On February 14, 2018, FDA released a final guidance titled “Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry.” The guidance provides information about the regulatory classification of pharmaceutical co-crystal solid-state forms, the data that applicants should submit to support the appropriate classification, and the regulatory implications of the classification.
The guidance describes co-crystals as “crystalline materials composed of two or more different molecules, typically active pharmaceutical ingredient (API) and co-crystal formers (‘coformers’), in the same crystal lattice.” Co-crystals provide a means to develop solid-state forms of an API beyond conventional solid-state forms, such as salts and polymorphs. Co-crystals can also be developed to enhance bioavailability, stability, and processability of APIs.
According to the guidance, co-crystals differ from both salts and polymorphs, and are more akin to solvates, since both solvates and co-crystals have multiple components in their crystal lattices. Thus, NDAs and ANDAs containing or claiming to contain a co-crystal form should include appropriate data supporting the classification of a co-crystal. In particular, applicants should provide evidence to demonstrate that:
(1) both the API and coformers are present in the unit cell;
(2) if both the API and coformer have ionizable functional groups, the component API and coformer co-exist in the co-crystal and interact nonionically (the guidance provides a general guideline based on the ΔpKa between the API and its coformer); and
(3) substantial dissociation of the API from its co-crystal form occurs before reaching the site of pharmacological activity.
A co-crystal with a pharmaceutically acceptable coformer that meets the above conditions can be considered to be a pharmaceutical co-crystal. The guidance notes that such co-crystals have a regulatory classification similar to that of a polymorph of the API, and are not regarded as a new API. In addition, a co-crystal that is composed of two or more APIs (with or without additional inactive coformers) will be treated as a fixed-dose combination product, and not as a new single API.