FDA drafts guidance on the regulatory classification of pharmaceutical cocrystals
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The FDA published in December of 2011 its first opinion on pharmaceutical cocrystals.  Crystallics’ Chief Scientific Officer Marcel Hoffmann has reviewed the documents and provides some thought as to its guidance. 

Surprisingly, in this guidance document, the FDA does not rank cocrystals in the same league as salts and polymorphs, all well known solid state presentations of pharmaceutical entities.  The FDA sees a cocrystal as a molecular interaction between an API and an excipient, very much the same way an API is captured in a cyclodextrin doughnut or the way APIs and excipients interact with each other in amorphous dispersions.  In this draft guidance the FDA states that traditionally APIs are grouped as either polymorphs or salts.  This classification assumes that an API is a salt or a polymorph whereas in fact it is both.  A salt is the result of a reaction between an acid and a base which after precipitation from solution can be either crystalline or amorphous.  A polymorph is a specific organization of molecules in a crystal lattice.  Hence a salt can appear in multiple polymorphs.  In fact, cocrystals are by definition crystalline and can therefore appear in multiple polymorphic forms.

In the guidance document the FDA recognizes the continuum between salts and cocrystals and differentiates between both on the basis of the differences in pKa value of the acid and base.  If this ΔpKa is less than 0 it would be a cocrystal and a ΔpKa of more than 3 would be a salt.  In between 0 and 3 it becomes a gray area.  This definition sees a salt crystal or cocrystal as a static entity where in fact it is more dynamic and the proton will constantly be moving between the two parts.  In a salt the majority of the time the proton will be on the base and in a cocrystal the proton will be located most of the time on the acid.  Carboxylic acids are well known for their ability to either form a salt or a cocrystal.  An even more complex situation is published by Pop et al (J Pharm Sci. 2009 May; 98(5):1820-34) on tiotropium fumarate.  In this publication it is shown that one carboxylic acid moiety interacts as salt by proton transfer whereas the second carboxylic acid group of fumaric acid interacts as a cocrystal by the formation of hydrogen bonds.  This example demonstrates that the FDA guidance is not clarifying as the above described mixed salt/cocrystal (which are not rare) are “in between”. 

This continuum between salts and cocrystals demands a different classification than the FDA proposes in this guidance document. 

An alternative approach would be to consider salts and cocrystals as equal and apply the same rules to cocrystals as those applied for salts.  Applying the ΔpKa rule to salts present in marketed products will likely show that several of those are in fact cocrystals and not salts.

For further information please contact Marcel Hoffmann on +31 20 820 2690 or This e-mail address is being protected from spambots. You need JavaScript enabled to view it

The FDA guidance can be accessed at the following link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM281764.pdf