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Research and Analysis the Residual Solvents in Pharmaceutical Samples

Author: LiuFengHua
Tutor: JiangZuo
School: Hebei Medical University
Course: Pharmaceutical Analysis
Keywords: cefotetan disodium headspace gas chromato-graphy residual solvents thermal stability detection Strontium Ranelate headspace injection capillary column gas chromatography sensitivity ionic liquids headspace gas chromatography Adefovir Dipivoxil Rsidual solvents ionic liquids Bisphosphonates
CLC: R927
Type: Master's thesis
Year: 2008
Downloads: 440
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Abstract

Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of drug substance or excipients, or in the preparation of drug products. The residual solvents that were not totally removed by practical manufacturing techniques have no curative effect and always have potential risk to human health from the toxicity, so the detection of residual solvents in pharmaceuticals was to regard as important by the government of medicine.Headspace (HS) injection is the most commonly used sampling techniques for residual solvents testing in pharmaceuticals with gas chromatography (GC), but sometimes, the dissolubility of some sample matrix in headspace diluents is poor, or enrichment efficiency of volatile analytes in definite headspace diluents is low, in this case, direct injection was still used. Comparing with headspace injection, in direct injection gas chromatography, sample matrix and solvents were introduced, which contaminate the GC system and shorten the service life of capillary column, more seriously, detection sensitivity was low as its little injection volume, or detector would have been contaminated.In this project, thermal stability of cefa-type drugs was studied, and the interference of thermal decomposition substance for residual solvents analysis was also investigated. The results showed that the thermal decomposition substance was polar, which separated well from the analytes on a proper capillary column. Comparing with direct injection, in headspace-gas chromatography, only volatile components among thermal decomposition substance were introduced, which reduced the contamination of GC system, and a better sensitivity was obtained with higher headspace temperature.In this study, the dissolubility of some water-insoluble sample were researched, especially the dissolubility in ionic liquids' dissertation">ionic liquids, meanwhile, the enrichment efficiency of residual solvents in different headspace diluents was also studied. The results showed that: Ionic liquids posses better dissolve ability for some water-insoluble sample matrix, and better behavior for enriching residual solvents, meanwhile, it almost do not contaminate GC system. All those merits made ionic liquids as potential nice headspace diluent.According to results studied, residual solvents in some indissolubility pharmaceutical samples were detected by HS-GC methods with proper headspace diluents, the sensitivity is perfect.1 Determination of Residual Organic Solvents in Cefotetan disodium by Capillary GC with headspaceObjective: To establish a HS-GC method of detection residual solvents in some thermal unstable cefa-type drugs, which provided basis for determination Acetone and Acetidin residual in cefotetan disodium.Methods: Thermal stability of thermal unstable cefa-type drugs were studied, especially the thermal stability of cefotetan disodium in water, DMSO and ionic liquid-[bmim]BF4. The influence of the thermal decomposition substance for detection of residual solvents also was studied. An Agilent DB-5 capillary column and FID detector were used, the temperature of injector and detector was set at 120℃, 150℃respectively, and the capillary column was maintain at 50℃.Results: Cefa-type drugs were unstable at a higher temperature, the polar thermal decomposition substance separated well from the analytes on a proper capillary column. Under the method established, both solvents had good linearity in the determination range. The average recovery were 99.5%、99.7% respectively, and RSD of the assay were less than 1.1%(n=3). The maximum residual of Acetone and Acetidin was 6.96×10-3, 5.12×10-3μg/mg respectively.Conclusion: The analytes were not interfered by polar thermal decomposed substance. The method established is accurate and reliable for the determination the residual solvents in cefotetan disodium. 2 Determination of Residual Organic Solvents in Strontium Ranelate by headspace Capillary gas chromatography Objective: To establish HS-GC method of determination residual solvents in Strontium Ranelate by studying its dissolubility in different headspace diluents.Methods: By Investigating the dissolubility of Strontium Ranelate in different solvents ([bmim]BF4, the solution of EDTA-2Naand H3PO4) search the proper solvents as headspace diluent. A HS-GC method with a HP-5 capillary column and FID detector was established, and N-hexane was used as internal standard substance for detection residual solvents in Strontium Ranelate.Results: The solution of H3PO4 with concentration 2 mol/L was used as headspace diluent. The linearity of all analyte is good in their determination range, recoveries were between 97~99%, and RSD were less than 3.7%.Alcohol and benzene were not observed, the maximum residual of acetone was 34 ppm.Conclusion: The solution of H3PO4 with concentration 2 mol/L was used as headspace diluents, the method for determination of residual solvents in Strontium Ranelate is sensitive and accurate. 3 Room temperature ionic liquid as matrix medium for the determination of residual solvents in Adefovir Dipivoxil by static headspace gas chromatographyObjective: To establish HS-GC method with ionic liquid [bmim]BF4 as headspace diluent for determination the residual solvents in Adefovir Dipivoxil by studying the enrichment efficiency of residual solvents in different headspace diluents.Methods: The ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in DMSO and [bmim]BF4. DB-624 capillary column with temperature program was employed with an initial temperature of 40 ?C for 4 min; this was increased at 40 ?C/min to120 ?C and held for 10 min. The injector and FID were maintained at 150 ?C and 200 ?C respectively. Sample equilibrated at temperature 110 ?C for 10 min.Results: Adefovir Dipivoxil has better dissolubility in [bmim]BF4, and enrichment efficiency of residual solvents is higher 2~3 times in [bmim]BF4 than in DMSO. The recoveries of analytes with this method were between 96%~102%, and RSD was less than 5%.The maximum residual of methylbenzene and n-butyl ether were 6 and 8 ppm.Conclusion: It have demonstrated that [bmim]BF4 was better headspace dilunet comparing with DMSO for enrichment efficiency of analytes employed in this study. And the method is sensitivity and better specialization. 4 ionic liquid [bmim]BF4 as headspace diluent for the determination of residual solvents in Bisphosphonates by static headspace gas chromatographyObjective: To investigate dissolubility of Etidronate, Pamidronate and Ibandronate in different solvents, comparing enrichment efficiency of analytes in different solvents. Looking for proper headspace diluents, and establish HS-GC determine residual solvents in this Bisphosphonates.Methods: The ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in DMA and [bmim]BF4. DB-624 f capillary column with temperature program was employed, initial temperature at 50 ?C maintain for 4 min, and then increased at 15 ?C/min to110 ?C and held for 5 min. The injector and detctor temperature was set at 120 ?C and of 150 ?C respectively.Results: Etidronate, Pamidronate and Ibandronate dissolved better in [bmim]BF4, the enrichment efficiency of analytes will be best when sample heat at at temperature 120 ?C for 20 min. all solvents determined had good linearity in the determination range, the recoveries were between 97%~99%, and RSD was less than 4%. The maximum of acetone residual was 0.0046%, the other residual solvents were not detected.Conclusion: Ionic liquids [bmim]BF4 were potential nice headspace diluents for its better dissolving ability of Bisphosphonates. The enrichment efficiency will increase with higher equilibrium temperature and have no contamination for GC system. The method established for determination of residual solvents in Etidronate, Pamidronate and Ibandronate is sensitivity and better specialization.

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