Complexation of nifedipine with substituted phenolic ligands.

Abstract

The bioavailability of nifedipine in man is highly variable. This may be partly due to its poor aqueous solubility (5-6 micrograms/ml over pH 2.2-10.0, as determined in this laboratory). We initiated this study to examine the enhancement of aqueous nifedipine solubility via complexation. A series of substituted aromatic ligands was studied to identify those structural features important for complexation with nifedipine. The studies were performed at 25 degrees C employing the solubility technique, using pH 2.2 or 7.0 buffers at an ionic strength of 0.25 M. The apparent equilibrium complexation constants for the 1:1 and/or 1:2 complexes were determined, where appropriate. A linear free-energy approach was used to relate K1:1 with Hammett's sigma (sigma) and fractional partition coefficient (pi) parameters. The following correlation was obtained: log (K1:1/K0) = 0.31 sigma + 0.10 pi + 0.36 (r2 = 0.86, P less than 0.003, N = 9), where K0 is the complexation constant for phenol. Statistical analyses showed that sigma was more important than pi in affecting nifedipine complexation. The exact location of this interaction on the nifedipine molecule is undefined at present.