Bottom-up particle engineering via solvent-mediated polymorphic transformation: a novel strategy for pharmaceutical...

Bictegravir free acid exhibits one of the most complex polymorph landscapes reported for pharmaceutical compounds, presenting both a significant development challenge and a unique engineering opportunity. During the development of a long-acting injectable (LAI) formulation of bictegravir, initial top-down efforts (crystallization followed by micronization) produced a highly cohesive API with poor flowability, rendering drug substance and drug product manufacturing impractical. This work reports a novel bottom-up particle engineering strategy that leverages the complex polymorph landscape of bictegravir to overcome the processability challenges. By deliberately harnessing selected hydrated forms as crystallization precursors, two solvent-mediated polymorphic transformation (SMPT) processes were developed to convert metastable polymorphs and pseudopolymorphs to the thermodynamically most stable form. The resulting API has a small particle size, a narrow and unimodal particle size distribution, and significantly enhanced flowability, meeting all critical quality attributes required for the LAI formulation. Raman spectroscopy was implemented to monitor transformation kinetics in real time, and multivariate analysis of the response surface (particle size) was used to identify the optimal operating range. This methodology is most applicable to compounds that possess accessible and isolable hydrates within a controllable water-activity window, and where a metastable-to-stable SMPT pathway exists that yields a more favorable crystal habit, offering a powerful and versatile means of particle engineering.