Studies On Clopidogrel Bisulfate Tablets

To improve the stability of clopidogrel bisulfate, this paper developed clopidogrel bisulfate tablets which were stable and effective. In addition, we combined clopidogrel bisulfate and aspirin as a compound preparation to enhance the curative effect and improve patients’ compliance.UV, HPLC and UPLC-MS-MS methods for both the in vitro and in vivo sample analysis of clopidogrel bisulfate as well as its preparation were established. All the methods were accurate, liable, convenient and rapid. UV spectrophotometry was developed and validated for the in vitro dissolution determination of clopidogrel bisulfate tablets. Different HPLC-UV methods were applied to detect the content and related substance of clopidogrel bisulfate crude drug, aspirin crude drug, clopidogrel bisulfate tablets and compound tablets. The dissolution of clopidogrel bisulfate compound tablets were also determined by HPLC. A specific UPLC-MS-MS method was developed for quantification of clopidogrel bisulfate in dog plasma.The systematic preformulation study showed that both the apparent solubility and the o/w partition coefficient of clopidogrel bisulfate were somewhat pH dependent. Clopidogrel bisulfate and aspirin were both stable under acid conditions and unstable under alky conditions. The two drugs had somewhat interactions with each other in solution at 37℃. The results of stress testing showed that light, humidity and high temperature had effect on the stability of clopidogrel bisulfate, while light and high temperature had little effect on the stability of aspirin. And aspirin was unstable under moist conditions. The results also showed that the two drugs had no interactions with each other in their physical mixture.Based on the single-factor tests, we decided the formulation and preparing technology of. clopidogrel bisulfate tablets and compound tablets. Comparing the dissolution rate of self-made tablets and commercially available tablets, we found that the dissolution rate of clopidogrel bisulfate from self-made tablets was faster than that from the commercially available tablets. The preliminary stability experiments showed that except for under RH 92.5% conditions, the two self-made preparations were stable.With two-crossover design, the pharmacokinetics of clopidogrel bisulfate of self-made tablets in dogs were studied comparing with the reference tablets. The t_1/2, T_max,C_max ,AUC_0-12 and AUC_0-∞ of clopidogrel bisulfate in both reference and test tablets were （2.65±1.35） h and （2.53±0.86） h, （1.42±0.26） h and （1.29±0.29） h, （424.98±85.19） ng·mL^-1 and（498.47±150.02） ng·mL^-1, （972.44±247.35） ng·h·mL^-1 and （1127.36±512.05） ng·h·mL^-1, （988.24±241.40） ng·h·mL^-1 and （1160.85±515.60） ng·h·mL^-1, respectively. The relative bioavailability of clopidogrel bisulfate was （116.81±47.41）%. The results of two one-sided r-test and confidence interval analysis demonstrated that the self-made tablets and reference tablets were not bioequivalent.