Mechanistic Studies on Hydrotropic Solubilization of Nifedipine in Nicotinamide Solution

• Published in: Chemical & pharmaceutical bulletin Vol. 46; no. 1; pp. 125 - 130
• Main Authors: SUZUKI, Hideshi, SUNADA, Hisakazu
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.01.1998; Maruzen; Japan Science and Technology Agency
• Subjects: Biological and medical sciences; complex formation stability constant; Drug Stability; General pharmacology; hydrophobic interaction; hydrotropic solubilization; Medical sciences; Niacinamide - analogs & derivatives; Niacinamide - chemistry; nicotinamide; nifedipine; Nifedipine - chemistry; Nikethamide - chemistry; Nipecotic Acids - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Solubility; Temperature; Thermodynamics; Urea - analogs & derivatives; Urea - chemistry; Pharmaceutical technology; Calcium antagonist; Association constant; Hydrophobic interaction; B-Vitamins; Solubilization; Nifedipine; Pyridine derivatives; Hydrotropy; Medium effect; Water solubility; Reaction mechanism; Ureas; Dihydropyridine derivatives; Nicotinamide; Thermodynamic properties; Physicochemical properties
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.46.125

Nicotinamide is a hydrotropic agent that has been demonstrated to solubilize a wide variety of drugs through complexation. Past investigations on the potential interaction of nicotinamide with a solubilized drug have inadequately focused on aliphatic hydrotropes. This study examined the mechanism for the hydrotropic solubilization of nifedipine, a poorly water-soluble drug, in the aqueous solution of nicotinmide using not only nicotainamide analogues but also urea analogues as aliphatic hydrotropes. The values of stability constants, K1 : 1 and K1 : 2, at different temperatures in nicotinamide solution were determined by the phase solubility technique, and were utilized to estimate the thermodynamic parameters of complex formation between nifedipine and nicotinamide. The enthalpy change values suggested the participation of intermolecular forces other than hydrogen bonding in complexation. The aqueous solubility of nifedipine was measured in the presence of nicotinamide, urea and their analogues : N-methylnicotinamide, N, N-diethylnicotinamide, nipecotamide, methylurea, ethylurea and butylurea. The drug solubility increased in proportion to the amount of alkyl substituent on the amide nitrogen, and the solubilizing effect of butylurea was as high as that of nicotinamide. Furthermore, the relationship between the logarithmic drug solubilities in 1.0 M aqueous solutions of nicotinamide or urea analogues versus the logarithmic octanol-water partition coefficient values of ligands as an indication of hydrophobicity was found to be linear. The significant contributor to the hydrotropic solubilization of nifedipine with nicotinamide was therefore the ligand hydrophobicity rather than the aromaticity of the pyridine ring.