Studies On The Enantiomeric Separation And Pharmacokinetic Properties Of Several Chiral Drugs

The enantiomeric separation of chiral drugs plays an important role at present scientific fields. Two enantiomers of chiral drugs usually possess different pharmacokinetic, pharmacodynamics and pharmacological action. Accordingly, to develop an enantiomeric separation method of fast, accurate and high-performance is of great importance for developing new drugs, monitoring enantiomeric stereoselectivity and researchering enantiomeric physiological activity. In this paper, high performance liquid chromatography method using chiral mobile phase additive(CMPA) has been developed for the separation of zopiclone and oxybutynin enantiomers, and chiral stationary phases (HPLC-CSP) has been applied for the separation of four chiral drugs: tiopronin, bifonazole, zopiclone and oseltamivir. Chiral HPLC determination of enantiomeric impurity for dextro-zopiclone and the stereoselective Pharmacokinetics and the chiral inversion of ofloxacin hydrochloride in rat plasma have also been studied.1. Studies on the enantiomeric separation of zopiclone and oxybutyninHigh performance liquid chromatographic methods have been used for the direct separation of zopiclone enantiomers withβ-cyclodextrin as the chiral mobile phase additive and oxybutynin enantiomers with hydroxypropyl-β-cyclodextrin as the chiral mobile phase additive with C₁₈ reversed-phase column as the stationary phase. The effect of some factors such as the kind and concentration of chiral mobile phase additive, organic modifier and buffer system, mobile phase pH, column temperature and flow rate on the enantiomeric separation were investigated. And the two chiral drugs were separated perfectly on the optimized conditions.2. Studies on the enantiomeric separation of enantiomers for tiopronin, bifonazole, zopiclone and oseltamivir HPLC methods have been developed for the enantiomeric separation of tiopronin, bifonazole and zopiclone on a Chiralpak AD-H Chiral column under normal phase mode. And the enantiomeric separation of oseltamivir on a Sumichiral OA-2500s chiral column under normal phase has also been developed. The influences of organic solvent, the concentration of acid and base, column temperature and flow rate on the enantiomeric separation were investigated. The four drugs enantiomers can be separated completely. The proposed method was established to be simple, rapid and reproducible.3. Studies on chiral HPLC determination of levo enantiomer of dextro-zopicloneDextro-zopiclone has better therapeutic effect than zopiclone. At present, Dextro-zopiclone has been studied as a new chiral drug in clinical research. For dextro-zopiclone, levo enantiomer needs quality control as impurity. A proposed HPLC method using Chiralpak AD-H column was used for chiral separation and determination of enantiomeric impurity of dextro-zopiclone. The study provides a sensitive and reproducible method for the quality evaluation and control of levo enantiomer in dextro-zopiclone material and formulation.4. Studies on the stereoselective Pharmacokinetics and the chiral inversion of ofloxacin hydrochloride in Wistar rat plasmaA chiral ligand-exchange chromatography method to determine the enantiomers of ofloxacin hydrochloride in Wistar rat plasma was established. Stereoselective Pharmacokinetics and the chiral inversion were studied of ofloxacin enantiomer after a single oral administration at a dose of 40mg/kg to Wistar rats. The result showed, the plasma levels for dextro-ofloxacin were always higher than its antipode in six Wistar rats' plasma. The mean AUC_0-t and C_max values for dextro-ofloxacin were 1.33 and 1.71 times of those of levo enantiomer, respectively, indicating that the Pharmacokinetics of ofloxacin hydrochlorid in Wistar rats was stereoselective. And through monitoring the concentration of dextro-ofloxacin in Wistar rat plasma, it was certificated that the chiral inversion of ofloxacin hydrochloride could not occur in Wistar rats.