Study Of The Enrichment Efficiency Of Ionic Liquids, Conventional Matrix Mediums By HS-GC And The Method Of Determining Residual Solvents In Pharmaceutical Samples

Residues in pharmaceuticals are commonly detected by gas chromatography, which includes direct injection and headspace sampling. HS injection is more frequently used than drect injection for its good seperation and sensitivity. However, for some thermal unstable drugs or ones having poor dissolubility in headspace diluents such as water, DMA, DMSO et al, direct injection is still adopted to determine residues in these drugs, and which has the low sensitivity and the GC system contaminated seriously. In determinating organic residual solvent by HS-GC, the reasonable choice of matrix medium is directly related to sensitivity and accuracy of detective methods. On account of volatility, conventional solvents not only affect the enrichment efficiency of residual solvents, but wide chromatographic peak produced in the process of analysis also interfere with analytes, even result in detector's intoxication. Furthermore, some headspace matrix medium such as DMSO in themselves may produce many varieties of volatile impurities,when stored for a long time or heat. In that case, the result of the analysis of organic residual solvents should be correct by the blank matrix medium. In a word, the sensitivity of analysis of trace residues is influenced by the above factors to a large extent. Accordingly, looking for the ideal headspace matrix medium plays an important role in improving the sensitivity of the analysis of residues in pharmaceuticals.Ionic liquids (ILs) as novel solvents show many unique properties, such as extraordinary dissolution, negligible vapor pressure, chemical stability, good thermal and wide liquid range. In addition, compared with traditional solvents, ILs can be better worked out, and it is possible to design ILs for practical application by varying structures of cation and anion. Therefore, ILs as fine headspace matrix medium may be applied for the detection of organic residual solvents in pharmaceuticals. It was reported that ILs had more sensitive enriching ability than DMSO for analytes with high boiling point or some water-insoluble drugs. However, the analysis of these residues, such as alkanes, spirits, aromatichydrocarbon or residues with low boiling point, is not reported recently.The purpose of our research is to choose the suitable headspace matrix medium to analyze residues in Chlorphenamine Maleate, Sodium Azulenesulfonate, Ibandronate Sodium and some water-insoluble sample such as Paclitaxel, Naftifine, Ibuprofen , et al. By studying solubility of ILs and comparing ILs with traditional solvents, further to improve detective sensitivity. The results showed: Ionic liquids possed better behavior than water and DMSO for enriching some water-solution organic solvents and some spirits. The enrichment efficiency of some alkane or ones with low boiling point in ILs was much higher than that in DMSO and DMA. Furthermore, there was no contamination from matrix medium for its property of negligible vapor pressure, and a steady baseline could be attained. But ILs had lower enriching ability than water at the same temperature in the analysis of Aromatic hydrocarbon residuals, even though the temperature was gradually elevated. In addition, ILs with [PF6]- possed better dissolving ability for some water-insoluble sample matrix such as Naftifine than ones with [BF₄]-. Ibuprofen dissolved better in [Hmim][BF₄] than that in [Bmim][BF₄]. However, some salts such as Sodium Azulenesulfonate and Ibandronate Sodium dissolved worse in ILs than that in water, so traditional solvents were selected for testing in the end on the basis of conditions in laboratory.According to the results studied above, ILs could be suitable as novel matrix medium for improving detection sensetivity, and this will be a new analytical mean to determine residues in the raw materials, which contribute to quality control in pharmaceutical studies. But to aim directly at some special water- insoluble pharmaceuticals, which have worse dissolubility in ILs, the conventional matrix medium could be still selected. PART 1 The application of ionic liquids as novel headspace matrix medium for residuals analysis in pharmaceuticals.(â… ) Room temperature ionic liquid as matrix medium for the simultaneous determination of residual solvents by static headspace gas chromatography.Objective: To study ideal behaviors of ILs, water and DMSO to improve the detective sensitivity of water-soluble organic residual solvents and establish a sensitive, accurate and specific method for the determination of acetone, tetrahydrofuran, dioxane, pyridine and toluene in Chlorphenamine Maleate.Methods: By HS-GC, the ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in [Emim][BF₄], water and DMSO. The analytes were equilibrated with oven temperature 100℃for 10 min and the volume injected was 1.0 mL. The chromatographic analysis was carried out on ZB-1 capillary column. The injector and detector temperature was set at 180℃and 150℃, respectively. The GC temperature program was 60℃isothermal for 4 min, and then increased at 4℃·min- 1 to 130℃and held for 10 min.Results: Enrichment efficiency of the most residual solvents is higher in [Emim][BF₄] than in DMSO and water, and [Emim][BF₄] as matrix midium do not interfere detection. Good linear relationships of acetone, tetrahydrofuran, dioxane, pyridine and toluene were abtained in the range of 3.13¹00, 2.25⁷2.0, 1.13³6.0, 0.625²0.0 and 2.78⁸9.0μg·mL^-1, respectively. The recoveries of five analytes were during 86.0%⁹6.9%, and RSD were less than 5.0 %.Conclusion: Ionic liquid as a headspace solvent can improve the sensitivity of water-soluble residues such as acetone, tetrahydrofuran and pyridine, and because of its property of negligible vapor pressure, can avoid contamination of chromatographic system with conventional headspace solvents.The method is novel, sensitive, accurate and specific, and could be used to detect residuals in Chlorphenamine Maleate. (â…¡) Study of [Emim][BF₄] and DMSO, DMA as Matrix Medium in Determining Trace Residual Solvents in Paclitaxel by HS-GC.Objective: To research the peak intensity and detection limit of five residues for making better of the sensitivity of residues with low-boiling point and alkanes, also to establish a sensitive, accurate and specific method for determining extraction solvent such as acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane in water-insoluble Paclitaxel.Methods: The peak intensity and detection limit of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane residues in [Emim][BF₄], DMSO and DMA were systematically compared by HS-GC, respectively. The sample was equilibrated at temperature 110℃for 20 min, and the volume injected was 1.0ml. The condition of chromatograph showed: the injector was maintained at 180℃with a splitless injection, and temperature of the FID was set to 200℃. The column oven temperaure program involved an initial temperature of 50℃for 5min, then this was increased at 40℃/min to 120℃and held for 10min.Results: The experimental results showed that the peak areas of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane in [Emim][BF₄] were as about 2.10, 2.50, 2.80, 3.40, 1.30 times as those in DMSO, and were as about 2.04, 4.50, 3.00, 3.00, 6.00 times as those in DMA, respectively. The detection limits of several organic residuals in [Emim][BF₄] was also higher than that in DMSO and DMA, and the baseline of ILs blank matrix medium was steady. Five solvents detected had good linearity in the ranges of 31.3⁵00, 1.82²9.0, 31.3⁵00, 4.50⁷2.0 and 31.3⁵00μg·mL^-1, respectively. The recoveries of five analytes were during 90.8%⁹7.8% and RSD were less than 4.0%.Conclusion: The enrichment efficiency of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane residues in [Emim][BF₄] is two or six times higher than those in conventional solvents, and ILs can minimized the contamination of chromatographic system. The method is novel, sensitive, accurate and specific, and could be adopted to detect residuals in Paclitaxel, and It provides a new way for determining residues in Pharmaceutical.(â…¢) Study of ionic liquids and DMSO, water as Matrix Medium in Determining Trace Residual Solvents in water-insoluble Niftifine by HS-GC.Objective: To choose a headspace solvent with good dissolubility and high enrichment efficiency, and establish a sensitive, accurate and specific method for determining methanol, ethanol isopropyl alcohol and toluene in water-insoluble Niftifine.Methods: The static equilibrium method was first used to determine solubilities of the drug in [Bmim][BF₄] and [Bmim][PF6], and the comparison of [Bmim][BF₄], [Bmim][PF6], DMSO and water as matrix medium respectively were carried out in this study, based on the partition coefficients between liquid and gas phases. The chromatographic analysis was performed by using DB-624capillary column. The injector temperature at 180℃and the FID detector with the temperature of 200℃. The column oven temperaure program involved an initial temperature of 45℃for 3min, then this was increased at 25℃/min to 120℃and held for 5min. The headspace sampler vials was equilibrated at 100℃for 20min.Results: The dissolubility of the drug in [Bmim][PF6] could get by 120 mg·mL^-1 at 90℃, while in [Bmim][BF₄] it had less than 90 mg·mL^-1at the same temperature. Enrichment efficiency of methanol, ethanol and isopropyl alcohol in two kinds of ionic liquid is higher than that in DMSO and water, futhermore, [Bmim][BF₄] was the best headspace matrix medium of all. However, enrichment efficiency of toluene in water was highest. Because Naftifine is a water-insoluble drug, [Bmim][BF₄] was the final selection as solvent. Good linear relationships of four residuals were abtained in the range of 3.00×10^-11.50×10², 5.00×10^-12.50×10², 5.00×10^-12.50×10²and 0.140⁸9.0μg·mL^-1, respectively. The average recoveries were 95.6%, 95.1%, 92.0% and 94.9% respectively. RSD was less than 4.0%.Conclusion: The dissolubility of the drug in [Bmim][BF₄] is lower than that in [Bmim][PF₆], but the enrichment efficiency of methanol, ethanol and isopropyl alcohol in [Bmim][BF₄] is higher than that in [Bmim][PF₆], especially in water and DMSO. According to the above studies, [Bmim][BF₄] was selected as matrix medium in the end, and deployed to the futher analysis. The method is novel and accurate, and the sensitivity was improved finally.(â…£) The mixed Ionic liquid as matrix medium for the determination of residual solvents in Ibuprofen by HS-GC.Objective: To use the mixed ionic liquid as matrix medium to solve the drug's bad dissolubility and low sensitivity of some residues.Methods: The enrichment efficiency of residual solvents and dissolubility of Ibuprofen in [Bmim][BF₄] and [Hmim][BF₄] were investigated by HS-GC. Sample equilibrated at temperature 110℃for 30min. The condition of chromatograph showed: HP-1 capillary column with temperature programmed was used with an initial temperature of 50℃for 5min, then increased at 10℃/min to130℃and held for 5min. The injector and FID were maintained at 180℃and 200℃, respectively.Results: The mixed [Bmim][BF₄] and [Hmim][BF₄] as matrix medium (the ratio is 2:1) can increase the dissolubility, which could get by 100mg·mL^-1 also can improve sensitivity. Good linear relations of isopropyl alcohol, trichlormethane and toluene were abtained in the ranges of 5.00⁴00μg·mL^-1, 6.00×10-2⁶.00μg·mL^-1 and 0.890⁷1.2μg·mL^-1, respectively. The average recoveries were 97.1%, 93.8% and 96.9%, respectively. RSD were less than 4.0%.Conclusion: The mixed ionic liquids as matrix medium could be used to solve the problem that the single ionic liquid has bad dissolubility of the drug while has good enrichment efficiency of residual solvents or which has good dissolubility of the drug while has bad enrichment efficiency. The method is novel, sensitivity and accurate with the mixed ionic liquids; It provides a new means for determining residues in Pharmaceutical.PART 2 The application of traditional headspace matrix medium for residuals analysis in pharmaceuticals.(â… ) DMSO as headspace diluent for determining residual organic solvents in Sodium Azulenesulfonate by Headspace Capillary GC.Objective: To select a agreeable headspace solvent, which has good dissolubility of the drug, and estabilish a method for determining 1,2-dichloroethane and 1,4-dioxane residuals in sodium azulenesulfonate.Methods: The dissolubility of sodium azulenesulfonate and the enrichment efficiency of residual solvents in water, DMSO and ILs with good dissolubility were investigated, respectively. The headspace sampler vials was equilibrated at 80℃for 30min. DMSO was matrix medium. The chromatographic analysis was performed by using DB-624capillary column. The injector temperature at 180℃and the FID detector with the temperature of 200℃. The column oven temperaure program involved an initial temperature of 60℃for 6min, then this was increased at 30℃/min to 130℃and held for 5min.Results: Sodium Azulenesulfonate dissolved better in water, whereas the lytic response happened when it was heated, and the enrichment efficiency of ananlytes could be effected. the dissolubility of the drug in ILs with limidazolium reached to only 20mg·mL^-1. there was no water in DMSO, and the hydrolysis to the drug did not happen, futhermore, Sodium Azulenesulfonate dissolved better in DMSO. Therefore the headspace diluent DMSO was eventually selected. Good linear relationships of 1,2-dichloroethane and 1,4-dioxane were 3.13×10^-2⁵.00×10^-1, 2.38³8.0μg·mL^-1, respectively. The average recoveries were 95.6% and 97.2% with RSD of 2.0 % and 1.5 %, respectively.Conclusion: The dissolubility of the drug was better in DMSO, which could meet the requirement of detection and avoid the drug hydrolysis. DMSO is used as the headspace matrix medium and fit to determine residual organic solvent.(â…¡) Water as headspace matrix medium for determining methylbenzene and chlorobenzene residuals in Ibandronate Sodium by Capillary GC.Objective: To choose a suitable solvent to improve the sensitivity of methylbenzene and chlorobenzene, and establish a HS-GC method for quantification of residual organic solvents in Ibandronate Sodium with water as matrix medium.Methods: The enrichment efficiency of methylbenzene and chlorobenzene in water, DMA and ILs were investigated, The column oven temperaure program involved an initial temperature of 50℃for 3min, then this was increased at 20℃·min-1to 130℃and held for 20min. The sample was equilibrated at temperature 60℃for 30min, and the volume injected was 0.5mL.Results: The dissolubility of the drug and the enrichment efficiency of residual solvents is higher in water than these in ILs. So water is selected as the headspace matrix medium. Good linear relationships of toluene and chlorobenzene were 5.56⁸9.0μg·mL^-1, 2.25³6.0μg·mL^-1, respectively. The average recoveries were 91.1% and 93.7% with RSD of 1.6% and 1.4%, respectively. The detection limits were 0.35 and 1.13μg·mL^-1, respectively.Conclusion: Water is the ideal dillute for aromatic hydrocarbon residuals, and used to detect residuals in water-solubility drugs.