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FDA redefines cocrystals as APIs and not drug-product intermediates.
Although pharmaceutical manufacturers prefer to formulate APIs in solid-dosage form, many drug candidates do not readily form stable crystalline solids. In addition, a growing percentage of APIs in development suffer from poor bioavailability and/or other undesirable properties. There are many approaches for addressing these issues, such as the formation of amorphous dispersions, salts, and cocrystals.
Cocrystals are attractive because, like solvates and hydrates, they allow the modification of an API’s properties without altering its chemical structure. They also provide an option for APIs that lack ionic functionality and thus cannot form salts. The synthesis of cocrystals may also be advantageous from a cost standpoint (1).
There has been, however, significant hesitation in the pharmaceutical industry regarding the use of cocrystals since the issuance of FDA’s initial guidance on cocrystals in April 2013 (2).
In that guidance, FDA defined cocrystals as “drug product intermediates (DPIs)” rather than APIs. This decision raised questions about expiration dates, intellectual property protections, and the consistency of the US approach with those adopted by other regulatory bodies (1).
A new draft guidance issued by FDA in August 2016 (3) redefines cocrystals as APIs. Classified as a special case of solvates and hydrates in which the coformer is nonvolatile, cocrystals are now to have a regulatory classification similar to that of polymorphs of APIs.
Cocrystals have crystalline lattice structures that are different from the pure API and consequently often have different physical and chemical properties. The formation of cocrystals can reduce hygroscopicity and change the particle size and shape and melting point to help overcome compaction problems for improved manufacturability. The stability of an API can also be enhanced. As importantly, dissolution properties in the body can be significantly modified. In addition, because cocrystals are neutral combinations of APIs with conformers, they can be prepared for compounds without acid or base functionality, which is required for salt formation.
The most common property targeted for improvement via cocrystal formation is an improved aqueous dissolution rate compared to an API free acid or base, according to G. Patrick Stahly, chief operating officer at Triclinic Labs. “Cocrystals are like amorphous materials in that they provide a supersaturated concentration of an API in the body for a time sufficient for absorption to occur (a supersaturating drug delivery system),” he explains. He adds that it needs to be realized, however, that a cocrystal typically does not affect the equilibrium solubility of an API; cocrystals usually dissociate in solution because they are held together by relatively weak chemical bonds.
Cocrystals also may offer benefits from an intellectual property perspective, according to Stahly. “At the current level of the science, it is not possible to predict cocrystal properties based on the molecular structures of the components. Solid-form screening, including cocrystal screening, is an empirical process. Since the formation of cocrystals is currently unpredictable, cocrystals that are discovered and found to have advantageous properties can be patented,” he notes.
It should be recognized, however, that cocrystals are still not regarded as new APIs. “Drug products that are designed to contain a new cocrystal are considered analogous to a new polymorph of the API,” according to the 2016 FDA draft guidance.
The redefinition of cocrystals as APIs is important for several reasons, according to Stahly. First, it allows the use of existing FDA guidance to provide information necessary for development. Second, existing manufacturing facilities and supply chains that make and distribute APIs can be used, and there is no need to add cocrystal manufacturing capabilities to existing drug-product manufacturing facilities. Third, API expiry dating begins at the time of cocrystal manufacture. Fourth, there is now consistency among FDA guidance, international guidance, and scientific reality.
“After the first FDA guidance was issued, there was confusion within the pharmaceutical industry about the viability of cocrystals. My personal experiences led me to believe that scientists (myself included) were unhappy because they felt the guidance was wrong from a scientific standpoint. I believe the guidance presented unnecessary obstacles to development of cocrystals, which would discourage some companies from utilizing them. Those dealing with the facilities and regulatory issues seemed to be more pessimistic. There was talk that cocrystals were ‘dead’ in the pharmaceutical industry,” comments Stahly.
Triclinic Labs did cocrystal screening and other development activities for clients in the period between issuance of the old and new guidance, indicating that not everyone felt that the original guidance eliminated the use of cocrystals.
With the new guidance, however, cocrystals were, if ‘dead’ before, now ‘reborn’, according to Stahly. “The development pathway is clear and cocrystals should now be considered another tool in the box of tools used to improve solid-state properties,” he says.
An issue addressed by the new FDA guidance is the nature of the interaction of components in a cocrystal where one component is acidic and the second component is basic. The drug manufacturer must demonstrate that there are no ionic interactions in such a cocrystal, which can be done either using the acid dissociation constants of the API and the coformer or via spectroscopic analysis.
It is important, according to Stahly, to realize that there are various analytical techniques that can be used to probe the extent of proton transfer. “A common method is single-crystal x-ray structure determination, which is an excellent technique only if used properly. It is easy for a novice to believe protons have been actually located when often they are simply left to ride on the atom to which they are bonded; the protons are in assumed instead of refined positions,” he notes. A single-crystal study is not always necessary, however, and other techniques such as infrared (IR) spectroscopy can often be used.
What drove the agency to make this significant change to its guidance on cocrystals? Stahly believes the strong response from industry was the major driving force. In 2012 at an Indo-US Bilateral Meeting held from Feb. 2-4, 2012, 46 attendees co-authored a publication presenting their consensus “… on the need to define cocrystals more broadly and to classify them like salts” and their recommendation “… that the classification of cocrystals in pharmaceutical science should be consistent with current scientific thought” (4).
Also in 2012, a working group of the International Consortium for Innovation & Quality in Pharmaceutical Development (IQ Consortium) submitted a comment paper to FDA recommending that “FDA considers classification of co-crystals within existing guidance[s], which provides discrete, industry understood points where quality attributes are measured and controlled to ensure product quality and patient safety (i.e., the drug substance and drug product)” (5).
“The primary messages from those groups were that the original guidance was inconsistent with both current scientific understanding of the nature of cocrystals and existing FDA guidance relating to drug development. In addition, the guidance would lead to negative regulatory and manufacturing consequences and be inconsistent with the European Medicines Agency provisional guidance outlining submission requirements for cocrystals. It appears that FDA seriously considered industry’s comments and revised the guidance,” Stahly observes.
1. C.A. Challener, Pharm. Tech. 38(5) (2014).
2. FDA, Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals (Silver Spring, MD, April 2013).
3. FDA, Draft Guidance for Industry: Regulatory Classification of Pharmaceutical Co-crystals (Silver Spring, MD, Aug. 2016).
4. S. Aitipamula, et al., Cryst. Growth Des.12, 2147-2152 (2012).
5. IQ Consortium, “IQ Comments on FDA Draft Guidance Regulatory Classification of Pharmaceutical Co-Crystals,” March 1, 2012.
Vol. 40, No. 11
When referring to this article, please cite it as C. Challener, “’Rebirth’ of Cocrystals?" Pharmaceutical Technology 40 (11) 2016.