Polymorph Study

It is estimated that 30-50% of Active Pharmaceutical Ingredients (APIs) exhibit polymorphism - defined as the ability of a compound to exhibit two or more crystalline phases. Polymorphic forms differ in internal structure (solid state) and may consist of changes in packing, kinetics, mechanical, spectroscopic, surface and thermodynamic properties. Each of these dimensions can greatly influence the bioavailability of the API. As a consequence, polymorph screening and selection play a vital role in the drug development process, not only to optimise performance but also to secure new intellectual property (IP) positions and ensure robust IP protection.

Crystec’s mSAS® supercritical fluid (SCF) technology is a highly effective tool in isolating ‘known’ stable and metastable polymorphs, as well as in identifying polymorphic forms unique to the high-pressure SCF environment. As such, mSAS® is often seen as an enhanced polymorph screening technique for both new chemical entities and currently marketed APIs. It has been used to separate complex polymorphs including:

• Packing polymorphs - packing and arrangement of structure of different forms are significantly different)

• Conformational polymorphs - the same molecule in different polymorphic modification with a low energy difference between the different conformations

• Pseudo-polymorphs – a new structure of a compound that is hydrated or solvated

Crystec mSAS® Case Study

The aim of this project was to discover new polymorphs of an API to strengthen an existing IP position (only one polymorph was known to exist). An enhanced mSAS® polymorph screen was carried out, identifying one new form. An analytical data package was generated in support of arising patent applications.

Product Development

Developing the product involved:

• A kinetic solubility study of solvents and solvent mixtures to be used for processing.

• A feasibility study to determine if the API was compatible with the mSAS® process.

• Testing the solubility of the API in supercritical carbon dioxide (scCO₂) to determine the best experimental design space for screening experiments.

• A process screen to scout for new polymorphs, mapping out different regions of the phase diagram. This explored regions where stable and non-stable polymorphs would be formed.

• Analysis of samples by Powder X-Ray Diffraction (PXRD) and Differential Scanning Calorimetry (DSC) to determine the polymorphic form of samples generated.

• Additional analysis of new polymorphic forms to determine particle habit, size, morphology and physical stability as required.

Product Analysis and Performance

A new polymorphic form of the API was identified. The new solid state form was characterised by PXRD and DSC analysis. Particle size and habit were determined using Scanning Electron Microscopy (SEM).