X-ray crystallographic characterization of nilvadipine monohydrate and itsphase transition behavior

Crystals of nilvadipine monohydrate were obtained from aqueous acetonitrile solution and characterized by powder and single crystal X-ray crystallogra phy and thermal analysis. Water molecules of crystallization exist in nilva dipine monohydrate crystals in a molar ratio of 1:1 (drug-to-water) and wer e fixed by three hydrogen bonds with two carbonyl groups of the methyl and isopropyl eaters, respectively, and one imino group of neighboring nilvadip ine molecules. The conformation of the methyl and isopropyl eaters in the m onohydrate crystal was the reversal of that in the anhydrate crystal due to the presence of hydrogen bonds with water in the former crystal. The monoh ydrate crystal was slowly converted to the dehydrate at low humidity, and t he latter rapidly converted to the former at high humidity. Powder X-ray di ffraction studies indicated that the dehydrate retains the original structu re of the monohydrate, i.e., a layer structure stacked on the ac plane perp endicular to the b-axis The solubility of the monohydrate in water was lowe r than that of the dehydrate and anhydrate forms, although the initial diss olution 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 hydro gen bonds with water molecules of crystallization, and the water molecules are mobile through the void spaces formed between the layers in crystals. ( C) 2000 Elsevier Science B.V. All rights reserved.