This work presents the solid-state evaluation of a new polymorph (Form M) discovered during the early-stage pharmaceutical development of a new chemical entity GDC-6599. Form screening and active pharmaceutical ingredient (API) crystallization development identified Form A of GDC-6599 as the experimentally most stable polymorph, although more stable polymorphs were predicted by crystal structure prediction (CSP). Later, a new polymorph, Form M, was discovered in the crystallization of a kilogram-scale API batch. The powder X-ray diffraction (PXRD) pattern of Form M was consistent with the calculated pattern of the predicted most stable polymorph (Rank 1) by CSP. Form A and Form M were subsequently speculated as enantiotropic polymorphs according to their melting temperatures and enthalpies. Slurry competition (SC) experimentally confirmed Form M as the more stable polymorph at temperatures relevant to pharmaceutical development. To support API manufacturing, a quantitative PXRD method was successfully developed for controlling the Form A percentage during the API crystallization process. To understand the impact of Form M on the drug product performance, pharmaceutical and biopharmaceutical evaluations were carried out. The intrinsic solubility of Form M was found to be 56% of the intrinsic solubility of Form A, consistent with their calculated solubility ratio based on the Gibbs free energy difference predicted by CSP. Biopharmaceutical assessment further suggested that the observed solubility reduction would not impact the biopharmaceutical performance of GDC-6599 at doses relevant for the proposed clinical studies, providing form selection flexibility for clinical formulation development. Accordingly, Form M was recommended for future API manufacturing and solid dosage form development. Meanwhile, Form A was confirmed to be physically stable in a suspension formulation for extemporaneous preparation and was recommended to support the early cohorts of Phase I clinical studies.

By Wei Zhang, Antonio Di Pasquale, Jerry Phan, Cheng W. Chiang, Jia Liu, Po-Chang Chiang, Allen Y. Hong, Shijia Tang, Hao Helen Hou, Karthik Nagapudi, Joseph W. Lubach