Complexation of zolpidem with 2-hydroxypropyl-β-, methyl-β-, and 2-hydroxypuopyl-γ-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 CH3COOD/D2O was investigated by H-1 and C-13 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 a-fold longer ataxic induction times than controls. (C) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association.