The US FDA has published draft guidance to help companies submit marketing applications for API-excipient co-crystals.
At AAPS in October Jon Clark, associate director for policy at the US Food and Drug Administration (FDA), said the draft, which at the time was in clearance, defines the term ‘co-crystal’ and how it affects applications.
“Co-crystals are solids that are crystalline materials composed of two or more molecules in the same crystal lattice”, the FDA wrote in draft guidance . Within its regulatory framework the FDA classes co-crystals as dissociable active pharmaceutical ingredient (API)-excipient molecular complexes.
Companies submitting NDAs (new drug application) or ANDAs (abbreviated new drug application) containing, or claiming to contain, co-crystals should generate certain supporting data for the FDA.
“If pre-conditions are met, an API that has been processed with a cocrystallizing excipient to generate an “API-excipient” co-crystal should be treated as a drug product intermediate”, the FDA wrote.
Classing the co-crystal as an intermediate affects how the FDA views products. “Co-crystal containing drug products will not be considered to contain new APIs, but rather to contain a specifically designed formulation component called a co-crystal drug product intermediate”, the FDA wrote.
The FDA said co-crystals can improve solubility, dissolution and other elements of drug performance. “A key advantage of co-crystals as a solid form of an API is the possibility of achieving the high dissolution rate comparable to that of the amorphous form”, wrote Finnish researchers in 2008.
The FDA wants to see data that shows the API and excipient exist in their neutral states and connect via non-ionic interactions. If the components connect via ionic interactions the FDA classifies the crystalline solid as a salt form.
“Spectroscopic tools may be needed to probe the extent of proton transfer and ionization states to define where the solid-state form exists within the co-crystal/salt continuum”, the FDA wrote.
The FDA also wants data relating to pharmacological activity. Data should be submitted to show that the API dissociates from its excipient before reaching the site of action.