Pharmaceutical cocrystals can improve solubility, dissolution, and bioavailability of poorly water soluble drugs. However, true cocrystal solubility is not readily measured for highly soluble cocrystals because they can transform to the most stable drug form in solution. The objectives of this study are to develop a method to estimate the cocrystal solubility in pure solvent and establish the influence of constituent drug and ligand (i.e., coformer) properties. Cocrystal solubility and solubility product were derived from transition concentration measurements where a solution is in equilibrium with solid drug and cocrystal. Transition concentrations and solubilities are reported for carbamazepine cocrystals in water, ethanol, isopropanol, and ethyl acetate. The aqueous solubility for seven carbamazepine cocrystals was estimated to be 2-152 times greater than the solubility of the stable carbamazepine dihydrate form. Cocrystal solubility is shown to be directly proportional to the solubility of constituent reactants for carbamazepine, caffeine, and theophylline cocrystals. The ligand transition concentration is also correlated with ligand solubility. Transition concentration measurements reveal drug solubilization by ligand for several of the cocrystals studied. The correlation established between constituent and cocrystal solubility was not effectively predicted by fusion properties of the various crystal forms considered.

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The crystal engineering design strategy facilitates supramolecular synthesis of 13 new crystalline phases of carbamazepine (CBZ), an analgesic and anticonvulsant with known problems related to solubility and polymorphism. CBZ forms supramolecular complexes with the following molecules, all of which are complementary to CBZ in terms of hydrogen bonding and can therefore act as cocrystal formers:  acetone (1a); DMSO (1b); benzoquinone (1c); terephthalaldehyde (1d); saccharin (1e); nicotinamide (1f); acetic acid (1g); formic acid (1h); butyric acid (1i); trimesic acid (1j); 5-nitroisophthalic acid (1k); adamantane-1,3,5,7-tetracarboxylic acid (1l); and formamide (1m). Two distinct strategies based upon selection of complementary hydrogen-bond functionalities and previously known supramolecular synthons were utilized:  strategy I exploits the exofunctional nature of the carboxamide dimer as either a hydrogen-bond donor or a hydrogen-bond acceptor and thereby retains the carboxamide dimer that is present in all previously isolated forms of CBZ; strategy II perturbs the carboxamide homosynthon by forming a heterosynthon between the carboxamide moiety of CBZ and the carboxylic acid moieties. The latter approach profoundly modifies crystal packing and should therefore affect the physical and pharmaceutical properties of CBZ. A full analysis of crystal packing and a discussion of what these results might mean in the broader context of crystal engineering and pharmaceutical solids is presented.

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The purpose of this work was to develop a mathematical model that describes the solubility of cocrystals by taking into consideration the equilibria between cocrystal, cocrystal components, and solution complexes. These models are applied to the phase diagrams of carbamazepine/nicotinamide (CBZ/NCT) cocrystal in organic solvents. The CBZ/NCT (1:1) cocrystal solubility was measured by suspending cocrystal in solutions of varying nicotinamide concentrations in ethanol, 2-propanol, or ethyl acetate. Results show that the solubility of the cocrystal decreases with increasing nicotinamide concentration. Mathematical models demonstrate that (1) the solubility of a cocrystal AB is described by the solubility product of cocrystal components and by solution complexation constants, (2) these equilibrium constants can be determined from solubility methods, and (3) graphical representation of the cocrystal solubility dependence on ligand concentration will serve as a diagnostic tool for the stoichiometry of solution complexes. CBZ/NCT cocrystal K sp values increase as the cocrystal solubility increases, while K 11 values decrease. The dependence of cocrystal solubility on solubility product and complexation constants provides a powerful approach to design cocrystal screening methods and to formulate solutions with cocrystal components where crystallization does not occur.

A mechanism for cocrystal synthesis is reported whereby nucleation and growth of cocrystals are directed by the effect of the cocrystal components on reducing the solubility of the molecular complex to be crystallized. The carbamazepine:nicotinamide cocrystal (CBZ:NCT) was chosen as a model system to study the reaction cocrystallization pathways and kinetics in aqueous and organic solvents. Fiber optic Raman spectroscopy and Raman microscopy were used for in situ monitoring of the cocrystallization in macroscopic and microscopic scales in solutions, suspensions, slurries, and wet solid phases of cocrystal components. This study demonstrates the advantages of reaction cocrystallization methods to develop rational approaches for high-throughput screening of cocrystals that can be transferable to control batch and continuous cocrystallization processes.

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