The Bioequivalence Studies Of Compound Ranitidine Dispersible Tablets And Metformin Hydrochloride Enteric Dissolving Capsules

Objectives:To develop methods for the determination of ranitidine, bismuth and metformin in human plasma, respectively, and apply the methods to evaluate the bioequivalence of different formulations.Methods:The plasma containing ranitidine was extracted with acetyl acetate after alkalization, and then the analyte and internal standard famotidine were separated on a Diamonsil C18 column (150 mm×4.6 mm,5μm) and detected by ultraviolet detector. The detection was set at a wavelength of 320 nm. The mobile phase was consisted of methanol-2% glacial acetic acid-triethylamine (15:84:1, v/v/v). The plasma containing bismuth was nitrated with nitric acid, and then the analyte and internal standard thallium were detected by inductive coupled plasma-mass. Mass-to-charge ratios detected (m/z) were 205(205Tl) and 209(209Bi). A high performance liquid chromatography method with ultraviolet detection was developed to determine the concentration of metformin in human plasma. After a simple protein precipitation with acetonitrile, the analyte and internal standard atenolol were separated on a Diamonsil C18 column (150 mm×4.6 mm,5μm). The mobile phase was consisted of acetonitrile-0.03 mol·L-1 potassium dihydrogen phosphate (containing 5 mmol·L-1 sodium dodecyl sulfate) (32.5:67.5, v/v).The detection was set at a wavelength of 233 nm.Results:The linear calibration curve of ranitidine was obtained in the concentration range of 15-1500 ng·mL-1. The intra-and inter-day precision (RSD) was less than 7.7%, and the accuracy was within 94.3%-100.0%. The main pharmacokinetic parameters after a single oral dose of test and reference preparations containing 150 mg ranitidine to 20 healthy volunteers were as following:Cmax(609±188), (615±227) ng·mL-1, Tmax(2.5±0.5), (2.6±0.4) h, AUC0-t(2627±801), (2687±779) ng·h·mL-1, AUC0-∞(2788±833), (2851±787) ng·h·mL-1, t1/2(5.31±1.73), (5.20±2.04) h, respectively. The linear calibration curve of bismuth was obtained in the concentration range of 0.4-100 ng·mL-1. The intra-and inter-day precision (RSD) was less than 7.7%, and the accuracy was within 98.2%-100.4%. The main pharmacokinetic parameters after a single oral dose of test and reference preparations containing 110 mg bismuth to 20 healthy volunteers were as following:Cmax(36.3±21.8), (35.1±22.8) ng·mL-1, Tmax(0.73±0.31), (0.76±0.36) h, AUC0-t(135.9±82.7), (133.8±85.7) ng·h·mL-1, AUC0-∞(161.7±99.1), (157.4±101.5) ng·h·mL-1, t1/2(10.92±3.10), (11.04±3.14) h, respectively. The linear calibration curve of metformin was obtained in the concentration range of 20-5000 ng·mL-1. The intra-and inter-day precision (RSD) was less than 8.8%, and the accuracy was within 96.1%-104.3%. The main pharmacokinetic parameters after a single oral dose of test and reference preparations containing 1000 mg metformin to 20 healthy volunteers were as following:Cmax(1729±483), (1715±456) ng·mL-1, Tmax(4.1±0.9), (4.6±0.9) h, AUC0-t(9322±2499), (9214±2501) ng·h·mL-1, AUC0-∞(9594±2589), (9511±2596) ng·h·mL-1, t1/2(4.17±0.54), (4.27±0.52) h, respectively.Conclusions:The three methods can be utilized for bioequivalence study of ranitidine, bismuth and metformin preparations, respectively, which provide the advantage of sensitivity, specificity and simplicity.