The US Food and Drug Administration (FDA) on Wednesday finalized a revision to its guidance on the regulatory classification of pharmaceutical co-crystals.
Specifically, FDA says the guidance is meant to clarify how co-crystals are classified and what information sponsors of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) should provide to support the classification of a co-crystal.
FDA defines pharmaceutical 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."
According to the agency, co-crystals provide a number of opportunities to improve drugs over "conventional solid-state forms of an API" as they can be used to improve bioavailability and stability, and can make APIs easier to process during manufacture.
While the guidance is largely similar to the draft version released in August 2016, FDA says it has provided additional clarification about the regulatory classification of co-crystals and their relationship to solvates and hydrates.
"From a physical chemistry and regulatory perspective, co-crystals can be viewed as a special case of solvates and hydrates, wherein the second component, the conformer, is not a solvent (including water), and is typically nonvolatile," FDA writes.
FDA says that co-crystals meeting its requirements are classified similar to polymorphs and are not regarded as new APIs. "From a regulatory perspective, drug products that are designed to contain a new co-ccrystal are considered analogous to a new polymorph of the API," FDA writes, adding that co-crystals that contain two or more APIs are considered to be fixed-dose combination (FDC) products rather than new APIs.
However, FDA says that companies already marketing drugs containing a material the agency previously considered to be a co-crystal can continue to do so, though new applications for those products should include evidence of the agency's previous co-crystal designation.
For drugs containing or claiming to contain a co-crystal, FDA says sponsors should submit evidence demonstrating that "both the API and the conformers are present in the unit cell."
FDA also says that sponsors should show that the API and conformer co-exist in the co-crystal and interact nonionically if both components have ionizable functional groups.
And FDA says that sponsors should demonstrate that the API will be substantially dissociated from its co-crystal form before the drug reaches the site of pharmacological activity.
"Given that the interaction of the API with its conformer is of similar magnitude to the interaction of the API with solvents in solvates, an in vitro evaluation based on dissolution and/or solubility is generally considered sufficient to demonstrate that the API dissociates from its conformer before reaching the site of pharmacological activity," FDA writes.
Guidance, Federal Register Notice