The crystallisation of polymorphic forms – understanding the mechanism

Crystallisation from solution is a major process by which chemical companies transform synthetic products into solid forms suitable for formulation into commercial products. It is well known in the literature that impurities can have wide ranging effects on crystallisation, from delaying the onset of nucleation to modifying the particle morphology and changing the crystalline form. Impurities can be introduced from many areas e.g. variation in manufacturing process, solvent stabilisers. During API development, it is common to change the route of synthesis to become more efficient, this can change the levels or change the nature of the impurities present, which can in turn control which polymorph is observed. This may be different to that previously thought to be the thermodynamically preferred polymorph and hence give rise to significant problems of product consistency and reproducibility.

Within pharma companies impurities have been implicated in several polymorphic control problems on active compounds. These are typically rectified by controlling the purity profile, either by column chromatography or other slurry based rework procedure. What has yet to be understood, however, is the mechanism by which the different polymorphs are stabilised by impurities; in particular, the deconvolution of effects of impurities on nucleation of a particular polymorph from the effects on crystal growth. Once understood, this mechanism may be better controlled by modifying parameters in the crystallisation process such as seed point and supersaturation control, reducing the need for time consuming extra reworks or chromatography.

The student will learn and apply modern techniques of solid state and solution chemistry to this problem – X-ray diffraction, FTIR, Raman and UV/vis spectroscopy, calorimetry and high throughput experimentation. The work is supported by a leading UK pharma company.