To enhance the bioavailability of an Active Pharmaceutical Ingredient (API), it is typically desirable to prepare small API crystals. The process of interest involves a polymorph transformation from an undesired mixture of forms to the neat desired stable form. Conventional crystallization processing yielded crystals that were out of particle size specification (D[90] > 60 μm, spec D[90] < 30 μm). A novel crystallization method, crystallization via polymorph transformation facilitated by high shear, was employed to produce small, uniform crystals of the desired stable form. In this work, the undesired form of an API is suspended in a solvent mixture in a crystallizer. The slurry is re-circulated from the crystallizer through a Wet-Mill and back to the crystallizer at room temperature. During this re-circulation, the crystals are observed to transform to the desired form via in-situ Raman spectroscopy. Particle size analysis by laser light diffraction (Malvern) showed that crystal size distribution has a D[90]<30 μm – which is within specifications.

In this presentation, we will discuss the development of the crystallization transformation process, and the laboratory and scale up results.