| Quetiapine Fumarate as a new atypical antipsychotic,is a first-line medicine drug for the treatment of schizophrenia and bipolar disorder manic episodes.It works by blocking dopamine D1,D2 and 5-hydroxytryptamine receptors（5-HT）5-HT1A,5-HT2A in the central nervous system.And it has significantly lower side effects than traditional antipsychotic drugs.Therefore,we used HPMC as the backbone extended-release material to designed and developed Quetiapine Fumarate extended-release tablet,and carried out quality analysis for it.Firstly,I did a preformulation research to examined the physical and chemical properties of Quetiapine Fumarate,and measured its equilibrium solubility in different media and compatibility with various excipients under different conditions.At the same time,the method for the determination of release was established and verified.Secondly,I studied the formulation and technics of Quetiapine Fumarate extended-release tablet.It was prepared by dry granulation tableting process.Single factor experiment was carried out,including different viscosity and dosage of HPMC,different dosage of lactose,and different tablet hardness.Then,by using orthogonal experimental design,I got the best prescription and prepared three batches of small test samples.By testing dissolution,assay and related substance of these samples,I qualified these samples and verified the feasibility of the process parameters.Also,the dissolution of these samples were compared with RLD to determine whether the prescription was similar to RLD by using the similarity factor of f2value.Then,I studied the quality of Quetiapine Fumarate extended-release tablet,and established the quality standards for the main test method.Also,I verified the methods of assay and related substance.Finally,I prepared three pilot scale samples,and studied their stability to provide basis for the selection of material and the validity period.The following conclusions can be obtained:The result of equilibrium solubility of Quetiapine Fumarate in different media showed that Quetiapine Fumarate in pH4.8 citrate buffermeets and pH6.6 citrate/phosphate buffer meets the requirements of the release test,which conforms the requirement of the leakage condition.So I choose them as the solvents for dissolution test.In the first 4h,pH4.8 citrate buffer 900ml was used;and in 5to 24h,changed pH6.6 citrate/phosphate buffer 1000ml.Samples were taken out at 1h,2h,4h,6h,8h,10h,12h,16h,20h and 24h.The concentration of Quetiapine Fumarate in the test solution was determined by high performance liquid chromatography（HPLC）.The method validation showed that the method was specific,high precision and good accuracy.It can well measure the concentration of Quetiapine Fumarate at each time point.The compatibility of the excipients with the main drug was good under different conditions.And the results of single factor experiment of Quetiapine Fumarate showed that the viscosity and dosage of HPMC and the dosage of lactose had a significant effect on the drug release rate.So I choose the dosage of HPMC K100Lv,HPMC K4M and lactose as factors to design three levels orthogonal experiment.The results showed that the best prescription was made of 20%HPMC K100Lv,14%HPMCK4M,and 8%lactose.The quality research results of three batches of samples were in accordance with the requirements,and which were very closly,indicating that the process has a good repeatability.The values of the similarity factor f2was greater than 50,which showed that the self-developed sample had consistent with RLD.It proved that the prescription is good and the process condition has a good stability.Related substances and assay were all determined by high performance liquid chromatography（HPLC）,and the results of method validation showed that these methods had good specificity,high accuracy and good reproducibility.They could be well used for the quality test of the product.The stability test results of the three pilot scale samples showed that the product had good stability at high temperature and light conditions.But it was easier to absorb moisture under high humidity,so it needed airtight performance of better packaging,and placed in a dry and ventilated place. |
