Crystallisation in the Salt-cocrystal Continuum: A Tale of Two Morphologies

Crystallisation design is a critical step in the development of many APIs. Optimisation of this process so that it is both scalable and robust can be a time-consuming, labour-intensive process not guaranteed to obtain desirable results. As crystallisation is governed by kinetics as well as thermodynamics, alterations in heat and mass transfer during process scale-up can lead to the appearance of previously unseen and undesirable phenomena on scale. The formation of transient polymorphs and oil-to-crystal transformations which are often short-lived so as to be difficult to observe at lab scale, can become process-limiting on multi kilogram scale. The advent of high-resolution process analytical technology means that such phenomena can be observed at reduced scale. In this presentation, we describe a rational design for the crystallisation of a metastable cocrystal using both modelling and a range of in-situ measurements to minimise experimental burden. A Dynochem® model is developed which describes the crystallisation process and is used to control litre-scale processes from milligram-scale solubility measurements. In process measurements of solution concentration, particle size, particle morphology and crystal form are then used to inform and validate the model. For this, the BlazeMetrics 900 probe is used to identify process changes and guide circumvention of unwanted phenomena. The crystallisation of the metastable cocrystal is successfully scaled-up to validate the model and an accurate prediction of the particle size distribution by the model is realised.

This webinar was presented by Dr Joe Harris from Johnson Matthey, who kindly sponsored the session.