(231d) Solvent Entrapment of BI 763963 By Solid Solution Formation

The entrapment of solvents in the final API post-isolation is a common problem in pharmaceutical development. The residual solvent levels in the final API are required to be controlled below certain limits, based on expected toxicity per ICH guidelines. Some solvents are stringently controlled at lower levels, as in the case of acetonitrile, which has a limit of 410 ppm. Other more benign solvents can be tolerated at higher levels, such as ethanol having a limit of 5,000 ppm. The physiochemical mechanisms that are responsible for solvent entrapment of today’s APIs are poorly understood and hence resolutions have been largely empirical. Generally, solvent entrapment can occur due to 1) solvate formation with the solvent, 2) mother liquor inclusion and 3), solid solution formation. Solvates are readily identifiable by structural analyses such as XRPD. Mother liquor inclusions are pockets either within individual crystals or agglomerates that contain solution, which remain with the solid phase after filtration and drying. These inclusions can be identified by e.g. microscopy or thermal analysis. In contrast, solid solutions are notoriously difficult to detect with common analytical techniques and hence their prevalence among APIs is largely unknown. In addition, solid solution formation with solvents have been poorly studied and very few reports are available in the literature.

This presentation is focused on an industrial case study using a terminated API, which was originally developed as a RORc inhibitor. BI 763963 is unusually prone to solvent entrapment and exhibits relatively slow crystallization kinetics in most solvents. This API is not polymorphic and was only obtained as an anhydrous crystal form. No solvates exists and the crystal lattice is densely packed without voids capable of incorporating solvent molecules. Nevertheless, over 2% isopropanol was routinely entrapped in the solid phase during crystallization. The reason for the solvent entrapment is explored and established to stem from solid solution formation with the crystallization solvent. This is demonstrated using a variety of orthogonal approaches, including binary T-w diagrams, thermal analysis, microscopy and reslurry/recrystallization experiments assisted by mechanically-induced attrition. Furthermore, the solubility of the API was measured as a function of residual solvent levels, showing solubility enhancements up to 50% in the same solvent. These results show unambiguously how the composition of the solid phase is responsible for solubility enhancements of solid solutions.

Finally, the solvent entrapment was monitored during crystallizations in two solvents carried out at different supersaturation ratios. It is shown how the early part of the crystallization is associated with higher solvent entrapment, followed by decreasing residual solvent levels as equilibrium is approached. This behavior led to gradients in solvent levels within the final material with corresponding differences in intrinsic solubilities. The addition of a structurally similar impurity is demonstrated to completely alter the solvent entrapment leading to a 63% reduction. Implications for pharmaceutical development are discussed together with industrial mitigation measures for controlling residual solvents.