| Objective: In this paper,the metformin hydrochloride tablets used as a reference,which were produced by NIPPON SHINYAKU CO.LTD.(Japan New Drug Co.,Ltd.).By determining the reference formulation were made imitations of formula composition,the base formulation optimization study of the quality and the manufacturing process.At the same time,the difference in in vitro release and stability of the self-product and the reference preparation was investigated to evaluate the consistency of the self-product and the reference preparation.Method: 1.By project research,combined with the original drug reverse engineering,and further analysis to determine the initial prescription and craft of metformin hydrochloride tablets.2.Screening of prescriptions for self-made products,through reversed engineering analysis and preliminary confirmation of prescriptions,inquiring the original drug,and confirming that the basic processes were wet granulation,extrusion spheronization,and fluidized bed coating.Through continuous improvement of prescription dosage,and production stage tests,the process parameters of each link were optimized.3.With reference to the physical and chemical properties of the drug and the relevant requirements of the pharmacopoeia,the HPLC method for determination of related substances in metformin hydrochloride tablets,the analytical method for content determination and the analytical method for ethanol residue were established respectively.4.Three batches of self-made products and two batches of reference preparations were selected,and their dissolution differences were measured by dissolution apparatus.The differences in stability between self-made products and reference preparations were determined according to accelerated tests and long-term tests.Result: 1.It was finally determined that the prescription composition of self-produced metformin tablets was: metformin hydrochloride was 250.00 mg,mannitol 12.00 mg,microcrystalline cellulose 34.00 mg,CMS-Na 10.00 mg,hydroxypropyl methyl cellulose 2.40 mg,magnesium stearate 2.50 mg,film coating agent(stomach-soluble type)4.65 mg.The best production process was determined as follows:(1)Metformin hydrochloride 100 mesh screen was added crushed,mannitol(Mannitol)through a 60 mesh screen,weighed and the amount of spare formulation;(2)Weigh Hydroxypropyl methyl cellulose(Hydroxypropyl methyl cellulose)into a mixing tank,add purified water to prepare a 6% Hydroxypropyl methyl cellulose solution,stir well and set aside;(3)Add the prescription amount of metformin hydrochloride,mannitol,microcrystalline Cellulose and CMS-Na into the wet mixing granulator,pre-mix for 5 minutes;add the binder and wet granulate;use 16 mesh nylon screen for wet granulation;use FG-120 boiling dryer to boil and dry the granules,control Moisture limit of 2.0% ～ 3.5%;adopt 2.0 # sieve for dry granulation;(4)Add the granules and magnesium stearate to the HLT-1500 lifting hopper mixer,set the speed to 15 rpm,and mix for 5 minutes;(5)Use a φ9.5mm shallow round die to granulate tablets;⑹ Weigh a prescribed amount of ethanol,add purified water,and stir to make 88% ethanol;weigh a film coating agent(gastric-soluble type)and slowly add 88% Ethanol,and stir at the same time to prepare 10% film coating liquid for film coating;use plastic bottle packaging line for plastic bottle packaging,100 tablets//bottle or use aluminum plastic packaging line for aluminum plastic packaging,12 tablets / board.The process verification results showed that the data of each process meets the requirements of the production process,the process parameters were no different from the small-scale production stage,and the entire production process of the production process had no deviations.2.The established methods could meet the methodological requirements,and could be used for the detection of related substances in metformin hydrochloride tablets,content determination and ethanol residue analysis;3.Self-made and reference preparations were equivalent in in vitro dissolution and stability.Conclusion: The self-product had a reasonable prescription,and the production process had good stability and reproducibility,which could meet the needs of large-scale production.The appearance of the self-made product was consistent with the original drug,and the quality analysis results met the quality standards of metformin hydrochloride tablets.The dissolution behavior and stability in the four dissolution media were similar to those of the original drug. |
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