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乙醇检测在试剂和药典中的应用

乙醇检测在试剂和药典中的应用. 斯百全化学（上海）有限公司 Spectrum China Ltd. Spectrum 质检部. 800.720.5720. www.spectrumchina.com.cn. 乙醇. C2H6O 46.07 Ethanol. Ethyl alcohol CAS#: [64-17-5]. 应用： 饮料 汽车燃料 消毒剂 有机合成原料 溶剂 稀释剂 萃取剂 洗涤剂. Spectrum 乙醇品种. A2176 Alcohol, Denatured, 190 Proof

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乙醇检测在试剂和药典中的应用

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  1. 乙醇检测在试剂和药典中的应用 斯百全化学（上海）有限公司 Spectrum China Ltd. Spectrum质检部 800.720.5720 www.spectrumchina.com.cn

  2. 乙醇 • C2H6O 46.07 • Ethanol. Ethyl alcohol • CAS#: [64-17-5]. • 应用： • 饮料 • 汽车燃料 • 消毒剂 • 有机合成原料 • 溶剂 • 稀释剂 • 萃取剂 • 洗涤剂

  3. Spectrum 乙醇品种 • A2176 Alcohol, Denatured, 190 Proof • A1038 Alcohol, Anhydrous, Completely Denatured • A1040 Reagent Alcohol, Denatured, Reagent, ACS • E1020 Ethyl Alcohol, 190 Proof, FCC • E1028 Ethyl Alcohol, Absolute, 200 Proof, Reagent, ACS • E1029 Ethyl Alcohol, 190 Proof, Reagent, ACS • E1068 Dehydrated Alcohol, 200 Proof, USP, EP, BP • E1421 Alcohol, 190 Proof, BiotechGrade • E1424 Dehydrated Alcohol, 200 Proof, BiotechGrade • ET107 Dehydrated Alcohol, 200 Proof, Undenatured, USP • ET108 Alcohol, 190 Proof, USP • HP612 Reagent Alcohol, Denatured, Exceeds A.C.S. Specifications, HPLC Grade • HS002 Reagent Alcohol, Denatured, Histological Grade • EX0278 Alcohol, Denatured, OmniSolv(R) • EX0289 Ethyl Alcohol, MultiPharm, 200 Proof, EP, JP, USP • EX0290 Ethyl Alcohol, Pure, 190 Proof, HPLC Grade • *Proof: 酒精纯度, 一个酒精纯度相当于0.5％的酒精含量.

  4. E1028, Ethyl Alcohol, Absolute, 200 Proof, Reagent, ACS • TEST SPECIFICATION • ASSAY (by VOLUME) 99.5 % -- • COLOR (APHA) – 10 • SOLUBILITY IN WATER TO PASS TEST • WATER -- 0.2 % • RESIDUE AFTER EVAPORATION -- 0.001 % • ACETONE TO PASS TEST (limit about 0.001 %) • ISOPROPYL ALCOHOL TO PASS TEST (limit about 0.003 %) • TITRABLE ACID -- 0.0005 meq/g • TITRABLE BASE -- 0.0002 meq/g • METHANOL (CH3OH) -- 0.1 % • SUBSTANCES DARKENED BY (H2SO4) TO PASS TEST • SUBSTANCES REDUCING PERMANGANATE TO PASS TEST

  5. GB/T 678-2002 无水乙醇

  6. A1040, Reagent Alcohol, Denatured, Reagent, ACS • TEST SPECIFICATION • ASSAY: ETHANOL + METANOL (v/v) 94.0 - 96.0 % • ISOPROPANOL (v/v) 4.0 - 6.0 % • WATER -- 0.5 % • COLOR (APHA) – 10 • RESIDUE AFTER EVAPORATION -- 0.001 %

  7. HP612, Reagent Alcohol, Denatured, Exceeds A.C.S. Specifications, HPLC Grade • TEST SPECIFICATION • ASSAY: ETHANOL + METANOL (v/v) 94.0 - 96.0 % • ISOPROPYL ALCOHOL (v/v) 4.0 - 6.0 % • ULTRAVIOLET ABSORBANCE (1 cm cell vs. water)-- TO PASS TEST • 205nm 1.00 • 210nm 0.65 • 220nm 0.35 • 230nm 0.20 • 250nm 0.04 • 270nm 0.01 • 300nm ＜0.005 • COLOR (APHA) – 10 • RESIDUE AFTER EVAPORATION -- 4 PPM • WATER -- 0.1 %

  8. E1068, Dehydrated Alcohol, 200 Proof, USP, EP, BP • TEST SPECIFICATION • ASSAY (by VOLUME) 99.5 % -- • CLARITY OF SOLUTION TO PASS TEST • COLOR OF SOLUTION TO PASS TEST • ACIDITY OR ALKALINITY TO PASS TEST • RELATIVE DENSITY 0.790 - 0.793 • SPECIFIC GRAVITY @ 15.56oC -- 0.7962 • UV ABSORPTION TO PASS TEST • VOLATILE IMPURITIES TO PASS TEST • NONVOLATILE RESIDUE TO PASS TEST • IDENTIFICATION TO PASS TEST • RESIDUAL SOLVENTS TO PASS TEST

  9. 乙醇含量检测的应用 • 相对密度法 • USP<841>, Specific Gravity. ET107, Dehydrated alcohol, 200 proof, undenatured, USP • 蒸馏法 • USP <611>, Method Ⅰ. • 中国药典2005版一部：附录Ⅸ M 乙醇量测定法Ⅱa, b, c • 气相色谱法 （GC） • USP <611>, Alcohol determination, Method Ⅱ. BE115, Belladonna Tincture • ACS 10th, Ethyl alcohol. HP612，Reagent Alcohol, Denatured, Exceeds A.C.S. Specifications, HPLC Grade • USP <467>, Residual solvents, class 3. • 中国药典2010版二部：附录Ⅶ E 乙醇量测定法 • 中国药典2005版一部：附录Ⅸ M 乙醇量测定法Ⅰ

  10. Alcohol content: ≧ 99.2%, by weight; ≧ 99.5%, by volume, at 15.56℃. 原理: 25℃下, 相同体积乙醇和水的重量比值, 折算成15.56℃下乙醇的重量含量或体积含量. 方法: 使用同一比重瓶，先將先将一定体积的烧开过的蒸馏水放入其中, 分別称量25 ℃下空瓶和水装入后的总重量, 兩者之差就是25 ℃下水的重量. 同理測量 25 ℃下乙醇的重量. 乙醇和水的重量比为25 ℃下乙醇的比重. 通过查找USP reference table – Alcoholometric table中的数据，确定15.56℃下乙醇的体积含量或者重量含量. 比重瓶 相对密度法 - USP<841>, Specific Gravity, method Ⅰ ET107, Dehydrated alcohol, 200 proof, undenatured, USP

  11. USP reference table – Alcoholometric table

  12. 蒸馏法 - USP <611>, Method Ⅰ中国药典2005版一部：附录Ⅸ M 乙醇量测定法Ⅱ • 适用范围 • USP <611>, Method Ⅰ: 流浸膏剂,酊剂 • 中国药典2005版一部：附录Ⅸ M 乙醇量测定法Ⅱ: 流浸膏剂,酊剂,中药制剂 • 原理 • 根据样品的不同性质, 加入不同物质, 进行预处理. • 蒸馏, 获得乙醇馏出物. • 测定蒸馏物的相对密度, 折算出乙醇的含量. • 方法(中国药典2005版一部：附录Ⅸ M 乙醇量测定法Ⅱ) • Alcohol content≦30%: 称取20℃下样品25ml, 置于150-200ml蒸馏瓶中, 加水约25ml, 蒸馏. 待馏出物达23ml时, 停止蒸馏. 加水至刻度, 测量乙醇在20℃下的相对密度, 计算出乙醇含量; • Alcohol content﹥30%: 称取20℃下样品25ml, 置于150-200ml蒸馏瓶中, 加水约50ml, 蒸馏. 待馏出物达48ml时, 停止蒸馏. 加水至刻度, 测量乙醇在20℃下的相对密度, 计算出乙醇含量; • 样品含有挥发性物质, 如挥发油, 三氯甲烷, 乙醚,樟脑等. 可先加入氯化钠使之饱和, 后加入乙醚, 使溶液分层, 取水层按常规检测. • 样品含有游离氨或挥发性酸. 可先加入稀硫酸或氢氧化钠溶液, 调节酸碱度, 再按常规检测.

  13. 蒸馏法 - USP <611>, Method ⅠB1068, Benzalkonium Chloride Solution, 50 Percent, NF • Alcohol content≦10.0% • 25℃下量取样品25.0ml, 加水100ml, 365℃下蒸馏. 馏出物大约23ml时, 停止蒸馏, 在25℃下定容到25ml. 因馏出物浑浊, 加入CaCO3振摇, 过滤. 使用10ml比重瓶测量25℃下乙醇比重, 折算出乙醇含量. • 结果: 乙醇馏出物比重@ 25℃ : 0.9938 乙醇含量: 4.2%

  14. 气象色谱法 (GC) - ACS 10th: Ethyl Alcohol. HP612, Reagent Alcohol, Denatured, Exceeds A.C.S. Specification, HPLC Grade Specifications, HPLC Grade • Application: Ethyl Alcohol content ≧95.0% • GC method • Column: methyl silicone capillary • Column temperature: 40℃ for 5 min, programmed to 220 ℃ at 10 ℃ /min, hold 2 min • Injector temperature: 150-220 ℃ • Detector temperature: 250 ℃ • Sample size: 0.2 μl splitless • Carrier gas: helium at 3 ml/min • Detector: TCD • Measure the area under all peaks, and calculate the ethyl alcohol content in area percent

  15. HP612, Reagent Alcohol, Denatured, Exceeds A.C.S. Specification, HPLC Grade Specifications, HPLC Grade

  16. 气相色谱法 (GC) - USP <611>, Alcohol determination, Method Ⅱa. BE115, Belladonna Tincture • Application: Alcohol content: 65.0% - 70.0%. • Column: DB-624 • Column temperature: 120℃, • Injector temperature: 210℃ • Detector temperature: 210℃ • Sample size: 5 μl • Carrier gas: nitrogen or helium • Detector: FID • Standard solution: 5ml each USP Alcohol RS and USP acetone RS together diluted by water to 50ml. • Test stock solution: Dilute sample stepwise to get a 2% alcohol solution. • Test solution: 5ml each test stock solution and USP acetone RS together diluted by water to 50ml. • System Suitability Test: • R≧2 (alcohol to acetone) • tailing factor: ≦2.0 (alcohol) • RSD≦2.0% (ratio of alcohol to acetone)

  17. BE115, Belladonna Tincture, Alcohol Content

  18. 气相色谱法 (GC) - USP<467> Residual Solvents • Application: Alcohol content: ﹤5000ppm. • Column: DB-624 • Column temperature: 40℃ for 20 min, programmed to 240℃ at 10℃/min, hold 20 min • Injector temperature: 140℃ • Detector temperature: 250℃ • Sample size: 5 ml, headspace • Carrier gas: helium • Detector: FID • Split ratio: 5:1 • System Suitability Test: • R﹥1.0 • RSD≦2.0%

  19. SU124, Sulfacetamide Sodium, Monohydrate, USP, Residual Solvents - Ethanol

  20. 中国药典2005版一部：附录Ⅸ M 乙醇量测定法Ⅰ • 适用范围： 测定制剂中在20℃时乙醇的含量（%，ml/ml） • 色谱条件与系统适应性试验：用键合交联聚乙二醇为固定液的毛细管柱；起始温度为50 ℃ ，维持7分钟，再以每分钟10 ℃的速率升温至110 ℃ ；进样口温度190 ℃ ；FID检测器温度220 ℃。理论板数按正丙醇峰计算应不低于8000，乙醇峰与正丙醇峰的分离度应大于2.0. • 校正因子测定：精密量取恒温至20 ℃的无水乙醇4ml、5ml、6ml，分別置100ml量瓶中，分別精密加入恒温至20 ℃的正丙醇（内标物质）5ml，用水稀释至刻度，摇匀，精密量取上述各溶液1ml，分別置100ml量瓶中，用水稀释至刻度，摇匀（必要时可进一步稀释），作为对照品溶液。取上述三种溶液各适量，注入气相色谱仪，分別连续进样3次，测定峰面积，计算校正因子，所得校正因子的相对标准偏差不得大于2.0%。 • 测定法：精密量取恒温至20 ℃的供试品适量（相当于乙醇约5ml），置100ml量瓶中，精密加入恒温至20 ℃的正丙醇5ml，用水稀释至刻度，摇匀，精密量取该溶液1ml，置100ml量瓶中，用水稀释至刻度，摇匀（必要时可进一步稀释），作为供试品溶液。取1μl注入气相色谱仪，测定，即得。

  21. CNAS T0546 能力验证气相色谱法测定药品中乙醇含量 • 样品名称: • T1064盲样 • 方法: • 中国药典2005版一部：附录Ⅸ M 乙醇量测定法Ⅰ;或实验室常用气象色谱法 • 能力验证結果 • 实验结果: 47.92% • 平均值: 46.39% • Z绝对值: 7.12>3, 不合格结果 • 复测结果 • 实验结果: 46.23% • 平均值: 46.39% • Z绝对值: 0.2﹤1, 满意结果

  22. 原因分析

  23. CNAS T0546 能力验证气相色谱法测定药品中乙醇含量 — 直接进样

  24. CNAS T0546 能力驗證气相色谱法测定药品中乙醇含量 — 顶空进样

  25. CNAS T0546 能力驗證气相色谱法测定药品中乙醇含量 — 顶空进样

  26. 总结 • 方法偏离和确认 • 方法验证 • 精密度 • 准确度 • 专属性 • 线性 • 仪器比对 • 人员比对 • 方法比对 • 实验室间比对

  27. 小知识：Alcohol, Aldehyde-free 无醛乙醇的制备 • USP - Dissolve 2.5 g of lead acetate in 5 mL of water, add the solution to 1000 mL of alcohol contained in a glass-stoppered bottle, and mix. Dissolve 5 g of potassium hydroxide in 25 mL of warm alcohol, cool the solution, and add it slowly, without stirring, to the alcohol solution of lead acetate. After 1 hour shake the mixture vigorously, allow it to stand overnight, decant the clear liquid, and recover the alcohol by distillation. • 溶解2.5g醋酸铅于5ml水中，将溶液加到装有1000ml乙醇的具塞玻璃瓶中，混合。溶解5g氢氧化钾于25ml温的乙醇中，冷卻，將此溶液缓慢地加到醋酸铅的乙醇溶液中，不用搅拌。1小时后，剧烈振荡该混合液，放置过夜，轻轻倒出澄清液体，蒸馏，得到无醛乙醇。 • EP - Mix 1200 ml of ethanol (96%) with 5 ml of a 40% w/v solution of silver nitrate and 10 ml of a cooled 50% w/v solution of potassium hydroxide . Shake, allow to stand for a few days and filter. Distil the filtrate immediately before use. • 將1200ml乙醇和5ml的40%的硝酸银溶液，以及10ml的冷卻的50%的氢氧化钾溶液混合。振荡，放置数天后过滤。使用前蒸馏滤液，得到无醛乙醇。

  28. 小知识：Alcohol, Neutralized中性乙醇的制备 • USP—To a suitable quantity of alcohol add 2 or 3 drops of phenolphthalein TS and just sufficient 0.02 N or 0.1 N sodium hydroxide to produce a faint pink color. Prepare neutralized alcohol just prior to use. • 一定量的乙醇中，加入2-3滴酚酞指示液，滴加0.02N或0.1N的氢氧化钠溶液至溶液呈粉红色。在使用前将乙醇调成中性即可。

  29. 小知识：Diluted Alcohol稀乙醇的制备 • Diluted Alcohol is a mixture of Alcohol and water containing not less than 41.0 percent and not more than 42.0 percent, by weight, corresponding to not less than 48.4 percent and not more than 49.5 percent, by volume, at 15.56 , of C2H5OH. • Diluted Alcohol may be prepared as follows: • Alcohol500 mL，Purified Water500 mL • Measure the Alcohol and the Purified Water separately at the same temperature, and mix. If the water and the Alcohol and the resulting mixture are measured at 25 , the volume of the mixture will be about 970 mL. • Specific gravity: between 0.935 and 0.937 at 15.56 , indicating between 41.0% and 42.0%, by weight, or between 48.4% and 49.5%, by volume, of C2H5OH. • 稀乙醇为重量分数为41.0%-42.0%，体积分数为48.4%-49.5%的乙醇水溶液。 • 在25C时，将500ml乙醇和500ml水混合，得到大约970ml的溶液。 • 稀乙醇比重@15.56C：0.935 – 0.937

  30. 小知识： 70%，80%，90%乙醇的制备 • 在25C时，水和乙醇按照以下比例混合，分別得到70%，80%，90%的乙醇，相应比重参照下表。

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