Nucleation and Growth Kinetics in a Polymorphic System – The Case of Tolfenamic Acid

Abstract

The control of crystallization processes in polymorphic systems remains a long-term goal at both laboratory and industrial scales. The rational design of processes that yield specific, desired crystal structures with suitable physical properties requires not only phase equilibrium data but also insights into the relative nucleation and growth rates of available crystal forms. For polymorphic systems that crystallize concomitantly, not only is such data largely unavailable, but also it is difficult to measure. This study determines the nucleation and growth kinetics of tolfenamic acid forms I and II from induction time distributions obtained from their crystallization in isopropanol in small volumes. The significant influence of crystal growth on both the form and analysis of induction time distributions has been examined, and methods to appropriately account for this effect are discussed. An analytical solution is developed, describing the induction time distribution in a dimorphic system in terms of the nucleation and growth kinetics of both forms. Despite the relevance of such data, this appears to be the first occasion in which such kinetic data have been obtained in a concomitantly crystallizing system.