| The residual solvent in the drug is used in the production of raw materials or auxiliary materials, as well as in the preparation process of the preparation,but in the process of the process can not completely remove the organic solvent.In the link of pharmaceutic preparation, appropriate solvents can be selected to improve the yield of synthetic pharmaceutical ingredients or change the properties of pharmaceutical products, such as crystal structure,purity and solubility, etc.Therefore, organic solvents are the essential and crucial factors in synthesis reaction.Residual solvents in pharmaceutical products have no curative effect,whose existence has the potential pharmaceutic toxicity risk, for example,benzene is a kind of carcinogen which can cause leukemia, leading to many types of leukemia or primary cancer of the blood.ICH and International Pharmaceutical industry and administrative departments gradually pay attention to the residual solvents in pharmaceutical products, and from the revised contents of inspecting methods for residual solvents in each country's different versions of Pharmacopoeia, the varieties of organic solvents which need to be managed now develop to be tens from several initially, with significantly increased content requirements for residual solvents in Chinese Pharmacopoeia 2010 and 2015.Gas chromatography with high sensitivity and good selectivity, can analyze complex samples, is the most suitable method for the analysis of residual solvents in pharmaceuticals.GC is divided into three categories:Direct Sampling GC, Headspace GC and Solid-phase Micro extraction GC.In Chinese Pharmacopoeia 2010 and 2015, many varieties add detecting items for residual solvents;Meanwhile, detecting methods for multiple residual solvents are similar or identical.In this paper, raw materials and organic solvents which are used in the productive process of 15 antibiotics are examined, and according to the varieties of residual solvents listed under the text of each variety in the Pharmacopoeia, it is confirmed that there are 17 kinds of frequently-used residual solvents which need to be determined. In this paper, head space gas chromatography is used to first develop a unified, high-efficiency and method of residual solvent determination. Thus, multiple residual solvents in multiple pharmaceuticals can be determined at the same time under one chromatographic condition. This method is used for routine inspection in lab of enterprises. And it's expected to improve the working efficiency by 30%and reduce the cost of human resource and equipment meanwhile,significantly saving inspecting cost for pharmaceutical companies of antibiotic.In this paper, GC is used to develop the analytic method for residual N,N-dimethylacetamide in Amoxicillin;Develop the analytic method for residual Chloroform in Cefminox Sodium;Develop the analytic method for residual solvents in Fucoxanthine;And realize high-sensitivity determination of multiple residual solvents in pharmaceuticals.Part 1 Development and Investigation of Analytic Method for Residual Solvents in PharmaceuticalsObjective:Develop a head space GC to simultaneously analyze multiple residual solvents in multiple pharmaceuticals.Methods:With headspace GC, select different polar capillary columns,separately examine the three chromatographic columns' isolating effect on 17 kinds of residual solvents, which are polar chromatographic column HP-FFAP,medium polar chromatographic column DB-624 and nonpolar chromatographic column HP-1, compare the availability of the two quantitative methods, Internal Standard Method and External Standard Method, to screen that HP-1 is chromatographic column and that External Standard Method has the best detecting effect in quantitative methods, develop head-space GC and use FID detector to determine the 15 kinds of residual solvents in the 15 kindsof pharmaceuticals.Results:Under the above-mentioned conditions, 15 kinds of residual solvents can be effectively separated, and it's validated by methodology that the linearity within the concentration rangeis good(r>0.99), with all recoveries ranging from 80% to 120% and all RSDs less than 10%.Conclusion:This method is fast, accurate and specific, which is suitable for simultaneously detecting multiple residual solvents in multiple drugs under one chromatographic condition to improve the detecting efficiency.Part 2 Development of Detecting Method for Residual N, N-dimethylaceta mide in AmoxicillinObjective:Select appropriate sampling method and solvent suitable for Amoxicillin, which can't dissolve in water, and use GC to analyze the content of residual organic solvent with high boiling point-N, N-dimethylacetamide in these API.Methods:With GC, compare the two sampling methods, headspace sampling and direct liquid sampling, examine the solubility of Amoxicillin and N, N-dimethylacetamide in water, methanol and ethyl acetate, screen the appropriate sampling method and soluble media and use DB-WAX capillary column and FID detector to determine the content of residual N, Ndimethylacetamide in pharmaceuticals.Results:Select methanol as soluble media and immerse the samples to be detected with moderate methanol for 30 minutes to make N,N- dimethylacetamide in samples completely lixiviate, then centrifuge it at the speed of3000 r/min for 20 minutes. Take supernatant as solution to be detected.Analyze with direct liquid sampling method.The develop capillary GC is validated by methodology that: The linearity of the detected components is good, with its correlation coefficient being r=0.9995, recovery being 99.4% and RSD being 1.0%.In the three batches of samples, the maximum residual content of N,N-dimethylacetamide is 0.024%.Conclusion:N,N-dimethylacetamide can dissolve in methanol withmethanol as extraction solvent.The developed GC is highly sensitive and specific, which is suitable for the limit detection of residual N, Ndimethylacetamide in Amoxicillin.Part 3 Development of Detecting Method for Residual Chloroform in Cefminox SodiumObjective:Select appropriate headspace solution and use capillary GC to realize high-sensitivity determination of volatile organic solvent- Chloroform in Cefminox Sodium.Methods:Compare the solubility of water, methanol and DMSO in Chloroform and select appropriate headspace solution according to the solubility of detected pharmaceuticals.Use DB-624 capillary column and FID detector to detect and head-space sampling method to analyze residual Chloroform in Cefminox Sodium.Weigh 150 mg of Chloroform in 50 ml graduated flask with trace methanol,size it to scale with methanol and take it as reference stock solution.Accurately measure 4?l of reference solution in the 20-ml head-space bottle with 2ml of purified water as reference solution.Prepare test solution with purified water as head-space solvent.The develop capillary GC is validated by methodology that:The linearity of the detected components is good, with its correlation coefficient being r=0.9995, recovery being 95.0% and RSD being 1.1%.Result:Weigh 150 mg of trichloromethane in 50-ml volumetric flask with trace methanol, size it to scale with methanol and take it as reference stock solution.Accurately measure 4?l of reference solution in the 20-ml head-space bottle with 2ml of purified water as reference solution.Prepare test solution with purified water as head-space solvent.The develop capillary GC is validated by methodology that:The linearity of the detected components is good, with its correlation coefficient being r=0.9995, recovery being 95.0%and RSD being 1.1%.In this three batches of samples, the maximum residual content of Chloroform is 0.0012%.Conclusion:Dissolve Chloroform with methanol first to preparereference stock solution.Then take in trace reference stock solution and dissolve it into purified water to prepare reference solution.The develop headspace GC has high sensitivity and is specific, which is suitable for the limit detection of Chloroform in Cefminox Sodium.Part 4 Development of Inspecting Method for Residual Solvents in Fucus-xanthineObjective:Develop a head-space capillary GC to determine residual solvent in Fucusxanthine.Methods:Use HP-1 capillary column and FID detector to analyze.Use the program to elevate column temperature; Keep column temperature at 40?for 5 minutes, elevate it to 150? with a speed of 10?/min and keep it for 2minutes;FID temperature is 250 ?;Temperature of injection port is 200 ?;Determination of headspace sampling.Results:Under the above-mentioned chromatographic conditions, the developed analysis method is validated that:The linearity of each component is good, correlation coefficient of ethanol is 0.9998, and that of ethyl acetate is0.9999, with both more than 0.99.Recovery of ethanol is 95.8% and its RSD%is 2.9% while recovery of ethyl acetate is 95.6% and its RSD is 2.1%;In this three samples, ethanol is not found while the contents of ethyl acetate are separately 0.0051%, 0.0047% and 0.0042%.Conclusion:This method has high sensitivity, which also is specific.Head-space GC can reduce the pollution from pharmaceuticals to chromatographic columns, which is suitable for the limit detection of residual solvents in Fucusxanthine. |
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