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, 17 beta-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 = 5.23 M-1 and K1:2 = 8.6 M-2; for griseofulvin, K1:1 = 5.54 M-1 and K1:2 = 8.82 M-2; for progesterone, K1:1 = 5.48 M-1 and K1:2 = 42.47 M-2; for 17 beta-estradiol, K1:1 = 5.38 M-1 and K1:2 = 36.9 M-2; and for testosterone, K1:1 = 5.07 M-1 and K1:2 = 27.47 M-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.(ABSTRACT TRUNCATED AT 250 WORDS)