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The utility of the recently developed nonrandom two-liquid segment activity coefficient (NRTL-SAC) model has been reported for solvent selection in support of industrial crystallization process design. In this paper, we present a recent successful application with NRTL-SAC to screen solvents for a crystallization medium with the goal to maximize API solubility and to minimize solvent usage. The NRTL-SAC model parameters for the molecule in development are first identified from a minimal set of solubility experiments in selected solvents. We then perform numerous in silico virtual experiments to explore the solubility behavior of the molecule in other pure solvents and mixed solvents. The modeling results suggested optimal solvent systems for the crystallization medium which are validated in physical laboratories and chosen for process scale-up. This study demonstrated the effectiveness of the NRTL-SAC model and supports its use as a tool in drug development.

A research scale continuous reactor system was designed and developed for high pressure asymmetric hydroformylation (AHF) reactions with an 8 h reaction time. The continuous reactor achieved high k L a, low axial dispersion, and an 8 mL liquid holdup volume. The reactor consisted of 20 vertical bubble flow pipes-in-series, connected by small diameter tubing jumpers. This type of continuous reactor is proven to be scalable up to 360 L in our GMP pharmaceutical manufacturing plant for high pressure hydrogenation. The continuous reactor was used for the AHF of styrene and 2-vinyl-6methoxynaphthalene catalyzed by rhodium(bisdiazaphospholane) (BDP) complexes. The CSTRs-in-series numerical model fit the experimental data better than the plug flow with dispersion model. Samples were taken along the length of the continuous reactor and used for kinetic data modeling. Vapor liquid mass transfer rate constants were about 3 orders of magnitude higher than reaction rate constants.

The hazard assessment of a telescoped Miyaura borylation and Suzuki coupling reaction employing bis­(pinacolato)­diboron (BisPin), used in the developmental synthesis of an intermediate for abemaciclib, led to the observation of hydrogen being generated. Quantitative headspace GC and solution 11B NMR were used to show that the rapid decomposition of the excess BisPin from the borylation under the aqueous basic conditions of the Suzuki reaction was responsible for H2 generation. The moles of H2 observed were found equal to the BisPin excess, which is rationalized by mass balance and a stoichiometric reaction. The possible generation of the stoichiometric levels of H2 should be considered in hazard assessments of this class of reaction. Kinetic and process modeling was used to minimize the risk upon scale-up, and results for commercial manufacturing batches are presented, which showed good agreement with the lab scale data. Furthermore, the hydrogen evolution potentials of other common borylating agents including bisboronic acid (BBA) and pinacol borane were demonstrated.

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