Clopidogrel Bisulfate Solid Dispersion Preparationand Its In Vitro Evaluation

The resultant dissolved drug solution in gastric compartment from weak base drug product may precipitate before absorption due to the drug nature and physiological property of the gastrointestinal(GI)tract,causing product variability in absorption and inaccurate prediction of its in vivo performance.Improving the solubility capacity and reducing the precipitation of weak base drug in GI tract become necessary so as to enhance the bioavailability.In addition,traditional pharmacopoeia dissolution method may fail to predict its in vivo performance of such kind of drug,a suitable biorelevant test method combining with physiological condition is needed.Thus,the candidate weak base Clopidogrel Bisulfate was selected as the modeling drug to perform the study.In this research,in vitro analysis method of the Clopidogrel Bisulfate was first established.Its methodology was also evaluated and meet the requirements.Then Clopidogrel Bisulfate solid dispersion(SD)were formulated with various carriers.The resultant SDs were evaluated by non-sink condition dissolution,two step dissolution and dissolution/precipitation of two-compartment medium transfer in vitro biorelevant method and characterized by Powder X-Ray Diffraction(PXRD)and Differential Scanning Calorimetry(DSC)to screen the best carrier soluplus which have more soluble drug and less precipitation in physiological pH 6.8 medium and enable to maintain the supersaturation.Meanwhile the biorelevant and discriminating dissolution/precipitation of two-compartment medium transfer approach was identified.At last,the soluplus SDs were prepared by solvent evaporation,hot melting extrusion,hot melting granulation and spray dry process which were commonly used in the industry.Utilized dissolution/precipitation of two-compartment medium transfer approach with different pump speed,PXRD and DSC characterization combining the processability and stability to assess such SDs to screen the optimum process.Meanwhile the pump speed was defined as the critical factor of the two-compartment medium transfer method to differentiate the SDs of various process.The biorelevance of the in vitro method was thus further provedThe study demonstrated the feasibility of improving solubility capacity and reducing the precipitation of weak base drug in physiological pH 6.8 medium by SD.Three different in vitro method to evaluate and screen the SDs of different carriers containing the same weak base drug for the first time.The physiological-based two-compartment medium transfer approach which could distinguish SDs of different process was identified and capable of applying to the development of such weak base drug and its SDs.