Evaluation of cyclodextrin solubilization of drugs

Abstract

The most common stoichiometry of drug/cyclodextrin complexes is 1:1, i.e. one drug molecule forms a complex with one cyclodextrin molecule, and the most common method for stoichiometric determination during formulation studies is the phase-solubility method. However, in recent years it has becoming increasingly clear that solubilizing effects of cyclodextrins are frequently due to the formation of multiple inclusion and non-inclusion complexes. The aqueous solubility of 38 different drugs was determined in pure aqueous solution, aqueous buffer solutions and aqueous cyclodextrin solutions, and the apparent stability constant (K1:1) of the 1:1 drug/cyclodextrin complexes calculated by the phase-solubility method. For poorly soluble drugs (aqueous solubility <0.1mM) the intrinsic solubility (S0) is in general much larger than the intercept of the phase-solubility diagram (Sint) resulting in non-linearity of otherwise linear (AL-type) phase-solubility diagram. This can lead to erroneous K(1:1)-values. A more accurate method for determination of the solubilizing efficiency of cyclodextrins is to determine their complexation efficiency (CE), i.e. the concentration ratio between cyclodextrin in a complex and free cyclodextrin. CE is calculated from the slope of the phase-solubility diagrams, it is independent of both S0 and Sint, and more reliable when the influences of different pharmaceutical excipients on the solubilization are being investigated.