(410c) Monitoring of Polymorphic Outcome In Cooling Crystallization of Carbamazepine Under Various Flow Conditions

In the pharmaceutical industry obtaining a desirable polymorphic crystal structure of a drug is crucial as they differ from each other in terms of their physical and mechanical properties. Objectives of this work were: 1) to investigate influence of process parameters, including stirring speed, cooling rate and supersaturation, on polymorphic outcome in cooling crystallisation of carbamazepine, and 2) to develop and test a novel laboratory setup for in situ, non-invasive monitoring of crystallisation kinetics and polymorphic outcome.

We found that stirring was a key controlling factor for the polymorphic outcome of carbamazepine crystallisation from anhydrous ethanol. For quiescent conditions, few large needle-like crystals of alpha form were formed from clear solutions, which were then slowly transformed to the more stable prism-like beta form crystals. In the case of vigorous stirring, either a) rapid onset of turbidity due to large number of small needle-like alpha form crystals was followed by subsequent transformation into many small beta form crystals, or b) in the case of long induction times, the initial appearance of turbidity was due to formation of large number of small beta form crystals, without significant presence of alpha form crystals.

Formation and subsequent transformation of solid state phases in suspensions under both quiescent and stirring conditions was monitored in situ through simultaneous measurements of transmitted and scattered light intensities and non-invasive Raman spectrometry. Crystallisation kinetics and polymorphic transformations were found to have characteristic trajectories when followed in plots of transmitted vs. scattered intensities, as confirmed by accompanying Raman measurements. Our results demonstrate novel measurement opportunities for convenient monitoring of polymorphic transformations for systems with well distinguished morphologies.