Mechanistic Studies on Hydrotropic Solubilization of Nifedipine in Nicotinamide Solution.

Abstract

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.

Solubility Improvement of Drugs using N-Methyl Pyrrolidone

“…For both drugs, the ΔG°c omp is negative which supports the theory of complex formation. The magnitude and the sign of ΔH°c omp for both drugs suggesting the presence of dispersion interactions between drug and NMP molecules (20).…”

Improving the Chemical Stability of Amorphous Solid Dispersion with Cocrystal Technique by Hot Melt Extrusion

“…It is well known amorphous drug generally dissolves faster than the relevant crystalline form because there is no lattice energy to be overcome. (2) NIC was reported as a hydrotropic agent to solubilize a wide variety of drugs through forming complex with drugs (41)(42)(43)(44)(45) or changing the nature of solvent, especially by altering the solventing ability via intermolecular hydrogen bonding (46). Here, NIC probably acted as a solubility enhancer to help CBZ dissolve faster through hydrogen bonding.…”

A simple and effective method to improve bioavailability of glimepiride by utilizing hydrotropy technique

“…Fluctuation Theory of Solutions (FTS) is employed to explain the mechanisms of hydrotropic drug solubilization (Shimizu et al, 2013). FTS has identified two major factors of hydrotrope-induced solubilization, one is preferential hydrotrope-solute interaction (Durand et al, 2009;Suzuki and Sunada, 1998) and the other is water activity depression (Badwan et al, 1982;Balasubramanian et al, 1989;Coffman and Kildsig, 1996;Cui, 2010;Cui et al, 2010;da Silva et al, 1999;Friberg et al, 1986). The former is dominated by hydrotrope-solute association, and the latter is enhanced by ionic dissociation and hindered by the self-aggregation of the hydrotrope (Booth et al, 2012).…”