Optimization of the stability constants of the ternary system of diclofenac/famotidine/β-cyclodextrin by nonlinear least-squares method using theoretical equations

[Display omitted] •Both of famotidine and diclofenac form inclusion complexes with β-cyclodextrin.•Diclofenac and famotidine interact with each other when included in β-cyclodextrin.•Optimization of the stability constants in a ternary system was succeeded. This study aimed to establish a new method for determining the stability constants of drug/β-cyclodextrin (β-CD) complexes when multiple drugs interacting with each other coexist in the solution of complexation. The basic drug famotidine (FAM) and the acidic drug diclofenac (DIC) were used as model drugs, their solubility decreasing owing to their mutual interaction. The dissolution of both FAM and DIC was characterized by AL-type phase solubility diagrams in the presence of the other’s 1:1 complex with β-CD. When the stability constant was calculated from the slope of the phase solubility diagram using the conventional phase solubility diagram method, it was modified in the presence of the other drug. However, by performing optimization calculations that considered the interactions between the drug/β-CD complex and the drug, drug/β-CD complexes, and drugs, we were able to accurately calculate the stability constant of DIC/β-CD and FAM/β-CD complexes even in the presence of FAM and DIC, respectively. The results of the solubility profile indicated that various molecular species, which are attributed to drug-drug and drug/β-CD interactions, interfere with the values of the dissolution rate constants and saturated concentration in the solubility profiles.