Cocrystals and Salts of Gabapentin: pH Dependent Cocrystal Stability and Solubility

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.