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The development of a regio- and stereoselective deoxyfluorination process for the manufacture of belzutifan (MK-6482) was challenging because of a combination of particular reaction and engineering sensitivities. These aspects were addressed through a series of mechanistic, range-finding, and mixing studies that enabled a robust process to be established. In particular, mixing studies led to the discovery of a second phase of perfluoro-1-butanesulfonyl fluoride in the reaction at cryogenic temperature, requiring the liquid–liquid dispersion to be controlled sufficiently to minimize the formation of side products. The changes implemented as a result of these investigations culminated in a process executed successfully on the pilot and commercial scales.

Precompetitive collaborations on new enabling technologies for research and development are becoming popular among pharmaceutical companies. The Enabling Technologies Consortium (ETC), a precompetitive collaboration of leading innovative pharmaceutical companies, identifies and executes projects, often with third-party collaborators, to develop new tools and technologies of mutual interest. Here, we report the results of one of the first ETC projects: the development of a user-friendly population balance model (PBM)-based crystallization simulator software. This project required the development of PBM software with integrated experimental data handling, kinetic parameter regression, interactive process simulation, visualization, and optimization capabilities incorporated in a computationally efficient and robust software platform. Inputs from a team of experienced scientists at 10 ETC member companies helped define a set of software features that guided a team of crystallization modelers to develop software incorporating these features. Communication, continuous testing, and feedback between the ETC and the academic team facilitated the software development. The product of this project, a software tool called CrySiV, an acronym for Crystallization Simulation and Visualization, is reported herein. Currently, CrySiV can be used for cooling, antisolvent, and combined cooling and antisolvent crystallization processes, with primary and secondary nucleation, growth, dissolution, agglomeration, and breakage of crystals. This paper describes the features and the numerical methods of the software and presents two case studies demonstrating its use for parameter estimation. In the first case study, a simulated data set is used to demonstrate the capabilities of the software to find kinetic parameters and its goodness of fit to a known solution. In the second case study, the kinetics of an antisolvent crystallization of indomethacin from a ternary solvent system are estimated, providing a practical example of the tool.

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 °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 °C; and (3) Form 1 to Form 2 rapid turnover occurs at temperatures ≥30 °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.

A recently proposed model to determine particle‐size distributions (PSDs) from chord length measurements has been applied to different particle morphologies, namely compact, platelet‐ and rod‐shaped particles. To study these systems, chord length distributions (CLDs) were measured at varying particle size and solids concentration for each compound and were subsequently utilized to determine the system‐specific parameters. Each model was successfully applied to its respective compound such that the experimental PSDs and model predictions were in good agreement. Moreover, the effect of other variables such as agitation rate and solvent composition was investigated and found to be negligible for the specific systems tested. Finally, potential model optimizations of the general model construct have been studied. Two variants of the CLD compression step, namely principal component analysis and a geometric model have been considered as surrogate models. However, neither of these approaches yielded superior results than the previously proposed approach.