the drug. This process was successfully transferred to the plant. This work highlights the importance of doing small-scale crystallization process development prior to manufacturing of a drug to save time and resources.

Material from different registration batch campaigns.



Relative stability of crystalline forms of drug.



Final crystallization process for drug.