Solvent Entrapment of BI 763963 by Solid Solution Formation

The underlying mechanism for solvent entrapment has been determined for terminated drug candidate BI 763963. Ethanol (EtOH) and isopropanol (IPA) were entrapped in the crystal lattice of BI 763963 through solid solution formation, as demonstrated through a combination of experimental methods and structural analysis. Two binary T-w phase diagrams were constructed showing the outline of the solidus and liquidus, where EtOH and IPA are present in the solid phase of BI 763963 at 0.54 and 1.5 wt %, respectively, at equilibrium. Importantly, the solvent solubility of BI 763963 was found to be dependent on the residual solvent level in the solid phase and in the case of EtOH increased by almost 50% at just 1.1 wt % EtOH entrapment. The implications of the effect of residual solvents on solvent solubility are discussed with respect to industrial processing and the pharmaceutical properties of the active pharmaceutical ingredient (API). Furthermore, recrystallization experiments were carried out on BI 763963 at different supersaturation ratios in both EtOH and IPA. Higher supersaturation yielded higher solvent entrapment initially, which in both solvents decreased linearly with API yield. The trends are discussed and compared to previous contributions showing similar behavior that appeared due to crystal nucleation of a solid solution. The solubility-enhancing effect from solvent entrapment is used to determine the actual supersaturation ratio during crystallization. The analysis shows that errors up to 55% in the supersaturation ratio can be introduced when assuming that the solid phase is pure or that the solubility of an API is independent of entrapped solvent. Finally, industrial mitigation measures are discussed to reduce residual solvent levels based on solid solution formation. It is demonstrated experimentally that other solid-state miscible impurities can completely alter the phase equilibria of the system, leading in one example to a reduction in IPA content from 2.2 to 0.86 wt %.