Interaction of naproxen with alpha-cyclodextrin and its noncyclic analog maltohexaose

Purpose. To study the effect of mechanical grinding on crystallinity change s of naproxen (NAP) in mixtures with alpha-cyclodextrin (alpha Cd), amorpho us alpha Cd, and maltohexaose (M6); and the possible formation of a pseudo- inclusion complex between NAP and M6 in aqueous solution. Methods. NAP-additive physical mixtures at 0.30, 0.18, and 0.10 mass fracti on of drug were tested, after increasing grinding times, by differential sc anning calorimetry (DSC) and X-ray powder diffractometry (XRD). Interaction in aqueous solution was examined by phase-solubility and fluorescence anal yses supported by molecular modelling. Results. In the mixtures with each additive the fusion enthalpy per unit ma ss of NAP decreased and the half width at half maximum of selected X-ray di ffraction peaks of NAP increased with the progress of grinding time followi ng the loss of crystallinity of the samples. The mechanical treatment appar ently did not affect the chemical integrity of the drug. Particularly activ e in the equimolar mixture was the best amorphizing agent, M6. Solution stu dies and molecular modelling confirmed M6 may have the feature of a supermo lecule for NAP, which forms a 1:1 pseudo-inclusion complex that was as stab le as the true inclusion complex with alpha Cd. Conclusions. The intrinsically amorphous linear analog of alpha Cd might be a potential amorphism-inducing agent and solubilizer for scarcely water so luble drugs.