Crystal Structure Prediction Synergizes with Crystallization Tendency Analysis: A Case Study in Polymorph Screening of a Novel PRMT5 Inhibitor

Polymorph screening is essential in pharmaceutical development to ensure the selection of optimal solid forms for active pharmaceutical ingredients. Here, we report an integrated crystal structure prediction and an experimental approach to map the polymorphic landscape of GTA182, a novel PRMT5 inhibitor. Computational energy landscape analysis identified low-energy structures corresponding to three experimentally observed anhydrous forms and revealed additional more stable forms not accessed by conventional screening. Although not the most thermodynamically stable form at room temperature, Form A emerged as the kinetically favored polymorph in crystallization experiments, a finding rationalized by a solution-based crystallization tendency analysis. Its predicted structure was confirmed by microcrystal electron diffraction (MicroED). This combined strategy guided targeted experimental screening, leading to the identification of 19 solid forms (anhydrates, hydrates, and solvates) and validating the predicted stability relationship between Forms A and O. The study establishes a practical workflow for derisking polymorph selection in drug development by providing critical insights into the interplay of thermodynamics and kinetics in crystalline form landscapes.