Study On The Key Technology And Preparation Formability Of A New Analgesic Drug S-1903

S-1903 is a structural analogue of L-tetrahydropalmatine(l-THP),an active ingredient of Corydalis yanhusuo.S-1903 mainly exerts analgesic effect by activating dopamine D1 antagonist receptor.S-1903 also antagonizes dopamine D2 and D3 receptors and stimulates 5-HT1 A.It is found that S-1903 can effectively treat methamphetamine mental dependence and brain injury.In this paper,S-1903 was used as a model drug,and pre-prescription research was carried out to make S-1903 into sustained-release preparation,and the factors affecting the stability of S-1903 preparation were investigated.Part Ⅰ: Pre-prescription research of S-1903Objective: To prepare safe,effective and stable preparations in a short time.Methods: The appearance of the drug was observed by scanning electron microscope,and the crystal form of the drug was determined by x-ray powder diffraction Measuring melting point by capillary method and differential scanning calorimetry;According to the general principles of Chinese Pharmacopoeia(2020edition),the loss on drying,the guiding principle of moisture absorption,and the optical rotation of S-1903.The ultraviolet absorption coefficient of S-1903 in methanol and acetonitrile was determined by five ultraviolet spectrophotometers.A high performance liquid phase analysis method was established.The solubility of S-1903 in different solvents and p H was investigated,and its apparent oil-water partition coefficient was determined by shaking flask method According to the guiding principle of stability test in Chinese Pharmacopoeia 2020,the factors affecting the stability of S-1903 API were investigated.Taking tablets as dosage forms,different kinds of auxiliary materials,such as fillers,adhesives,disintegrants and lubricants,and mixing powders were selected to investigate the compatibility of raw and auxiliary materials.Results: The drug was light yellow crystalline powder.The melting point is about 260℃ and the melting distance is 1.3℃.The loss on drying rate was 0.17%.Under different humidity conditions,the moisture absorption rate is more than 0.2%and less than 2%,indicating that S-1903 is slightly hygroscopic,and S-1903 is a levorotatory body with an optical rotation of-2.675.The absorption coefficients in methanol and acetonitrile are 159 and 156 respectively.According to its solubility in different solvents,solubility at different p H and apparent oil-water partition coefficient,it can be known that the solubility of S-1903 has no p H dependence and its water solubility is better than that of fat solubility.The test of influencing factors shows that S-1903 is stable under high humidity and unstable under high temperature and light.The compatibility results of raw and auxiliary materials show that the selected filler is compatible with raw materials,hydroxypropyl cellulose in adhesive,sodium carboxymethyl starch in disintegrant and magnesium stearate in lubricant.Conclusion: The compound has moderate fat solubility and water solubility,and good biofilm permeability,which is desirable for oral administration.These factors should be avoided in the preparation of S-1903 under the conditions of high temperature and light.Part Ⅱ: Study on preparation formabilityObjective: To develop S-1903 sustained-release tablets with good stability and sustained-release effect,and to explore the dissolution rule of S-1903sustained-release tablets.Methods: The release rate of S-1903 in vitro was determined by UV spectrophotometer,and the effects of hydrophilic matrix material HPMC,water insoluble material EC and corrosive matrix material stearic acid on the release of S-1903 were investigated,so as to explore the release rule of S-1903 sustainedrelease tablets.Conclusion: The mixture of stearic acid and a certain amount of HPMC can regulate the release of S-1903 drug to a certain extent.The third part: The test of influencing factors of the preparationObjective: To investigate the factors affecting the stability of the preparation,determine the packaging conditions of the preparation prescription,and investigate the rationality of the preparation prescription and the production process.Methods: The preparation was exposed to high temperature(60℃),high humidity(25℃,relative humidity 90% 5%)and strong light(4500lx±500lx)for10 days,and samples were taken on the 5th and 10 th days to investigate the changes of properties,related substances and in vitro release rate.Conclusion: The preparation is unstable under the conditions of high temperature,light and high humidity,and the release rate slows down with time.