Complexation of Nifedipine with Substituted Phenolic Ligands

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Abstract
The bioavailability of nifedipine in man is highly variable. This may be partly due to its poor aqueous solubility (5–6 µg/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°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 (σ) and fractional partition coefficient (π) parameters. The following correlation was obtained: log (Kl:l/Ko = 0.31σ + 0.l0π + 0.36 (r2 = 0.86, P < 0.003, N = 9), where Ko is the complexation constant for phenol. Statistical analyses showed that σ was more important than π in affecting nifedipine complexation. The exact location of this interaction on the nifedipine molecule is undefined at present.

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