The Study Of Formulation And Preparation Of Sodium Picosulfate Compound Granule

ObjectivePrepopik(?)(sodium picosulfate,magnesium oxide and anhydrous citric acid)for oral solution is indicated for cleaning of the colon as a preparation for colonoscopy in adults.The purpose of this paper is to study the formulation and preparation of the ANDA drug-WL,while the Reference Listed Drug(RLD)is Prepopik(?)(Ferring pharmaceuticals)MethodsFollowing QbD and the ICH guidelines,the formulation and small-sacle preparation technology of WL were studied according to the quality standard of Prepopik(?),then the technology for pilot-scale preparation was optimized and verified in the factory.The basic processes for the preparation of SGMD were developed according to the patent of Ferring Pharmacetieals and included two successive processes,instead of using API-sodium picosulfate directly,we used granules containing API and MgO with a granulation technique.The mixture was prepared using dry granulation method.the type and the amount of excipients was selected based on the package insert of Prepopik(?)and the results of drug-excipient compatibility testing and dissolution testing.the optimized formulation was then developed.1 Study on API\excipients\packaging materialsThe basic properties of API,such as hygroscopicity,density and fluidity,particle size,specific surface area and so on,were studied,and risk assessment was carried out according to its quality attributes.According to the reference formulation of Prepopik(?),the original formulation was selected,sucrose,three sucralose and orange flavor were selected as excipients.According to ICH guidelines and the function and dosage of the above excipients in this product,the raw materials of sodium Pyrosulfate preformed granules and excipients are mixed in a certain proportion,and then placed under the conditions of high temperature(60?,sealed),high temperature and high humidity(60?+5%water,sealed)for 30 days.Samples are test on day 0,10 and 30 respectively,and the properties of the samples are tested to inspect the compatibility of raw materials and excipients.This product is packaged by polyester/aluminum/polyethylene composite film for medical use.2 Formulation researchAccording to the product manual of American market,Prepopik(?) is an oral compound granule,containing 10 mg of picosate/3.5 g of magnesium oxide/12 g of anhydrous citric acid.In this paper,the original Formulation is used to imitate,except that the sweetener is changed from saccharin sodium to sucralose.Formulation is determined by the sweetness and taste at last.3 Process researchAccording to the general situation of preparation quality and the analysis of critical quality attributes(CQA),it is determined that the particle size,content,loss on drying and dissolution rate of the product in the formulation development are the key quality attributes,and may be affected by the variable factors in the formulation and preparation process.Therefore,we will focus on the research and discussion of prescription and process development.According to the material properties and process variables in the process of risk assessment,the high-risk factors were designed,and the control measures were taken to reduce them to low-risk factors.The effects of premixing time,roller gap,feeding speed/roller speed on particle quality were investigated in the small scale test.4 Stability researchIt is planned to investigate the influencing factors for 10 days,30 days,6 months for accelerated test and 12 months for long-term test.The main inspection indexes are content and related substances.ResultsThree consecutive,pilot-scale batches of SGMD were prepared and subjected to the quality evaluation.1 Study on API\excipients\packaging materialsAccording to the results of compatibility,the raw and auxiliary materials of this product have good compatibility.According to the results of stability study,it is feasible to pack the product with polyester/aluminum/polyethylene composite film.2 Formulation researchThe results of Formulation research are as follows:sodium sulfate,Magnesium Oxide,anhydrous citric acid,orange flavor and three sucralose.3 Process researchProcess of production is determined:mixing,dry granulation,screening,mixing,bagging,packaging related optimization conditions.4 Stability researchAccording to the results of stability study,under the proposed packaging materials(polyester/aluminum/polyethylene medical composite film)and storage conditions(sealed,stored in a dry place),the quality of the product is stable,the specific impurities-impurity Q,impurity J are not detected,the total impurity is less than or equal to 1.0%,the single impurity is less than or equal to 0.2%,the dissolution is 75%,and the content is 90.0%?110.0%.The product is consistent with the original research stability.The validity period of the product is tentatively 24 months.Conulusion1 The results showed that the developed granules met the quality standards of Prepopik(?),which indicated achievement of the study purpose.2 The related substance of ANDA is no so good as RLD,which compiled with ICH guidelines.It is determined by quality of API,which need more study in the future.