Improvement Of The Quality Standard Of Tinidazole And Glucose Injection

1 Objective Tinidazole and glucose injection is a sterilized aqueous solution of tinidazole and glucose,and there is no tinidazole injection abroad.This variety has many specifications,drug packaging materials,and injection route of drug delivery is a high-risk preparation.The current standard has some defects and needs to be improved.Therefore,by analyzing and studying the quality of tinidazole and glucose injection,this paper provides a technical basis for optimizing the prescription process and improving the quality standard of drugs.2 MethodsField investigation of manufacturers and 93 batches of tinidazole and glucose injection were tested and analyzed according to the current standards.Through the problems found,the corresponding exploration and research were carried out.The main research contents are as follows:(1)Impurity analysis.The impurity was identified by means of destruction experiment,high resolution mass spectrometry,organic reaction theory and so on.(2)Nitrite detection.To establish a UV-vis spectrophotometric method for the determination of nitrite in samples.(3)Ethylenediamine tetraacetic acid disodium.To establish a HPLC method for the determination of ethylene diamine tetraacetic acid disodium in samples.(4)Investigation of the prescription process.Effect of pH value,sterilization and activated carbon on product quality.(5)Preliminary investigation of sample stability.Accelerated test,low temperature and freeze-thaw test investigation.(6)Compatibility test of elemental impurities and packaging materials.The impurity and migration of elements were determined by ICP-MS and ICP-OES.(7)Biosafety test.Studies on passive skin allergy test,systemic active allergy test and vascular irritation test.(8)Applicability test of sterility check method.Study on membrane filtration method.(9)Determination of residual solvent in raw materials.To establish a gas chromatographic method for determination of ethanol,chlorobenzene and o-xylene residues in tinidazole.3 Results(1)Impurity analysis.Two oxidation destruction impurities in the impurity spectrum of injection were characterized.(2)Nitrite detection.The UV spectrophotometric method for the determination of nitrite content in samples was optimized.This method is practical and worthy of promotion.(3)Ethylenediamine tetraacetic acid disodium.HPLC method was established for determination of disodium ethylenediamine tetraacetic acid(EDTA)in samples.This method can be used for rapid and accurate determination of disodium ethylenediamine tetraacetic acid(EDTA)in tinidazole and glucose injection.(4)Investigation of the prescription process.The pH value was positively correlated with the content of impurity Ⅰ.In the case of strict control of pH value,excessive killing method can be used for sterilization;Activated carbon has no adsorption effect on glucose,but has certain adsorption effect on tinidazole.(5)Preliminary investigation of sample stability.Accelerated test for 3 months,18 batches of samples of related substances,5-hydroxymethylfurfural,nitrite were significantly increased;Rubber stopper of 1 batch of samples turned yellow;There were no significant changes in the characteristics,pH value,related substances,contents of5-hydroxymethylfurfural,tinidazole and glucose of 18 batches of samples after 3 cycles of low temperature and freeze-thaw tests.(6)Compatibility test of elemental impurities and packaging materials.Six elements including lead,cadmium,arsenic,mercury,copper and chromium in 18 batches of tinidazole,5 batches of tinidazole and 2 batches of glucose were determined by ICP-MS.The mercury element in 5 batches of tinidazole and 1 batch of tinidazole exceeded the standard(ICH Q3D: 0.3μg/g)and 3μg/ day,respectively.The migration of aluminum,magnesium,boron,potassium and calcium in18 batches of samples was determined by ICP-OES after 2 months of acceleration.The migration of aluminum,magnesium,boron and calcium was lower than the reference limit.(7)Biosafety test.Passive skin allergy test,systemic active allergy test and vascular irritation test were negative.(8)Applicability test of sterility check method.The film filtration method can be used as the sterility check method of this product.(9)Determination of residual solvent in raw materials.A gas chromatography method was established to determine the residual amount of ethanol,chlorobenzene and o-xylene in tinidazole raw materials,which was far below the limit.It was further verified that there was no need to control the residual solvent in tinidazole and glucose injection.4 ConclusionThe current standard of this product needs to be improved.According to the problems found in the inspection process and the research on the related factors affecting the quality of drugs,the draft quality standard of tinidazole and glucose injection was finally drawn up.It can control potential risks,improve the quality of drugs and serve enterprises.