Solubility Enhancement of Some Water-Insoluble Drugs in the Presence of Nicotinamide and Related Compounds

Abstract

The solubilities of five poorly water-soluble drugs, diazepam, griseofulvin, progesterone, 17β-estradiol, and testosterone, were studied in the presence of nicotinamide. All solubilities were found to increase in a nonlinear fashion as a function of nicotinamide concentration. The K1:1 and K1:2 stability constants were as follows: for diazepam, K1:1=5.23M−1 and K1:2 = 8.6M−2; for griseofulvin, K1:1 = 5.54M−1 and K1:2 = 8.82M−2; for progesterone, K1:1 = 5.48M−1 and K1:2 = 42.47M−2; for 17β-estradiol, K1:1 = 5.38M−1 and K1:2 = 36.9M−2; and for testosterone, K1:1 = 5.07M−1 and K1:2 = 27.47M−2. Two aliphatic analogues of nicotinamide (nipecotamide and N,N-dimethylacetamide) were studied as ligands with diazepam and griseofulvin and were found to increase the solubilities of both drugs in a linear fashion. The aromatic analogue, N,N-diethylnicotinamide, showed a nonlinear solubilization relationship similar to that seen with nicotinamide. In addition, three other aromatic analogues (isonicotinamide, 1-methylnicotinamide iodide, and N-methylnicotinamide) were studied. These ligands were not soluble enough in water to be studied over the wide range of concentrations used for nicotinamide and N,N-diethylnicotinamide; however, in the concentration range studied, these ligands solubilized diazepam and griseofulvin to a degree similar to that observed with comparable concentrations of nicotinamide. These results suggest that the aromaticity (Pi-system) of the pyridine ring is an important factor in complexation because the aromatic amide ligands were found to enhance the aqueous solubilities of the test drugs to a greater extent than the aliphatic amide ligands. To determine if self-association of nicotinamide in water is required for its solubilization effects, the behavior of concentrated solutions of nicotinamide was studied. Solutions of nicotinamide in water up to 400 mg/mL were found to follow Beer’s Law, but there was a slight initial decrease in the surface tension followed by a plateau with increasing nicotinamide concentration. Conductivity was found to increase, and the NMR spectra showed an upfield chemical shift with increasing nicotinamide concentration. The n-octanol–water partition coefficient of nicotinamide was found to increase in a nonlinear fashion with increasing concentration. These results suggest that at high concentrations, nicotinamide undergoes slight self-association in water, but the degree of formation of higher order species was not sufficient to account for the degree of enhancement observed in the solubilities of the test compounds. Self-association may contribute to solubilization by affecting the hydrophobicity of the medium, but our data suggest that the aromaticity of the pyridine ring, which may promote the stacking of molecules through its planarity, appears to be the most significant contributor to the overall solubilization process. The solubilization appears to be due to formation of both 1:1 and 1:2 complexes between the drugs and nicotinamide.