Cocrystals: defining the opportunity

However, these very clear opportunities are potentially constrained by an uncertain regulatory pathway. In 2013 the Food and Drug Administration (FDA) defined cocrystals as drug product intermediates (DPIs), deeming that the conformer is an excipient; in contrast, the European Medicines Agency (EMA) in 2014 defined cocrystals as being solid state variants of the APIs, aligning them with salts, polymorphs, hydrates or solvates.

The problem is that there appears to be no universally agreeable definition of cocrystals. There does appear to be a general consensus that cocrystals are homogeneous crystalline materials comprised of at least two different components with defined stoichiometry, however, the disagreement is centred on the properties of these constituent parts. The FDA went on to define cocrystals as “solids that are crystalline materials composed of two or more molecules in the same crystal lattice”. The FDA also indicates that, “traditionally, pharmaceutical solidstate forms of an API are grouped as either polymorphs or salts. Cocrystals, however, are distinguishable from these traditional pharmaceutical solid-state forms. Unlike polymorphs, which generally speaking contain only the API within the crystal lattice, cocrystals are composed of an API with a neutral guest compound conformer in the crystal lattice. Similarly, unlike salts, where the components in the crystal lattice are in an ionized state, a cocrystal’s components are in a neutral state and interact via non-ionic interactions.”

These definitions support the Agency’s current regulatory viewpoint, that is to say that co-crystals are dissociable “API—excipient” molecular complexes that should be treated as drug product intermediates (DPIs) and not as different variants of the API. As such the FDA guideline has encountered extensive criticism from the scientific community – both in academia and industry⁸.

In contrast, in the EMA’s reflection paper, their position is more aligned with the industrial and academic views that cocrystals are in fact different forms of the API⁶.

There will undoubtedly be many cocrystals that will form polymorphs, hydrates or solvates⁶. This is likely to cause significant regulatory confusion if these different forms need to be fully described in the drug product section of the regulatory application, rather than in the API section. Similarly, the exact description of cocrystals/salts can sometimes be open to significant uncertainty, and there can often be a salt-cocrystal continuum. For example, the crystal structure of escitalopram oxalate shows one oxalate dianion and one neutral oxalic acid molecule for every two escitalopram cations7. Thus, di-escitalopram oxalate is cocrystallised with oxalic acid, and can be viewed as being a cocrystal as well as a salt. Indeed, there are some marketed APIs that were approved as salts, but are in fact cocrystals, for example, caffeine citrate³ or escitalopram oxalate^8,7. In reality, there are doubtless many other examples where pharmaceutical salts are in fact cocrystals. However, some commentators have questioned whether it really matters whether a molecular ‘complex’ is either a salt or cocrystal, as long as the underlying design intent is achievable^9,10,6.

Thus, a fundamental understanding of physical/chemical mechanisms underpinning any physical change(s) are essential during drug formulation development¹¹ and should be part of any Quality by Design (QbD) drug development strategy^6,12.

However, it would appear that scientific understanding is not a constraining consideration in the industrial uptake of cocrystals, but rather it is the regulatory uncertainty and specifically the different approaches favoured by the FDA and EMA, that are likely to slow their more general usage¹³.

References

1. Qiao, N, et al. Pharmaceutical cocrystals: An overview, Int J Pharm 2011: 419: 1-11
2. Kim S, et al. Development and characterization of a cocrystal as a viable solid form for an active pharmaceutical ingredient. Org Proc Res Dev 2013; 17: 540-548.
3. Karki S, et al. Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding. Mol Pharm 2007; 4, 347-354.
4. Schultheiss N & Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des 2009; 9: 2950-2967.
5. FDA, US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Regulatory Classification of Pharmaceutical Cocrystals, 2013.
6. EMA, Reflection paper on the use of cocrystals and other solid state forms of active substances in medicinal products, EMA/CHMP/CVMP/QWP/136250/2014, 25^th February, 2014.
7. Harrison WTA, et al. Escitalopram oxalate: co-existence of oxalate dianions and oxalic acid molecules in the same crystal. Acta Cryst C 2007; 63: O129-O131.
8. Aitipamula S, et al.   Polymorphs, Salts, and Cocrystals: What’s in a Name? Cryst Growth Des 2012; 12: 2147-2152.
9. Aakeröy CB, et al. Cocrystal or salt: Does it really matter? Mol Pharm 2007; 4: 317-322.
10. Childs SL. The salt-cocrystal continuum: The influence of crystal structure on ionization states. Mol Pharm 2007; 4: 323-338.
11. Gao Y, et al. Physical stability of pharmaceutical formulations: solid-state characterization of amorphous dispersions. Trends Anal Chem 2013; 49: 137-144.
12. Huang J, et al. A Quality by Design approach to investigate tablet dissolution shift upon accelerated stability by multivariate methods. Eur J Pharm Biopharm 2011; 78: 141–150.
13. Challener C. Scientific advances in cocrystals are offset by regulatory uncertainty. Pharm Tech May 2, 2014. http://www.pharmtech.com/pharmtech/Ingredients+Insider/Scientific-Advances-in-Cocrystals-are-Offset-by-Re/ArticleStandard/Article/detail/842102. Accessed on 21st August 2014.