Process Optimization of a Complex Pharmaceutical Polymorphic System via In Situ Raman Spectroscopy

Abstract

In situ Raman spectroscopy was used to determine the rate of polymorph turnover for MK-A, a multipolymorphic compound in development at Merck Research Laboratories. The known crystal forms of MK-A include four anhydrous polymorphs, two hydrates, and numerous solvates. The penultimate and pure steps of this process involve a coupling reaction to generate a mixture of crystal forms followed by turnover to the desired polymorph, form A. This paper summarizes experiments to measure the kinetics of polymorph turnover from all relevant MK-A crystal forms to form A. Additionally, the turnover kinetics for polymorph reversion from form A to undesired forms were measured under simulated process upset conditions. The use of thermodynamic data to establish process boundaries and kinetic data to establish process time cycles resulted in the definition of a highly robust, cycle time efficient slurry turnover process to produce form A from any combination of other MK-A crystal forms.