Solubility and complexation behavior of griseofulvin in fatty acid-isooctane mixtures

The influence of complex formation on the solubility behavior of griseofulvin in the straight-chain fatty acids was investigated by using phase solubility analysis in isooctane (2,2,4-trimethylpentane) at 25 degrees C. The apparent molar solubility of the proton acceptor griseofulvin ([A]t) was determined spectrophotometrically in the presence of various total molar concentrations ([D]t) of each of the proton donors (acetic, propanoic, butanoic, hexanoic, and octanoic acids). Increasing [D]t caused a pronounced increase in [A]t according to a biphasic log-log relationship, suggesting the formation of two complexes, ADm and ADn. The data are in close agreement with a simple mathematical model which assumes that two complexes, ADm and ADn, are formed and that [D]t approximately equal to 2[D2], where D2 refers to the fatty acid dimer. Linear regression analysis showed that the data best fit the complexation models with n = 5 or 6 and m = 0, 1, or 2, depending on the fatty acid. Assuming values of the dimerization constants of the fatty acids as reported in the literature, the stability constants of the complexes, Kn and Km, were calculated and found to decrease with increasing chain length of the fatty acids. The proposed model was critically appraised. An alternative model, which takes into full account the fatty acid monomer while assuming that only one complex is formed, leads to unacceptable conclusions.