Bullet-Proofing Doravirine (Mk-1439) Starting Material Supply: Rapid Identification And Response To A New Polymorph Of Ethyl Ester

During large-scale crystallization of the ethyl ester (EE) starting material of Doravirine (MK-1439) (Huang et al. ACS Infectious Dis. 2020, 6, 64-73) four out of nine batches exhibited unique infrared spectra upon release testing and atypical powder X-ray diffraction (PXRD) patterns not conforming to the target crystalline phase, Form 1. This work presents the investigations triggered within MSD's laboratories on the polymorphism of EE and the strategy employed for identifying the nature of the form impurity and understanding its thermodynamic relationship with Form 1. The team's response for avoiding its reoccurrence through a bullet-proofed crystallization process consistently delivering Form 1 is also presented. The form impurity was identified as a new polymorph of EE, Form 2, which is revealed to have an enantiotropic relationship with Form 1 with a transition temperature at ca. 0-5 degrees C. Form 2 is thermodynamically favored above this transition temperature and at ambient conditions. A combination of X-ray powder diffraction and crystal structure prediction was used to solve the crystal structure of Form 2. The spontaneous nucleation of both physical forms and their competitive growth in ethanol (EtOH)/water revealed that (1) high supersaturation leads to primary nucleation of Form 2 below the transition temperature and is avoided by slow cooling rates; (2) the desired kinetic Form 1 grows much faster over Form 2, even in the presence of Form 2 particles at temperatures <= 25 degrees C; and (3) Form 1 to Form 2 rapid turnover occurs at temperatures >= 30 degrees C. As a result, a Form 1 seeded crystallization was developed with a controlled cooling rate and antisolvent addition followed by a final aging at low temperature. The process was implemented at multiple scales to maximize productivity through consistent delivery of Form 1 and avoidance of Form 2 that exhibits poor filtration performance.