When selecting the solid-state form of your Active Pharmaceutical Ingredient (API) for pharmaceutical development, one typically initiates an API salt and polymorph screen; however, consideration should be given to including a cocrystal screen. Cocrystals are crystalline solids having two or more components in their crystalline lattice in a stoichiometric ratio. The components include the API and the cocrystal former (coformer). Coformers are molecules that are pharmaceutically acceptable and generally regarded as safe (GRAS) including amino acids (L-proline), sweeteners (aspartame, saccharin, acesulfame, xylitol), organic acids (adipic acid, lactic acid, oxalic acid, succinic acid, malic acid, mandelic acid, L-pyroglutamic acid, citric acid), caffeine, urea, vanillin, nicotinamide, and others. Unlike an API salt in which a proton is transferred from one molecule to another, in a cocrystal the two molecules are held together by nonionic and noncovalent interactions, such as hydrogen bonding, Van der Waal attractive forces, and π-π interactions, and without a proton transfer.
Cocrystallization may provide unique advantages for solid form development to enhance the API physicochemical properties such as melting point, solubility, permeability, dissolution, tablet-ability, and stability. This can be especially useful because many new APIs in development are Biopharmaceutics Classification System (BCS) Class II (low solubility, high permeability) and BCS Class IV (low solubility, low permeability) molecules which have their inherent development challenges. For APIs without ionizable functional groups which is a prerequisite for salt formation, cocrystals offers the possibility of the formation of a crystalline solid.
There are several techniques that are used in searching for an API cocrystal in a screening procedure including solid state grinding, liquid assisted grinding, solvent-drip grinding, solvent evaporation, supercritical solvent crystallization, spray drying, freeze drying, resonant acoustic mixing, hot melt extrusion, and laser irradiation. The search for an API cocrystal is a trial and error method involving the choice of the coformer and the screening methodology.
Once prepared, the cocrystal is best analyzed by single crystal X-ray diffraction. In this manner any proton transfer that has occurred between the API and coformer can be discerned. Supporting analytical methods include DSC, TGA, FTIR, PXRD, and SSNMR.
Another advantage of an API cocrystal is the accompanying intellectual property. Cocrystals offer patent protection for the API because the cocrystal would be totally novel without any prior art; it would be pharmaceutically useful; and it would be nonobvious as any API cocrystal formation is unpredictable. Additionally, an API cocrystal would offer patent protection for any potential blockbuster drug and could be used for life cycle management.
There are several solid state examples of API cocrystals, including ibuprofen-nicotinamide, carbamazepine-saccharin, amoxicillin trihydrate-potassium clavulanate, and the API salt-cocrystal, ivabradine hydrochloride-(S)-mandelic acid.
Of further interest is the 2018 FDA guidance on cocrystals:
Center for Drug Evaluation and Research (CDER) Regulatory Classification of Pharmaceutical Co-crystals, Guidance for Industry. Food and Drug Administration. U.S. Department of Health and Human Services. Pharmaceutical Quality/CMC. Revision 1 (February 2018)
To summarize, when developing the solid state form of your API it is advisable and very advantageous to include a cocrystal screen in addition to your API salt and polymorph screens. Reach out to us today to learn more!
Written By: Gary M. Dull
August 3, 2024
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