Comparison of two methods currently used to determine the interaction between cyclodextrins and drugs: phase solubility diagrams and NMR spectroscopy

Two methods usually used in the literature to determine stability constant values (Kc) of cyclodextrin complexes were compared: the phase solubility diagram and NMR spectroscopy. Two model drugs were used to determine limitations of both techniques: betamethasone and miconazole, with three cyclodextrins: beta-cyclodextrine (betaCD), dimethylated-betaCD (Dimeb) and trimethylated-betaCD (Trimeb). This study shows that both techniques can give the same Kc value if they are used in exactly the same conditions with well defined cyclodextrins. As a matter of fact, if the degree of substitution of cyclodextrin is not well defined (as it is often the case with Dimeb), results are biased. This study also shows that when interactions between both molecules are weak (< 1000 M-1), stability constants can not be determined by NMR due to low chemical shift variations. The limitations of the phase solubility diagram method are an oversimplification of the solubility data which can lead to large errors in the calculation of the stability constant values. Moreover, this method is time and material consuming.