X-ray structural studies and physicochemical properties of cimetidine polymorphism.

Four crystalline forms of cimetidine, three anhydrous (forms A, B, and D) and a monohydrate (form C), obtained by slow evaporation of aqueous solutions of varying concentrations were characterized by IR spectroscopy, X-ray powder patterns, dissolution rates in deionized water, and thermal analyses. Among the three anhydrous forms of cimetidine, form A was thermodynamically more stable than the others. The structural conversion of form C into form A on dehydration was confirmed by IR spectroscopy and X-ray powder patterns. The structures of forms C and D were determined using X-ray diffraction. Form D was of spirally curled conformation; it was linked in a head-to-tail arrangement with the neighboring molecules via intermolecular hydrogen bonds between the imidazole nitrogen and guanidine nitrogen atoms. Form C was characterized by its folded conformation due to the weak stacking interaction between the imidazole and guanidine moieties; there was stabilization by double hydrogen bond formation with neighboring molecules and via water molecules of crystallization. The dissolution rate constant in deionized water for form C was approximately 1.29, 1.70, and 1.90 times greater than those measured for forms A, D, and B, respectively. There was a similar relationship among the four forms with respect to the rates of inhibition of stress ulceration. Regarding the molecular conformations of the crystalline forms and the rates of inhibition of stress ulceration, the gauche orientation of the guanidine group relative to the imidazole ring would be the conformation necessary for effective binding to the histamine H2-receptor. The compactly folded conformation of form C appears to be optimal for binding to the active site of the receptor and for clinical efficacy.