Structural characterization, physicochemical properties, and thermal stability of three crystal forms of nifedipine

In this study the single‐crystal X‐ray structure of the solvated species (nifedipine)2 · 1,4‐dioxane is reported for the first time. Included solvent molecules are located in isolated cavities in the crystal, yielding a very stable solvate. Desolvation of this species involves complete disruption of the crystal structure at the relatively high temperature of 150–153°C, i.e., 50° above the boiling point of 1,4‐dioxane, and yields a monoclinic polymorph (Modification I) with a melting point of 174°C. When exposed to an aqueous medium for 48 h, the solvate transformed into a dihydrate. The aqueous solubilities of the above species were in the order: 1,4‐dioxane solvate ≥ Modification I > dihydrate. The solubility of nifedipine was increased sixfold when transformed into an amorphous form by quenched fusion. This amorphous form was relatively stable at room temperature but converted to Modification I when suspended in water at pH 1. The fused materials also converted to Modification I through an intermediate, Modification III, within 6 days when kept at 40°C for 6 days. XRPD analysis showed that grinding increased the crystallinity of the amorphous form due to partial transformation to Modification I. The pulverized amorphous powder was more stable at 40°C and was approximately three times as soluble as Modification I. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2519–2533, 2003