As part of an effort to clarify and help advance the development of pharmaceutical co-crystals, the US Food and Drug Administration (FDA) on Tuesday released revised draft guidance providing information on the appropriate classification of co-crystal solid-state forms, the data that should be submitted to support the classification and the regulatory implications of such a classification.
“Co-crystals are crystalline materials composed of two or more different molecules, typically drug and co-crystal formers (‘coformers’), in the same crystal lattice. Pharmaceutical co-crystals have opened up opportunities for engineering solid-state forms beyond conventional solid-state forms of an active pharmaceutical ingredient (API), such as salts and polymorphs,” FDA explains. “Co-crystals can be tailored to enhance drug product bioavailability and stability and to enhance the processability of APIs during drug product manufacture. Another advantage of co-crystals is that they generate a diverse array of solid-state forms for APIs that lack ionizable functional groups, which is a prerequisite for salt formation.”
The new draft revises a previous guidance for industry, "Regulatory Classification of Pharmaceutical Co-Crystals" issued in April 2013, which classifies co-crystals as a drug product intermediate (or as an in-process material).
“This classification has contributed to uncertainty regarding the interpretation of the guidance because in a commercial setting, co-crystals are typically manufactured in drug substance facilities, yet when classified as a drug product intermediate, additional current good manufacturing practice requirements apply,” FDA says. “Therefore, the guidance has not been conducive to the development of co-crystals. In response to this and other feedback from stakeholders, FDA has reconsidered the appropriate classification of co-crystals.”
The short guidance also explains that co-crystals differ from salts and polymorphs, and are more similar to solvates, “in that both contain more than one component in the lattice. From a physical chemistry perspective, co-crystals can be viewed as a special case of solvates and hydrates, wherein the second component, the coformer, is nonvolatile. Therefore, co-crystals are classified as a special case of solvates in which the second component is nonvolatile.
“For NDAs and ANDAs containing or claiming to contain a co-crystal form, applicants should submit appropriate data that support the following:
- If both drug and coformer have ionizable functional groups, a conclusion that the component drug and coformer exist in their neutral states in the co-crystal and interact nonionically. Consider the following to guide your decision: Generally speaking, if the API and its coformer have a ΔpKa (pKa (base) - pKa (acid)) > 1, there will be substantial proton transfer resulting in ionization and potential formation of a salt as opposed to a co-crystal. On the other hand, if the API and its coformer have a ΔpKa (pKa (base) - pKa (acid)) < 1, there will be less than substantial proton transfer. If this criterion is met, the API-coformer entity should be classified as a co-crystal. If, however, you believe that the classification of the pharmaceutical solid as a salt or co-crystal is not predicated on these relative pKa values, use spectroscopic tools and other orthogonal approaches to provide evidence to the contrary.
- Assurance that substantial dissociation of the API from its co-crystal form occurs before reaching the site of pharmacological activity. Given that the interaction of the API with its coformer 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 active API dissociates from its coformer before reaching the site of pharmacological activity."
FDA adds that from a regulatory perspective, drugs designed to contain a new co-crystal are considered analogous to a new polymorph of the API.
“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 a new API. If you are using a material that the Agency previously considered to be a co-crystal, you may continue to do so,” FDA says.
Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry