Leveraging Supercritical Fluid Chromatography for Monitoring the Formation of Methanol Adducts of AR-LDD Antagonist BMS-986409 in Spray-Dried Dispersion Materials

BMS-986409 is a novel ligand-directed degrader of the androgen receptor developed by Bristol Myers Squibb Company for the treatment of metastable castration-resistant prostate cancer (mCRPC). The active pharmaceutical ingredient (API) has an (R,R) configuration and three minor stereoisomers, including (R,S), (S,R), and (S,S) isomers. During pharmaceutical formulation development, methanol adducts were found in spray-dried dispersion (SDD) materials at alarming levels. To investigate the formation mechanism of methanol adducts, we successfully developed an ultrahigh performance liquid chromatography achiral method and a supercritical fluid chromatography chiral method to separate all potential methanol adducts and stereoisomers of BMS-986409. It is concluded that ring-opening at the 2-position of the gluarimide moiety (Pathway 1) is the favored formation mechanism of methanol adducts during the BMS-986409 SDD manufacturing process and epimerization can be neglected. However, under basic conditions, ring-opening at the 6-position of the gluarimide moiety (Pathway 2) becomes dominant and, in the meantime, epimerization is promoted to a great extent. The knowledge collected by leveraging the SFC chiral method gives us the needed confidence in the analytical impurity control strategy that solely relies on the achiral method for monitoring methanol adduct impurities in SDD materials and sample release in future pharmaceutical development.