coformers

Coformers are small molecules that form co-crystals with another compound, usually an active pharmaceutical ingredient (API), through non-covalent interactions such as hydrogen bonding, π–π stacking, or halogen bonding. In a co-crystal, the API and the coformer are present in a defined stoichiometry and retain their molecular identities, unlike salts, which involve proton transfer and ionic bonds.

Coformers are used to tailor solid-state properties of APIs, including solubility and dissolution rate, stability against moisture and chemical degradation, melting point, and mechanical behavior. By modifying these properties, co-crystals can enhance bioavailability and processing performance without altering the chemical structure of the API. They are typically distinguished from solvates or hydrates by the absence of solvent molecules in the lattice.

Design and selection of coformers rely on complementary functional groups that enable robust hydrogen-bond networks with the API. Common coformer classes include carboxylic acids, amides, amines, and heterocycles. Selection considers the possibility of proton transfer (to avoid salt formation), regulatory status and safety of the coformer, and the coformer’s own solubility and stability. Widely used examples include nicotinamide, isonicotinic acid, glutaric acid, and benzoic acid.

Preparation and characterization methods include solution crystallization, solvent-assisted or neat grinding, slurry conversion, and anti-solvent crystallization. Characterization typically employs X-ray crystallography, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and solid-state NMR to confirm identity, stoichiometry, and stability of the co-crystal.

Regulatory and practical considerations involve treating a co-crystal as a distinct solid form of the API, with regulatory classification varying by jurisdiction. Challenges include scale-up, reproducibility, and phase stability, including potential polymorphism and coformer–API transformations, as well as ensuring the safety of the coformer within the intended use.