Mechanism and kinetic modeling study on the crystallization of concomitant polymorphs

Abstract

Concomitant polymorphs routinely observed in fine chemical industry could impact product purity and consistency; however, both molecular mechanism and process kinetics of concomitant crystallization remain elusive. Herein, we developed a population balance model to understand process kinetics of concomitantly dipolymorphic crystallization using DL‐methionine as a model compound. Kinetic parameters were estimated from induction time measurements and unseeded crystallization experiments. Experimental and simulation results demonstrate that the stable β form has a comparable nucleation rate with α form thanks to their close nucleation barrier leading to the concurrent nucleation. Several solution chemistry techniques were utilized to examine the speciation of solute molecules, together revealing the solutes' self‐association and the formation of micelle‐like aggregates driven by hydrophobic interactions, not hydrogen bonds. These aggregates show dynamic nature against conventional thoughts of classical nucleation kinetics. Finally, the molecular mechanism of concomitant crystallization was uncovered and the implications for polymorph selection and control were discussed.