The objective of this study is to identify factors and conditions governing the formation and stability of cocrystals with different stoichiometry. Carbamazepine−4-aminobenzoic acid (CBZ−4ABA) cocrystals were chosen as the model system. A 1:1 CBZ−4ABA cocrystal was discovered by the reaction crystallization method. This cocrystal is characterized by carboxylic acid···acid and amide···amide homosynthons. The stability of 2:1 and 1:1 cocrystals is shown to be dependent on ligand solution concentration. The cocrystal richer in ligand component is more stable at higher ligand solution concentrations. Solubility of cocrystals and crystalline drug is explained by 1:1 solution complexation, and both cocrystals follow solubility product behavior. Mathematical models based on cocrystal and solution chemistry were fit to experimental data to generate phase solubility and triangular phase diagrams.

Understanding how cocrystal solubility-pH dependence is affected by cocrystal components is important to engineer cocrystals with customized solubility behavior. Equations that describe cocrystal solubility in terms of solubility product, cocrystal component ionization constants, and solution pH are derived for cocrystals with acidic, basic, amphoteric, and zwitterionic components. Studies with carbamazepine-salicylic acid and carbamazepine-4-aminobenzoic acid show that cocrystals of a nonionizable drug achieve pH-dependent solubility when cocrystallized with ionizable coformers. These findings are in good agreement with predicted behavior and provide insight on the ability of coformer to determine the shape of the pH-solubility curve. It is shown that measurement of solution concentrations and pH at the eutectic point, C tr , is valuable to (a) estimate cocrystal solubility-pH dependence, (b) evaluate the effectiveness of coformer in stabilizing or precipitating cocrystal, and (c) guide cocrystal selection without the time and material consuming determination of full phase solubility diagrams.

Thirteen new multicomponent crystals (cocrystals and salts) of an anticonvulsant drug gabapentin with various carboxylic acid coformers have been discovered using the reaction crystallization method (RCM). These new forms are characterized by X-ray powder diffraction (XRPD), Raman and infrared spectroscopy, and differential scanning calorimetry (DSC). Crystal structures with 3-hydroxybenzoic acid (3HBA) 1, 4-hydroxybenzoic acid (4HBA) 2, salicylic acid 3, 1-hydroxy-2-napthoic acid (1H2NA) 4, and RS-mandelic acid 5 are also determined. While there is proton transfer from coformer to gabapentin in crystals 3−5, no proton transfer occurs in 1. Partial proton transfer is observed in crystal structure 2. Multicomponent crystals 1−5 are thermodynamically stable and do not transform to gabapentin hydrate in water suggesting that the multicomponent phases have equal or lower solubility than the components. pH has been shown to be an important variable in controlling solubility and stability. A mathematical model that describes the pH dependent solubility profile of a cocrystal with a zwitterionic drug and an acidic coformer is derived based on cocrystal dissociation and ionization solution equilibria. Predicted pH dependent cocrystal solubility and stability are in good agreement with experimental measurements. An important capability of these models is that it allows one to generate the solubility and stability dependence on pH from the knowledge of pK a values and solubility measurement at a single pH. Comparison of pH-solubility profiles of cocrystal and components establishes the pH-dependent stability regions for cocrystal and components.

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Image reproduced with permission from Abbie TrewinOther articles published in this issue include:Dipyrrin based homo-and hetero-metallic infinite architectures Stéphane A. Baudron, CrystEngComm, 2010,The nutraceutical compound pterostilbene is investigated for its propensity to form cocrystalline materials with active pharmaceutical ingredients. Three cocrystals of a 1 : 1 stoichiometric molar ratio of pterostilbene with caffeine (two polymorphs, Form I and Form II) and carbamazepine were prepared and characterized by crystallographic (XRPD, single-crystal) and thermoanalytical (TGA, DSC) techniques. Physical stability of the cocrystals with respect to relative humidity (RH) was examined and found to be dramatically improved in relationship to caffeine or carbamazepine. The carbamazepine : pterostilbene cocrystal was stable upon slurrying in water for 3 days; therefore, aqueous equilibrium solubility measurements were carried out, revealing that the cocrystal solubility was 7Â lower than carbamazepine dihydrate and 2.5Â lower than pterostilbene. Slurrying the caffeine : pterostilbene cocrystal (Form I) in water led to a solution that was supersaturated with respect to pterostilbene, resulting in the precipitation of pterostilbene after three days; therefore concentrations at specific time points were measured as opposed to equilibrium solubility. At five hours the concentration of the caffeine cocrystal was 33Â lower than the caffeine hydrate solubility, but was 27Â higher than the pterostilbene solubility.