Research On The Formula And Process Of Gemcitabine Hydrochloride For Injection

Gemcitabine is a kind of two fluorine nucleosides tumor drug resistance to the metabolic.The main mechanism is inhibiting DNA synthesis and replication of the tumor cell.It is widely used in locally advanced or metastatic non-small-cell lung cancer,pancreatic cancer,breast cancert,and so on.The main dosage form is lyophilized powder for injection.However,in the past for a long time,the freeze-drying time of the process was long,and the production efficiency was low.This paper aimed to study from the perspective of formula and process,selecting a better formula dosage and freeze-drying curve,in order to shorten the production cycle,improve production efficiency,reduce production cost,laying foundation for the further research of the product and the dosage form.Other excipients in the original formula were unchanged,except the amount of mannitol in the formula.Respectively added 3.33%,6.33%,9.33%mannitol samples[dosage of mannitol and the percentage of the dose(w/v,g/ml)].At the same time,desiged three groups of freeze-drying curven on the basis of the melting point of gemcitabine hydrochloride apis and mannitol mixed solution,and filtered.Studied on the quality and stability of the three batches of samples after freeze-dring.The main research results were summarized as follows:(1)The dissolved solution was turbid when the dosage of mannitol is 3.33%.The appearance of the frozen one,dissolved solution,content and excipients were within the rules when the usage was between 6.33%-6.33%.So we could determine the mannitol dosage of the product formula was 6.33%(w/v,g/ml),which is 190 mg,and the packing amout was reduced from 5 ml to 3 ml.(2)The lowest eutectic point of The optimized formula wass about-6.8℃.And general refrigeration dryer could meet the production requirement.We found that the longer the sublimation time lasted,more turbidity the complex solution was,while other things being equal.Eventually determined precool process was falling directly from the room temperature to-40℃,and then kept cool for 5-6 hours.Sublimation drying process was heating up directly from-40℃to 3 ℃,keeping warm for 14-15 hours,and then heated up to 40 ℃ for 7-8 hours.Then heated preservation at 40 ℃.The whole process was reduced from 42-45 hours to 28.5-34 hours,greatly reducing the freeze-drying time,shorten the production cycle,improve the production rate per unit time.(3)Stability study results show that Gemcitabine Hydrochloride for Injection was sensitive to alkali and oxygen,relatively stable to high temperature,high humidity and strong light.This product was compatibility stable used with sodium chloride solution.Through the inspection of 6 months’ accelerated test and 18 months’ long-term test of three groups of test samples after changing,6 months’ accelerated test and 36 months’ long-term test of three groups of test samples before changing,18 months’ long-term test of original drug,showed that all the indexes Conform to the standard of quality.We also found that the number of impurities of the samples after changing and before changing is 2,and the original drug is 3.The impurity was decreased by 33%after changing.The related substances after changing were all lower than 0.028.Telated substances before changing and the original drug were all higher than 0.049.It showed that the sample after changing were superior to samples before changing and the original drug.