Caffeine and nicotinamide enhances the aqueous solubility of the antimalarial agent halofantrine.

The aqueous solubility of the antimalarial agent halofantrine in phosphate buffers pH 5.9 and 7.0 (ionic strength 0.08) is increased by the addition of caffeine and nicotinamide. Solubility is increased to a greater extent in the presence of caffeine (12.5-125 mM) than nicotinamide (125 mM -2.0 M). The greatest increase in solubility was observed at pH 5.9 where the basal solubility of halofantrine rose from 0.91 to 435 microM when 125 mM caffeine was added. Phase solubility studies support the formation of a 1:1 complex between caffeine and halofantrine which is characterised by a K(1:1) constant of 2.75x10(3) M(-1) (pH 5.9). A less stable 1:1 complex is formed at pH 7.0 (K(1:1)=6.37x10(3) M(-1)). Differential scanning calorimetry of solid mixtures of caffeine and halofantrine showed the absence of the endotherms of the two drugs and the appearance of a distinct endotherm (with a smaller enthalpy) characteristic of the complex. An analysis of the 1H-NMR spectra of mixtures of caffeine and halofantrine revealed perturbations in the chemical shifts of the methyl group and proton at positions 4 and 8 of caffeine, and a change in splitting pattern of the H(9) proton of the phenanthrene ring in halofantrine.