![]() 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the development of pharmaceutical co-crystals, the US Food and Drug Administration (FDA) on Tuesday released revised draft guidance providing information on the appropriate classification of co-crystal solid-state forms, the data that should be submitted to support the classification and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.” DetailsThe 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:
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. |
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