硫酸特布他林的質(zhì)量控制方法研究
發(fā)布時間：2018-07-21 20:01
【摘要】：硫酸特布他林為選擇性β2受體激動劑,用于支氣管哮喘、慢性支氣管炎和其它伴有支氣管痙攣的肺部疾病,也可用于預(yù)防早產(chǎn)和胎兒窒息,具有選擇性高、副作用少等特點,在國內(nèi)外已得到廣泛應(yīng)用。本課題針對現(xiàn)行硫酸特布他林質(zhì)量控制的不足,就影響其質(zhì)量的關(guān)鍵指標(biāo)——殘留溶劑、工藝雜質(zhì)與降解產(chǎn)物以及含量分別進行研究,為硫酸特布他林的質(zhì)量評價和控制提供了新的方法和參考。在全面分析硫酸特布他林合成過程中所用溶劑的基礎(chǔ)上,首次建立了一種同時測定硫酸特布他林中甲醇、乙醇、丙酮、叔丁基甲基醚、乙酸乙酯、四氫呋喃、苯、醋酸、甲苯和氯化芐共10種殘留溶劑的頂空氣相色譜法;建立了超高效液相色譜高分辨質(zhì)譜聯(lián)用(UHPLC-Q-TOF-MS/MS)法,用于硫酸特布他林工藝雜質(zhì)與降解產(chǎn)物的結(jié)構(gòu)解析和鑒定;建立了高效液相色譜(HPLC)法,用于硫酸特布他林的含量測定。第一部分頂空氣相色譜法同時測定硫酸特布他林中10種殘留溶劑目的:建立測定硫酸特布他林中甲醇、乙醇、丙酮、叔丁基甲基醚、乙酸乙酯、四氫呋喃、苯、醋酸、甲苯和氯化芐共10種殘留溶劑的頂空氣相色譜法。方法:采用Agilent DB-624UI(30 m×0.32 mm,1.8μm)毛細管柱,柱溫采用程序升溫,起始柱溫為40°C,保持3 min,以10°C/min升至90°C,保持1 min,再以40°C/min升至200°C,保持5 min。FID檢測器,檢測器溫度為250°C,進樣口溫度為200°C。載氣為氮氣,流速為1.0mL/min;分流比為15:1。頂空進樣,頂空平衡溫度為90°C,頂空時間為30 min。定量環(huán)溫度為100°C,傳輸線溫度為110°C。壓力平衡時間為1min,進樣時間為1 min。結(jié)果:10種溶劑完全分離;在考察的濃度范圍內(nèi)線性關(guān)系良好,相關(guān)系數(shù)r均不小于0.9990,平均回收率為95.7%-102.4%,儀器精密度、重復(fù)性、穩(wěn)定性、檢測限和定量限均符合要求。3批供試品中甲醇的質(zhì)量分數(shù)分別為0.035%、0.043%、0.043%,乙醇的質(zhì)量分數(shù)分別為0.033%、0.034%、0.034%,丙酮的質(zhì)量分數(shù)分別為0.00059%、0.00062%、0.00062%,叔丁基甲基醚、乙酸乙酯、四氫呋喃、苯、醋酸、甲苯、氯化芐均低于檢測限(lod)。結(jié)論:建立的頂空氣相色譜法簡單、準(zhǔn)確、重復(fù)性好,可用于硫酸特布他林中殘留溶劑的測定。第二部分硫酸特布他林工藝雜質(zhì)與降解產(chǎn)物的uhplc-q-tof-ms/ms分析目的:采用超高效液相色譜高分辨質(zhì)譜聯(lián)用技術(shù)(uhplc-q-tof-ms/ms)對硫酸特布他林工藝雜質(zhì)與降解產(chǎn)物進行結(jié)構(gòu)解析和鑒定。方法:對硫酸特布他林質(zhì)譜裂解規(guī)律進行研究,然后將硫酸特布他林供試品分別進行酸、堿、氧化、高溫、高濕、光照降解及長期試驗,采用uhplc-q-tof-ms技術(shù)對獲得的14種降解樣品進行分析。色譜條件:采用phenomenexlunac18色譜柱(2.0mm×150mm,3μm),流動相為甲醇-10mmol/l甲酸銨(用甲酸調(diào)ph至3.2),梯度洗脫,流速為0.3ml/min,進樣量為5μl。質(zhì)譜條件:采用duospraytm離子源正離子模式,全掃描采集,采用動態(tài)背景扣除和信息依賴采集觸發(fā)二級碎片的采集,每一循環(huán)采集12個最強峰的二級質(zhì)譜圖。根據(jù)測得的各降解產(chǎn)物及其碎片離子的準(zhǔn)確質(zhì)量數(shù)和可能分子組成,以硫酸特布他林質(zhì)譜裂解規(guī)律為基礎(chǔ),比較降解產(chǎn)物與硫酸特布他林以及降解產(chǎn)物碎片離子之間的質(zhì)量數(shù)變化,對其進行結(jié)構(gòu)鑒定。結(jié)果:共鑒定出17個雜質(zhì),包括14個新的降解產(chǎn)物和3個已知雜質(zhì),其中3個已知雜質(zhì)既是工藝雜質(zhì),也是降解產(chǎn)物。結(jié)論:硫酸特布他林在氧化、堿性水解和光照(堿性溶液)條件下不穩(wěn)定;容易發(fā)生反應(yīng)的官能團為叔丁胺基、芐基碳和苯環(huán)。本研究首次對降解產(chǎn)物可能的降解途徑進行了推斷。第三部分硫酸特布他林的含量測定方法改進目的:對硫酸特布他林現(xiàn)有含量測定方法進行改進,建立高效液相色譜(hplc)法用于硫酸特布他林的含量測定。方法:選用agilentzorbaxsb-c18色譜柱(4.6mm×150mm,5μm);流動相為30mmol/l甲酸銨(用甲酸調(diào)ph至3.0)-甲醇(體積比為90:10);流速為1.0ml/min;檢測波長為276nm;進量樣為10μl;柱溫為室溫。結(jié)果:方法的線性范圍為0.01-0.40 mg/mL(r=1.000)。回收率為99.2%,RSD為0.8%(n=6)。儀器精密度、重復(fù)性、穩(wěn)定性、檢測限和定量限均符合要求。3批供試品中硫酸特布他林的含量分別為100.5%、98.9%、99.2%。結(jié)論:與現(xiàn)有電位滴定法和離子對高效液相色譜法(IP-HPLC)比較,改進的HPLC法更為簡單、快速、經(jīng)濟,并可以從液相色譜圖上直觀反映樣品中主要雜質(zhì)的變化,可用于硫酸特布他林的含量測定。
[Abstract]:Terbutaline sulfate, a selective beta 2 receptor agonist, is used in bronchial asthma, chronic bronchitis and other pulmonary diseases with bronchial spasm. It can also be used to prevent premature and fetal asphyxia. It has high selectivity and less side effects. It has been widely used at home and abroad. This subject is aimed at the quality control of current terbutaline sulfate. A new method and reference for the quality evaluation and control of terbutaline sulfate is provided for the quality evaluation and control of terbutaline sulfate, which is the key index which affects its quality, such as residual solvents, process impurities and degradation products and their content respectively, and a new method is established on the basis of the comprehensive analysis of the solvent used in the process of terbutaline sulfate synthesis. A headspace gas chromatographic method for the determination of 10 residual solvents of methanol, ethanol, acetone, tert butyl methyl ether, ethyl acetate, tetrahydrofuran, benzene, acetic acid, toluene and benzyl chloride in terbutaline sulfate, and a high resolution liquid chromatography high resolution mass spectrometry (UHPLC-Q-TOF-MS/ MS) method for the synthesis of impurities and degradation products in terbutaline sulphate process was established. Structure analysis and identification; a high performance liquid chromatography (HPLC) method was established for the determination of the content of terbutaline sulphate. The first part, headspace gas chromatography, was used for the simultaneous determination of 10 residual solvents in terbutaline sulphate. The determination of methanol, ethanol, acetone, tert butyl methyl ether, ethyl acetate, tetrahydrofuran, benzene, acetic acid, methyl in terbutaline sulfate was established. The headspace gas chromatography of 10 kinds of residual solvents of benzene and benzyl chloride. Method: using Agilent DB-624UI (30 m x 0.32 mm, 1.8 m) capillary column, the column temperature was programmed heating, the starting column temperature was 40 C, the 3 min was kept, 10 degree C/min to 90 C, 1 min, and then 40 [degree C/min] to 200 degrees C, and the detector temperature was 250 degrees. The sample mouth temperature is 200 C. nitrogen, the flow rate is 1.0mL/min, the flow ratio is 15:1. headspace sample, the headspace equilibrium temperature is 90 C, the headspace is 30 min. quantitative ring temperature 100 C, the transmission line temperature is 110 degree C., the pressure balance time is 1min, the injection time is 1 min. results: 10 solvents are completely separated; linear in the range of investigation is linear. The relationship is good, the correlation coefficient r is not less than 0.9990, the average recovery is 95.7%-102.4%, instrument precision, repeatability, stability, detection limit and quantitative limit all meet the requirements of the.3 batch test products, the mass fraction of methanol is 0.035%, 0.043%, 0.043%, and the mass fraction of ethanol is 0.033%, 0.034%, 0.034%, and the acetone's mass fraction is 0. respectively. 00059%, 0.00062%, 0.00062%, tert butyl methyl ether, ethyl acetate, tetrahydrofuran, benzene, acetic acid, toluene, benzyl chloride are lower than the detection limit (LOD). Conclusion: the set up headspace gas chromatography is simple, accurate, reproducible, and can be used for the determination of residual solution in terbutaline sulphate. The second part of the terbutaline process and the uh of the degradation products Plc-q-tof-ms/ms analysis objective: to analyze and identify the structure of impurities and degradation products of terbutaline sulphate by super high performance liquid chromatography (uhplc-q-tof-ms/ms) and high resolution mass spectrometry (high resolution mass spectrometry). Method: the fragmentation of terbutaline sulfate mass spectrometry was studied, and then acid, alkali and oxidation were carried out in terbutaline sulfate. High temperature, high humidity, light degradation and long term test, 14 kinds of degradation samples were analyzed by uhplc-q-tof-ms technology. The chromatographic conditions were: using phenomenexlunac18 column (2.0mm x 150mm, 3 mu m), the flow phase was methanol -10mmol/l formate (pH to 3.2), gradient elution, velocity of 0.3ml/min, and the sampling amount of 5 u mass mass spectrometry. Using duospraytm ion source positive ion mode, full scan collection, dynamic background deduction and information dependent acquisition trigger two stage debris collection, each cycle to collect 12 strongest peaks of two level mass spectrogram. According to the accurate mass number and possible molecular composition of each degradation product and its fragment ions, the pyrolysis of terbutaline sulfate mass spectrometry On the basis of the law, the mass changes between the degradation products and the terbutaline sulfate and the fragments of the degradation products were compared and the structure was identified. Results: 17 impurities were identified, including 14 new degradation products and 3 known impurities, of which 3 known impurities were both process impurities and degradation products. Conclusion: sulphuric acid terbuterol The forest is unstable under the condition of oxidation, alkaline hydrolysis and illumination (alkaline solution); the functional groups that are easy to react are tertiary Ding Anji, benzyl carbon and benzene ring. This study is the first time to infer the possible degradation pathways of the degradation products. The third part of the method for the determination of the content determination method of terbutaline sulphate: the present content measurement of terbutaline sulfate The method is improved, and a high performance liquid chromatography (HPLC) method is established for the determination of the content of terbutaline sulphate. Methods: agilentzorbaxsb-c18 column (4.6mm x 150mm, 5 mu m), mobile phase 30mmol/l formate (pH to 3) - methanol (volume ratio 90:10); flow rate 1.0ml/min; detection wavelength of 276nm; intake sample of 10 mu L; column temperature Room temperature. Results: the linear range of the method is 0.01-0.40 mg/mL (r=1.000). The recovery rate is 99.2%, RSD is 0.8% (n=6). The instrument precision, repeatability, stability, detection limit and quantitative limit are all conformed to the requirement of.3 batch, the content of terbutaline sulfate is 100.5%, 98.9%, 99.2%. conclusion: with the current potentiometric titration method and the ion pair high performance liquid phase Compared with the chromatography (IP-HPLC), the improved HPLC method is simpler, faster, economical, and can directly reflect the changes of the main impurities in the sample from the liquid chromatography, and can be used for the determination of the content of terbutaline sulfate.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R927
本文編號：2136701
[Abstract]:Terbutaline sulfate, a selective beta 2 receptor agonist, is used in bronchial asthma, chronic bronchitis and other pulmonary diseases with bronchial spasm. It can also be used to prevent premature and fetal asphyxia. It has high selectivity and less side effects. It has been widely used at home and abroad. This subject is aimed at the quality control of current terbutaline sulfate. A new method and reference for the quality evaluation and control of terbutaline sulfate is provided for the quality evaluation and control of terbutaline sulfate, which is the key index which affects its quality, such as residual solvents, process impurities and degradation products and their content respectively, and a new method is established on the basis of the comprehensive analysis of the solvent used in the process of terbutaline sulfate synthesis. A headspace gas chromatographic method for the determination of 10 residual solvents of methanol, ethanol, acetone, tert butyl methyl ether, ethyl acetate, tetrahydrofuran, benzene, acetic acid, toluene and benzyl chloride in terbutaline sulfate, and a high resolution liquid chromatography high resolution mass spectrometry (UHPLC-Q-TOF-MS/ MS) method for the synthesis of impurities and degradation products in terbutaline sulphate process was established. Structure analysis and identification; a high performance liquid chromatography (HPLC) method was established for the determination of the content of terbutaline sulphate. The first part, headspace gas chromatography, was used for the simultaneous determination of 10 residual solvents in terbutaline sulphate. The determination of methanol, ethanol, acetone, tert butyl methyl ether, ethyl acetate, tetrahydrofuran, benzene, acetic acid, methyl in terbutaline sulfate was established. The headspace gas chromatography of 10 kinds of residual solvents of benzene and benzyl chloride. Method: using Agilent DB-624UI (30 m x 0.32 mm, 1.8 m) capillary column, the column temperature was programmed heating, the starting column temperature was 40 C, the 3 min was kept, 10 degree C/min to 90 C, 1 min, and then 40 [degree C/min] to 200 degrees C, and the detector temperature was 250 degrees. The sample mouth temperature is 200 C. nitrogen, the flow rate is 1.0mL/min, the flow ratio is 15:1. headspace sample, the headspace equilibrium temperature is 90 C, the headspace is 30 min. quantitative ring temperature 100 C, the transmission line temperature is 110 degree C., the pressure balance time is 1min, the injection time is 1 min. results: 10 solvents are completely separated; linear in the range of investigation is linear. The relationship is good, the correlation coefficient r is not less than 0.9990, the average recovery is 95.7%-102.4%, instrument precision, repeatability, stability, detection limit and quantitative limit all meet the requirements of the.3 batch test products, the mass fraction of methanol is 0.035%, 0.043%, 0.043%, and the mass fraction of ethanol is 0.033%, 0.034%, 0.034%, and the acetone's mass fraction is 0. respectively. 00059%, 0.00062%, 0.00062%, tert butyl methyl ether, ethyl acetate, tetrahydrofuran, benzene, acetic acid, toluene, benzyl chloride are lower than the detection limit (LOD). Conclusion: the set up headspace gas chromatography is simple, accurate, reproducible, and can be used for the determination of residual solution in terbutaline sulphate. The second part of the terbutaline process and the uh of the degradation products Plc-q-tof-ms/ms analysis objective: to analyze and identify the structure of impurities and degradation products of terbutaline sulphate by super high performance liquid chromatography (uhplc-q-tof-ms/ms) and high resolution mass spectrometry (high resolution mass spectrometry). Method: the fragmentation of terbutaline sulfate mass spectrometry was studied, and then acid, alkali and oxidation were carried out in terbutaline sulfate. High temperature, high humidity, light degradation and long term test, 14 kinds of degradation samples were analyzed by uhplc-q-tof-ms technology. The chromatographic conditions were: using phenomenexlunac18 column (2.0mm x 150mm, 3 mu m), the flow phase was methanol -10mmol/l formate (pH to 3.2), gradient elution, velocity of 0.3ml/min, and the sampling amount of 5 u mass mass spectrometry. Using duospraytm ion source positive ion mode, full scan collection, dynamic background deduction and information dependent acquisition trigger two stage debris collection, each cycle to collect 12 strongest peaks of two level mass spectrogram. According to the accurate mass number and possible molecular composition of each degradation product and its fragment ions, the pyrolysis of terbutaline sulfate mass spectrometry On the basis of the law, the mass changes between the degradation products and the terbutaline sulfate and the fragments of the degradation products were compared and the structure was identified. Results: 17 impurities were identified, including 14 new degradation products and 3 known impurities, of which 3 known impurities were both process impurities and degradation products. Conclusion: sulphuric acid terbuterol The forest is unstable under the condition of oxidation, alkaline hydrolysis and illumination (alkaline solution); the functional groups that are easy to react are tertiary Ding Anji, benzyl carbon and benzene ring. This study is the first time to infer the possible degradation pathways of the degradation products. The third part of the method for the determination of the content determination method of terbutaline sulphate: the present content measurement of terbutaline sulfate The method is improved, and a high performance liquid chromatography (HPLC) method is established for the determination of the content of terbutaline sulphate. Methods: agilentzorbaxsb-c18 column (4.6mm x 150mm, 5 mu m), mobile phase 30mmol/l formate (pH to 3) - methanol (volume ratio 90:10); flow rate 1.0ml/min; detection wavelength of 276nm; intake sample of 10 mu L; column temperature Room temperature. Results: the linear range of the method is 0.01-0.40 mg/mL (r=1.000). The recovery rate is 99.2%, RSD is 0.8% (n=6). The instrument precision, repeatability, stability, detection limit and quantitative limit are all conformed to the requirement of.3 batch, the content of terbutaline sulfate is 100.5%, 98.9%, 99.2%. conclusion: with the current potentiometric titration method and the ion pair high performance liquid phase Compared with the chromatography (IP-HPLC), the improved HPLC method is simpler, faster, economical, and can directly reflect the changes of the main impurities in the sample from the liquid chromatography, and can be used for the determination of the content of terbutaline sulfate.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R927
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