X-ray crystallographic characterization of nilvadipine monohydrate and its phase transition behavior

Crystals of nilvadipine monohydrate were obtained from aqueous acetonitrile solution and characterized by powder and single crystal X-ray crystallography and thermal analysis. Water molecules of crystallization exist in nilvadipine monohydrate crystals in a molar ratio of 1:1 (drug-to-water) and were fixed by three hydrogen bonds with two carbonyl groups of the methyl and isopropyl esters, respectively, and one imino group of neighboring nilvadipine molecules. The conformation of the methyl and isopropyl esters in the monohydrate crystal was the reversal of that in the anhydrate crystal due to the presence of hydrogen bonds with water in the former crystal. The monohydrate crystal was slowly converted to the dehydrate at low humidity, and the latter rapidly converted to the former at high humidity. Powder X-ray diffraction studies indicated that the dehydrate retains the original structure of the monohydrate, i.e., a layer structure stacked on the ac plane perpendicular to the b-axis The solubility of the monohydrate in water was lower than that of the dehydrate and anhydrate forms, although the initial dissolution rate of the monohydrate was faster than that of the anhydrate. The present results indicated that the conformation of 1, 4-dihydropyridine-type calcium channel antagonists such as nilvadipine is easily changed by hydrogen bonds with water molecules of crystallization, and the water molecules are mobile through the void spaces formed between the layers in crystals.