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

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 su