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OBJECTIVE： To establish a method for simultaneous determination of residual solvents in phenylbutazone raw material. METHODS： Head-space GC was adopted. The determination was performed on Agilent HP-5 capillary column by temperature programming. The temperature of injector was 200 ℃， and detector was flame ionization detector with temperature of 250 ℃； carrier gas was nitrogen （purity：99.99％） at the flow rate of 2.0 mL/min. The split ratio was 5 ∶ 1. Headspace equilibrium temperature was 60 ℃， and equilibration time was 30 min. The sample size was 1 mL. RESULTS： The linear range was 0.15-4.5 μg/mL for methanol （r＝0.999 9）， 0.25-7.5 μg/mL for ethanol （r＝0.999 7）， 0.25-7.5 μg/mL for isopropyl alcohol （r＝0.999 7）， 0.03-0.9 μg/mL for dichloromethane （r＝0.999 3）， 0.25-7.5 μg/mL for ethyl acetate （r＝0.999 3）， 0.044-1.32 μg/mL for N，N-dimethyl formamide （r＝0.999 3）， respectively. The limits of detection were 0.05， 0.08， 0.08， 0.01， 0.08， 0.015 μg/mL. The limits of quantitation were 0.15， 0.25， 0.25， 0.03， 0.25， 0.044 μg/mL. RSDs of precision test were lower than 2.0％. RSDs of stability and reproducibility tests were lower than 3.0％. The recoveries were 98.75％-100.12％ （RSD＝0.56％， n＝9）， 98.07％-101.20％ （RSD＝1.12％， n＝9）， 98.36％-100.80％ （RSD＝0.92％， n＝9）， 98.33％-101.67％ （RSD＝0.98％， n＝9）， 98.11％-100.40％ （RSD＝0.72％， n＝9） and 98.75％-101.05％ （RSD＝0.89％， n＝9）. CONCLUSIONS： The method is simple， accurate， precise， stable， reproducible and durable， and can be used for simultaneous determination of 6 residual solvents in phenylbutazone raw material.
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Objective To establish a method for the determination of residual solvents in tulobuterol by GC and optimize the purified process of crude tulobuterol product by this method. Methods The analysis was performed on Agilent DB-624 capillary column (30 m×0.32 mm,1.8 μm).The carrier gas was nitrogen at 1 mL·min-1.The injector temperature was 250 ℃.Detector was FID with hydrogen at 45 mL·min-1and air at 450 mL·min-1.The detector temperature was 250 ℃.The column temperature program was used.And the flow ratio was 10:1.Dimethyl sulfoxide (DMSO) was used as solvent of reference and test solution. Results Ethanol,tert-butylamine,dichloromethane,tert-butyl-methyl ether,n-hexane and 1,4-dioxane were completely separated.The calibration curve of each solvent showed good linear correlation. The RSD of precision was less than 5.0% and the average recovery ranged from 97.0% to 104.0% (RSD<5%).By optimizing the purification process of toloterol,the residue of organic solvent in the preparation of tolobuterol was in accordance with the Chinese Pharmacopoeia ( 2015) limit. Conclusion Validated by methodology,this simple,rapid and precise method can be used for the test of residual solvents in tulobuterol.
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Objective:To summarize the differences and similarities in the detection methods for residual solvents between Safety and Technical Standards for Cosmetics 2015 edition and Chinese Pharmacopoeia 2015 edition so as to provide reference for the improve-ment of the detection methods for residual solvents in Safety and Technical Standards for Cosmetics. Methods:The type and limitations of residual solvents and the characteristics of the test methods for residual solvents between Safety and Technical Standards for Cosmetics 2015 edition and Chinese Pharmacopoeia 2015 edition were compared and analyzed. Results: The detection methods for residual sol-vents in Chinese Pharmacopoeia were more detailed. The detection methods for residual solvents in Safety and Technical Standards for Cosmetics were general detection method, and the process could be applied in the detection of more solvents. Some detection methods were short of limitations. Conclusion:The control of residual solvents in cosmetics should be improved if the limitations table of the limiting used solvents is introduced into Safety and Technical Standards for Cosmetics referring to Chinese Pharmacopoeia and increase the types of residual solvents detected by the general methods.
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OBJECTIVE: To introduce the application of the residual solvents determination methods in general chapter 0861 of Chinese pharmacopoeia 2015 edition. METHODS: Determination of the residual solvents of cefathiamidine was chosen as an example to indicate that how to use the residual solvents determination methods in general chapter 0861 of Chinese pharmacopoeia 2015 edition when the methods for the determination of residual solvent in monograph of cefathiamidine did not work. RESULTS: The residual solvents in cefathiamidine from different manufactures were determined accurately using methods in general chapter 0861 of Chinese pharmacopoeia 2015 edition. CONCLUSION: The residual solvents determination methods in general chapter 0861 of Chinese pharmacopoeia 2015 can be used to screening and confirm the unknown peaks by the two opposite polar column systems, which can help to establish the residual solvents method.
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In drug discovery research, residual solvent measurement is an integral part of purity analysis for synthesis of a drug candidate before it is used for toxicity testing. This is usually carried out using gas chromatography (GC) with direct injection sample introduction. This method requires testing compounds to be soluble at high concentrations ( > 50 mg/mL, usually in DMSO) to achieve acceptable sensitivity, a hurdle which is not always achievable for some samples such as cyclic peptides and oligonucleotides. To overcome the limitation associated with the direct injection approach, a new method using the Chromatoprobe thermal extraction device was developed for quantifying residual solvents of drug discovery compounds. This method not only consumes significantly less material (less than 1 mg), but also shows higher sensitivity than the direct injection approach. In addition, because no diluent is required with the Chromatoprobe thermal extraction, all residual solvents can be detected and measured without further method optimization. In our study, we compared data from GC residual solvent analysis using the Chromatoprobe solid sample introduction to those of the direct injection method for seven in-house samples. Our results showed a good agreement between the data from these two sample introduction methods. Thus, the Chromatoprobe sample introduction method provided a sample-sparing alternative to the direct injection method for the measurement of residual solvents in drug discovery. This method can be particularly useful for residual solvent analysis in samples that are available only in limited amounts, poorly soluble, and/or unstable in the diluents used for the direct injection method.
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Objective To establish a method of gas chromatography with head-space sampling for determination of five residual solvents ( acetone, ethyl acetate, isopropanol, dichloromethane, acetonitrile ) in raw material drug of cefotiam hexetil hydrochloride. Methods Agilent DB-624 capillary column(30 m×0.53 mm,3.0 μm)was used,with FID served as detector and DMF as the solvent. Results Linear relationships were obtained for the 5 residual solvents in their respective concentration ranges ( r=0.999 6-0.999 9,n=5) ,and the detection range was from 0.071 to 0.847μg. The stabilities measured as relative standard deviations ( RSD) for the 5 residual solvents were from 0.40% to 2.12% ( n=3) . The average recovery rates were 99.03% to 103.33%,and RSD were 0.54% to 3.41% ( n=3) . Conclusion The method is simple,sensitive and accurate for the residual solvent analysis in raw material drug of cefotiam hexetil hydrochloride.
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OBJECTIVE:To establish a method for the determination of ethanol,acetonitrile,dichloromethane,ethyl acetate, pyridine in vidarabine monophosphate. METHODS:Headspace GC was performed on the column of Agilent DB-624,programmed temperature,inlet temperature was 200 ℃,the detector was flame ionization detector,detecting temperature was 250 ℃,nitrogen was carrier gas,flow rate was 3 ml/min,split ratio was 1∶1,the top bottles equilibrium temperature was 100 ℃,and equilibrium time was 45 min,injection volume was 1 ml. external standard was used for quantitative analysis. RESULTS:The peaks of five re-sidual solvents could be completely separated from the other peaks respectively,The linear rang was 24.7-296.3 μg/ml for ethanol (r=0.999 6)、1.9-23.2 μg/ml for acetonitrile(r=0.999 0),2.8-33.6 μg/ml for dichloromethane(r=0.998 0),24.7-295.9 μg/ml for ethyl acetate(r=0.999 5),1.0-11.9 μg/ml for pyridine(r=0.998 6);RSDs of precision and reproducibility tests were lower than 4.35%;recoveries were 102.4%(RSD=2.0%,n=9)、102.1%(RSD=3.4%,n=9)、105.5%(RSD=4.8%,n=9)、100.3%(RSD=4.8%, n=9)、98.3%(RSD=4.0%,n=9). The minimum quantifation limit was 0.304 4-0.988 0 μg/ml and the minimum detection limit was 0.101 5-0.329 3 μg/ml. CONCLUSIONS:The method is simple,accurate and reproducible,and can be used for the determination of residual solvents in vidarabine monophosphate.
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OBJECTIVE:To establish a method for the determination of 4 kinds of residual solvents in racemic ketoisoleucine calcium. METHODS:Headspace gas chromatography was performed on the column of DB-624 capillary column by temperature programmed,detector was FID,inlet temperature was 200 ℃,detector temperature was 250 ℃,carrier gas was nitrogen,flow rate was 1.0 ml/min,injection volume was 1 ml by headspace sampling,equilibrium temperature was 70 ℃ and equilibrium time was 30 min. RESULTS:The linear range was 120.04-480.16 μg/ml for methanol (r=0.997 8),200.21-800.83 μg/ml for ethanol (r=0.998 5),204.05-816.19 μg/ml for ethyl acetate(r=0.999 2),28.35-113.39 μg/ml for tetrahydrofuran(r=0.998 9);detection limits were 6.002 μg/ml,50.05 μg/ml,51.01 μg/ml and 7.087 μg/ml;RSD of precision was lower than 3%;recoveries were 95.0%-105.6%(RSD=3.95%,n=9),97.5%-106.4%(RSD=3.67%,n=9),98.1%-105.9%(RSD=3.16%,n=9)and 88.8%-99.2%(RSD=3.79%,n=9),respectively;4 kinds of residual solvents were not detected. CONCLUSIONS:The method is simple,accu-rate and reliable,and can be used for the determination of residual solvents in racemic ketoisoleucine calcium.
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OBJECTIVE:To establish a method for the determination of residual solvent of ethanol and toluene in diphenhydr-amine hydrochloride raw material. METHODS:Headspace capillary gas charmatography and butanone as internal standard were used. The column was Agilent DB-624 capillary column,inlet temperature was 200 ℃,hydrogen flame ionization detector was 250 ℃,the carried gas was high purity nitrogen,flow rate was 3.0 ml/min with temperature programmed,the splitting-ratio was 20∶1,the containers of headspace injector were in equilibrium at 80 ℃ for 30 min,and the injection time was 1 min. RESULTS:With this chromatographic condition,ethanol,toluene and internal standard peak were well separated;there was a good linear rela-tionship of ethanol and toluene in the range of 0.02-0.8 mg/ml (r=0.999 8 and r=0.999 4);RSDs of precision and stability test were lower than 3%;recoveries were 95.50%-103.50%(RSD=2.6%,n=9) and 96.91%-103.74%(RSD=2.2%,n=9). CON-CLUSIONS:The method is simple,sensitive and accurate,and can be used for the determination of residual solvent of ethanol and toluene in diphenhydramine hydrochloride raw material.
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OBJECTIVE:To establish a method for the determination of 7 residual solvents(ethanol,n-hexane,benzene,tolu-ene,xylene,styrene,divinylbenzene)in Liuwei dihuang glycoside. METHODS:The column was DB-624 capillary column,carri-er gas was nitrogen,flow rate was 5.0 ml/min;detector was a hydrogen flame ionization detector with temperature of 250 ℃(pro-grammed temperature);equilibrium temperature was 80 ℃,sample loop temperature was 90 ℃,and transfer line temperature was 100 ℃;the equilibrium time of vial heating was 30 min,sample loop filling time was 0.05 min,injection time was 1.0 min;the carrier gas pressure was 95 kpa,and the vial pressure was 60 kpa. RESULTS:The linear range was 25-500 μg/ml for ethanol(r=0.998 7),0.025-10μg/ml for n-hexane(r=0.998 8),0.025-10μg/ml for benzene(r=0.999 9),0.1-40μg/ml for toluene(r=1.000 0),0.25-100 μg/ml for xylene(r=0.999 9),0.5-500 μg/ml for styrene(r=1.000 0) and 0.5-500 μg/ml for divinylbenzene (r=1.000 0);RSDs of precision,stability and reproducibility tests were lower than 4%;recoveries were 99.60%-102.70%(RSD=1.08%,n=9),90.70%-100.30%(RSD=4.51%,n=9),100.10%-109.80%(RSD=3.82%,n=9),99.50%-110.00%(RSD=4.40%,n=9),100.00%-109.10%(RSD=3.50%,n=9),93.40%-102.30%(RSD=3.73%,n=9) and 99.70%-101.70%(RSD=0.79%,n=9),respectively;the low limits of detection were 1.000,0.025,0.025,0.025,0.100,0.025,0.250 μg/ml respectively. CONCLUSIONS:The method is simple,stable and reproducible,and can be used for the determination of residual solvents(etha-nol,n-hexane,benzene,toluene,xylene,styrene,divinylbenzene)in Liuwei dihuang glycoside.
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Objective:To establish a method for the determination of 9 residual solvents including methanol, ethanol, acetone, i-sopropyl alcohol, acetonitrile, dichloromethane, methyl-butyl ether, ethyl acetate and methylbenzene by capillary gas chromatography. Methods:The residual solvents were separated on a Kromat KB-624(30 m × 0. 53 mm,3. 0 μm) capillary chromatographic column with temperature programming. Nitrogen was used as the carrier gas with the flow rate of 5. 0 ml·min-1 . The temperature of injector was 200 ℃. A flame ionization detector was used with the temperature of 250℃. The containers of head-space injector were in equilib-rium at 80℃ for 20 min. Dimethyl sulfoxide was used as the solvent and an external standard method was used for the determination of the 9 residual solvents. The injection volume was 1 ml. Results:Under the above conditions, the 9 solvents were well separated. There was good linear relationship within the concentration range, and the correlation coefficients were no less than 0. 9991. The average re-coveries were 99. 08%-105. 14% with RSD of 1. 1%-3. 3%(n=9). The LOQ was 15. 68, 25. 45, 1. 09, 10. 61, 4. 54, 5. 73, 1. 04, 10. 58 and 1. 89 μg, respectively. Conclusion:The established method is simple, accurate and reproducible, and can be used in the determination of residual solvents in irbesartan API.
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OBJECTIVE: To establish a method for determining nine residual solvents in cefotetan disodium by headspace gas chromatography. METHODS: The residual solvents including methanol, acetone, acetonitrile, dichloromethane, butanone, ethyl ace-late, tetrahydrofuran in cefotetan disodium were quantitatively determined on a DB-624 column (30 m×0.32 mm, 1.8 μm). Water was solvent media. The residual solvents of anisole and isocaprylic acid in cefotetan disodium were quantitatively determined on a HP-FFAP column (25 m×0.32 mm, 0.5 μm). The 20% dimethylsulfoxide (DMSO) was used as the solvent. RESULTS: Nine residual solvents were completely separated. Good linearity of the solvents were obtained within the determination ranges. There between 0.9988 and 0.9997. The average recoveries of three levels were in the range of 95.71%-103.55%. The RSDs were 0.39%-2.28%. CONCLUSION: The established two methods are accurate and sensitive, and can be used for the determination of residual solvents in cefotetan disodium.
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OBJECTIVE: To develop an analytical method for determination of unknown residual solvents in solid drug products by GC-MS in order to meet the need of supervision. METHODS: Fifty residual solvents including benzene, carbontetrachloride, 1, 2-di-chloroethane, 1, 1, 1-trichloroethane, acelonitrile, chlorobenzene, acetone, etc, were determined by GC/MS using selected ion monitoring (SIM) mode. RESULTS: Good linearity was obtained with correlation coefficients of more than 0.9975 for all the solvents. The average recoveries of the quality control samples at low, middle and high concentrations were from 88.8% to 109.8% and the relative standard deviations (RSDs) were lower than 11.6%. The limits of detection (TODs) were in the range of 0.00003-0.3μg·mL-1, while the limits of quantitation (LOQs) were in the range of 0.00009-1 μg ·mL-1. CONCLUSION: The method is simple, rapid, sensitive and accurate, and can be used for the simultaneous determination of 50 residual solvents in solid preparations such as tablets and capsules.
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OBJECTIVE: To establish a capillary GC method for the determination of residual solvents including ethanol, acetoni-trile, acetone, isopropanol, ethyl acetate, dioxane and THF in 2-[2-methyl-4-[[2-[4-(trifluoromethyl) phenyl] pyrimidin-4-yl] methylsulfanyl] phenoxy] acetic acid. METHODS: The residual organic solvents were separated on DB-1capillary column (30 m × 0.53 mm, 5.00 μm). FID was used as detector with a temperature of 250°C, and the inlet temperature was 160°C. The carrier gas was nitrogen, and the column temperature was programmed set. The contents of residual solvents were calculated by external standard method. RESULTS: The seven residual organic solvents were completely separated, the recovery rates and linear relationship were good, and three batches of samples all met the requirements. CONCLUSION: The method is simple, accurate, and reproducible, so it can be used for the detection of seven residual organic solvents in the raw.
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OBJECTIVES: The purpose of this study is to evaluate bonding efficacy by means of measuring the effect of remained solvent on Degree of conversion(DC) and microTBS and FE-SEM examination. MATERIALS AND METHODS: Two 2-step total etching adhesives and two single-step self etching adhesives were used in this study. First, volume weight loss of 4 dentin adhesives were measured using weighting machine in process of time in normal conditions and calculate degree of evaporation (DE). Reaction/reference intensity ratio were measured using micro-Raman spectroscopy and calculate DC according to DE. Then 2 experimental groups were prepared according to air-drying methods (under, over) and control group was prepared to manufacturer's instruction. Total 12 groups were evaluated by means of micro tensile bond strength and FE-SEM examination. RESULTS: Degree of evaporation (DE) was increased as time elapsed but different features were observed according to the kind of solvents. Acetone based adhesive showed higher DE than ethanol and butanol based adhesive. Degree of conversion (DC) was increased according to DE except for S3 bond. In microTBS evaluation, bond strength was increased by additional air-drying. Large gaps and droplets were observed in acetone based adhesives by FE-SEM pictures. CONCLUSIONS: Additional air-drying is recommended for single-step self etching adhesive but careful consideration is required for 2-step total etching adhesive because of oxygen inhibition layer. Evaporation method is carefully chose and applied according to the solvent type.