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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 nicotinamide using not only nicotinamide analogues but also urea analogues as aliphatic hydrotropes. The values of stability constants, 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 complexion. 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.

In the present aging society, easy-to-use dosage forms for elderly patients, whose swallowing function is often decreased, are in a great demand. It was shown that conventional tablets, capsules, and liquid or syrup preparations were not always easy-to-use dosage forms for elderly patients because of their decreased motor function.1,2) To deal with the demand, great efforts have been made to develop paste preparations and rapidly disintegrating tablets in the oral cavity, using jelly, water-absorbing and swelling gelated materials, or water-soluble polymers.

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The most prevalent means for producing solid dispersions of nifedipine, a poorly water-soluble drug, are the solvent based processes that bring problems of environmental and health. We have investigated the preparation of solid dispersions of nifedipine (mp 173 degrees C) by the fusion method, using nicotinamide, ethylurea, polyethylene glycol (PEG) 6000 and hydroxypropylmethylcellulose (HPMC) as carriers. All these solid dispersions were obtained by cooling at room temperature after heating at 140 degrees C for 15 min. As a single carrier, nicotinamide, ethylurea and PEG were used because nifedipine dissolved in their fused liquids. Compared with the physical mixtures, the solid dispersions with ethylurea or PEG led to a higher dissolution rate of the drug, whereas the difference in drug release between the physical mixtures and the solid dispersions with nicotinamide was not clear. This peculiarity might be due to the high solubilizing effect of nicotinamide for the drug. The fused mixtures of nicotinamide-, ethylurea- or PEG-HPMC were utilized as combined carriers. HPMC dissolved in the fused liquids of nicotinamide or ethylurea, which was effective in forming the amorphous nifedipine in solid dispersions. This resulted in not only the enhanced dissolution rate but also the supersaturation behavior of nifedipine. Further, for the nicotinamide-HPMC system, the supersaturation level of nifedipine increased with an increase in the HPMC content of solid dispersions. Nicotinamide was more applicable than ethylurea and PEG for preparation of the fused dispersions of nifedipine.