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Cocrystals formation is an engineering-based approach to develop a new active pharmaceutical ingredient (API) form with desirable properties, mainly enhanced solubility (also offers better bioavailability, stability, hygroscopicity and processability during drug product manufacturing like compaction, flowability, filterability, etc). Major global markets such as the US FDA and the European Medicines Agency (EMA) have already suggested some guidance for the category. On September 15, 2025 the Indian regulator Central Drugs Standard Control Organisation (CDSCO) made its views clear for the cocrystals and declared it as a new active substance which will be dealt with according to the guidelines prescribed for new drugs in the New Drugs and Clinical Trials Rules, 2019. In the clarification CDSCO has mentioned that cocrystal of already approved active substance may require validation of manufacturing process, stability studies, additional clinical and non-clinical studies, bioavailability/bioequivalence studies, to demonstrate its safety and efficacy. The applicant must demonstrate that the physicochemical (in vitro) and or pharmacokinetic (in vivo) properties of the multicomponent cocrystals/solid state form are superior to that of the physical mixture of the same chemical components.
Poor aqueous solubility is a major challenge to the drug substances and as per an estimate nearly 40 per cent of the developed new chemical entities (NCEs) are practically insoluble in water. Other methods for the solubility enhancement are particle size reduction, salt formation, solid dispersion, polymorphs, use of surfactant and complexation.
Polymorphs and salt formations are the techniques where we play with the APIs only but can’t be coined as engineered rather these are conventional techniques. In salts, the components are arranged in the crystal lattice predominantly based on ion-pairing. The components in cocrystals, whether they are neutral, acidic or basic, are assembled via weaker interactions, such as hydrogen bonding, p-p stacking or Van der Waals interactions. Salts are typically formed in an acid–base reaction by proton (H+) transfer from acid to base. The major advantage of cocrystals is that it can produce a range of solid-state forms for APIs that lack ionizable functional groups, which is a prerequisite for salt formation. The components - API and conformer (also known as solid solutions) co-exist in the cocrystal lattice with a defined stoichiometry which interact non-ionically. Nonetheless, both cocrystals and salts have defined stoichiometries, as well as a solubility product Ksp. Cocrystals aren’t new to supramolecular chemistry and have been found to be existing since around 40 years but their exploration in pharmaceuticals has started in the last decade.
A guidance document released in 2018 by the US FDA mentions the data requirement for a drug product (NDA and ANDA) containing cocrystals. The applicants should provide:
- Evidence to demonstrate that both the API and coformers are present in the unit cell.
- A conclusion that the components API and coformer co-exist in the cocrystal and interact non-ionically, if both API and coformer have ionizable functional groups.
- Assurance that substantial dissociation of the API from its cocrystal 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 API dissociates from its coformer before reaching the site of pharmacological activity.
- The type and extent of characterization and release testing performed on the cocrystal should be sufficient to ensure the identity, strength, quality, and purity of the API(s).
The US FDA further mentions that a cocrystal with a pharmaceutically acceptable coformer that meets the above conditions can be considered to be a pharmaceutical cocrystal and has a regulatory classification similar to that of a polymorph of the API. Specifically, it is not regarded as a new API. From a regulatory perspective, the drug products that are designed to contain a new co-crystal are considered analogous to a new polymorph of the API. A cocrystal 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 single API.
The European Medicines Agency has released a reflection paper on it in 2015 where it mentions that the ratio may not be strictly stoichiometric and the amount of coformer may vary over a given range at a given point in the lattice of a crystal structure. It understands that solvates including hydrates can be considered as a subgroup of cocrystals; nevertheless, the regulatory context may sometimes differ. Cocrystals and salts share many conceptual similarities and therefore also similar principles for documentation should be applied. In the case of a complex coformer additional documentation may be required; a scientific advice procedure is recommended. In this case the structure needs to be fully justified e.g. from batch-to-batch consistency and from a quality control point of view. It suggests that cocrystals, hydrates and solvates are held together by weak interactions that are in most cases broken upon dissolution. This is the same situation as with salts. Hence, with respect to oral administration, dissolution of such different forms of a drug substance in the stomach or the intestinal canal will lead to the release of the same substance, independent of the form that was taken in. It should be confirmed by the bioequivalence studies. Cocrystals, hydrates and solvates will therefore be considered eligible for generic applications in the same way as salts are (Article 10(2)(b) of Directive 2001/83/EC and Article 13(2)(b) of Directive 2001/82/EC) unless they differ with respect to safety and/or efficacy. The same concept may also apply to other routes of administration provided that it is possible to show that there is no difference with respect to safety and/or efficacy. Upon first receiving a marketing authorisation application, an assessment will be done by the regulatory authorities to ensure that when an active substance is claimed to be new, it is indeed new. The formation of cocrystals just like salts is normally subject to compliance with part II of the EU-GMP guide (active substances) and ICH Q7 (GMP guide for APIs). If, however, in more rare cases where a cocrystal is formed in a step during the drug product manufacturing process such as a wet granulation or hot melt extrusion the formation falls under Part I of the EU-GMP guide (finished product), while the Part II applies to active component(s) forming the cocrystal. It is generally considered that for a given active substance there are a larger number of possible coformers available to tailor the solid-state properties wanted, although simple, well-known molecules such as succinic acid, saccharin and caffeine are often recommended. Just as for any other component of a medicinal product, e.g. excipients or counter ions, coformers must be pharmaceutically acceptable, i.e. their safety and quality must be ensured. If not used previously in medicinal products within the EU/EEA, they should be justified. This may be documented in the same way as for a novel excipient which may, if applicable, include e.g. cross-references to community provisions based on toxicological data concerning additives in food stuffs. It may be possible to form cocrystals containing more than one active substance. A medicinal product containing such a solid-state form should be taken as a fixed dose combination (FDC). The individual active substances must be documented in line with current guidance on FDCs. The stoichiometry of the cocrystal does not have to be limited to equimolar amounts. A careful justification of the dose ratio of the individual active substances is required since it is determined and restricted by the relative stoichiometry within the cocrystal. Influence of the cocrystallization on the bioavailability of the individual active substances should be discussed in the submitted dossier. Normally, the strength of the medicinal product must be given as for other fixed dose combinations, i.e. stating the amount of each active substance rather than the amount of the cocrystals. The individual active substances of a cocrystals with more than one therapeutic moiety may qualify for new active substance status if it does not expose the patient for the same therapeutic moiety compared to already authorised medicinal products in the EU.
The documentation required in different EMA applications are:
- Having conceptual similarities between cocrystals and salts are there, so similar principles for documentation should be applied.
- All quality-related information should normally be provided in part 3.2.S of the dossier. This includes general information, as well as information regarding the manufacture, characterization, and control of the drug substance, reference standards or materials, container-closure system and stability. If desired, and if the prerequisites mentioned in section 3.1.5 are met, the applicant may employ the ASMF procedure.
- The pharmaceutical acceptability of coformers must be addressed. In line with ICH Q11, commonly available chemicals employed as coformers in the cocrystal manufacture would be considered as reagents. However, for more complex or novel coformers, details of the manufacture, characterization and controls, with cross references to supporting safety data should be provided for them, according to the drug substance format. In these cases, the applicant is encouraged to seek scientific advice on the classification of the coformer from the EMA or national competent authorities prior to submission.
- If a cocrystal is claimed, and to rule out the possibility of the formation of a purely physical mixture of two or more crystalline compounds, the formation of a cocrystal should be unambiguously demonstrated by means of adequate analytical techniques. Results from more than one technique and an orthogonal approach may be necessary.
- The (solid state) form of the active substance should be discussed in Module 3.2.P in relation to its fate during manufacture of the drug product. Where relevant for product performance, the preservation of integrity of the cocrystal should be evaluated and if appropriate experimentally confirmed.
(Author is a New Delhi based academician and R&D consultant, having working experience of global healthcare companies, can be reached at aamir_pharma@yahoo.com)
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