Complexation of zolpidem with 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin: effect on aqueous solubility, dissolution rate, and ataxic activity in rat.

The effect of some chemically modified cyclodextrins [namely, 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin (HP-beta-CD, Me-beta-CD, and HP-gamma-CD, respectively)] on the aqueous solubility and dissolution rate of the hypnotic agent Zolpidem (ZP) was investigated. Solid complexes were prepared by freeze drying and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. The solubility and dissolution rate of the drug were significantly improved by complexation with HP-beta-CD or Me-beta-CD. The structure of the inclusion complex ZP-HP-beta-CD in CH(3)COOD/D(2)O was investigated by (1)H and (13)C NMR spectroscopy, including NOE measurements. These measurements revealing a weak interaction between the tolyl moiety of the guest molecule and the HP-beta-CD cavity. The ataxic activity in rat was also investigated and it was found that ZP-HP-beta-CD and ZP-Me-beta-CD complexes showed almost 2-fold longer ataxic induction times than controls. Copyright 2000 Wiley-Liss, Inc.