Methodology of Crystallization Kinetics Investigation for Designing Isolation Process of Pure Metastable Polymorph

Formation of undesired polymorphs during the crystallization process of an active pharmaceutical ingredient (API) is a common challenge for the critical quality attribute (CQA) control of API products. Isolating the pure metastable crystalline form can provide benefits, including a better dissolution profile, better processability in subsequent steps, etc., but tends to be much more challenging than isolating the pure stable form. An effective approach to developing a robust API isolation process for production is to enable a right-first-time process design based on critical fundamental data and understanding of the thermodynamic and kinetic properties of the system. However, it is scarce at the early stages of drug development to have critical experimental data for an in-depth understanding of the involved polymorphic crystallization dynamics. In this study, we present a practical methodology for obtaining critical data and understanding to guide process design for robust polymorphic control. The methodology was developed through addressing the challenge of isolating either one of the two polymorphs that have a nearly overlapping solubility profile. It involves (a) determination of critical transition temperature (Tt) of an enantiotropic polymorphic pair by conversion kinetics measurement using in situ Raman spectroscopy and (b) nucleation kinetics assessment of the metastable polymorph at a lower temperature range using a polythermal method. It is illustrated how the critical data obtained from this methodology enable rational process design and control for isolation of a pure polymorph of either one, especially the metastable form within a lower temperature range.