Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest-host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: alpha-CD, beta-CD, gamma-CD and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 degrees C, and with beta-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid-base ionization constants (pK (a)s) for Diclo in the presence and absence of beta-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with alpha-, beta-, and HP-beta-CD. In contrast, Diclo forms soluble 1:1 Diclo/gamma-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/gamma-CD, but the 1:1 complex saturates at 5.8 mM gamma-CD with a solubility product constant (pK (sp) = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: gamma-CD > HP-beta-CD > beta-CD > alpha-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with gamma-CD, where the overall concentration of the latter exceeds 5.8 mM gamma-CD. Both H-1-NMR spectroscopic and molecular mechanical modeling (MM+) studies of Diclo/beta-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.