Solid state properties – polymorphism

Polymorphism, in its strict use, is the packing of an API (or other material) into more than one different crystal form. Hydrates and solvates are sometimes referred to as polymorphs, but this is not strictly true as they contain other material in the crystal structure (water or solvent), whereas polymorphs just contain the one material. That said, hydrates (often called pseudopolymorphs) and solvates have differences in physic-chemical properties that are of the same significant as polymorphs.

The properties of two different polymorphs can be of huge importance for the processing, stability and use of pharmaceutical products. This is especially true for poorly soluble APIs, as for these it is highly probable that changes in dissolution rate will alter the bioavailability. It is for this reason that regulatory authorities around the world, such as the FDA and EMEA, require the study of physical form for product registration, and why they will be especially concerned when the API is poorly soluble.

Different polymorphic forms have differences in properties such as melting point, flow, ability to mill and compress, as well as differences in chemical stability. Consequently, the selection of physical form is important not just to control bioavailability / dissolution, but also to optimise processability.

As only one form will be stable (at any one temperature and pressure) all other forms (and there may be many) are metastable, and the suitability for use comes from understanding the rate of conversion form the metastable to the stable form.

Consultancy is available for
• selecting the most appropriate polymorph screening strategy – doing the correct amount of work at the most appropriate stages in development
• problem solving, for batch-to-batch variability for example
• outsource company selection and management
• data interpretation

Remember studies of physical form should be considered as part of an overall strategy for the API. Whether it is a new chemical entity, life cycle management or generic, the form of the API will be an important consideration as part of the overall development. Graham will assist with keeping this aspect in proportion with the overall development goals.

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