阿司匹林及阿司匹林肠溶片的质量分析

阿司匹林及阿司匹林肠溶片的质量分析

一、目的要求

1.掌握中和滴定法、两步滴定法测定含量的原理及方法。

2.掌握药品全面质量分析的概念。

3.熟悉称量、滴定、过滤等基本试验操作技能。

二、仪器与试药

1.仪器

Mettler AL204电子天平 HHS 型电热恒温水浴锅

刻度移液管 规格：1mL 、5mL 、10mL 酸式滴定管 规格：25mL

容量瓶 规格：100mL 研钵 滤斗 定性滤纸

2.试药

阿司匹林肠溶片 规格：50mg/片 阿司匹林原药 水杨酸对照品

硫酸铁铵指示液 三氯化铁 乙醇 盐酸 硫酸 酒石酸 磷酸钠 氢氧化钠 酚酞指示液

三、实验原理

1．阿司匹林(Aspirin)的性状及鉴别试验

（1）三氯化铁反应（Ferric chloride reaction ) ：为芳环上酚性羟基的反应

阿司匹林水解产物水杨酸在中性或弱酸性条件下，与三氯化铁试液反应，生成紫堇色配合物。反应适宜的pH 为4～6，在强酸性溶液中配位化合物分解。

（2）水解(Hydrolysis)反应

阿司匹林与碳酸钠试液加热水解，得水杨酸钠及醋酸钠，加过量稀硫酸酸化后，水杨酸白色沉淀析出，并产生醋酸的臭气。

2. 阿司匹林(Asipirin )原料药的中和滴定法

阿司匹林的Ka 为3.27×10-4,故能用标准碱液直接滴定,等当点pH 值为7.0，以酚酞为指示剂指示终点。

3.阿司匹林(Asipirin )肠溶片两步滴定法

阿司匹林易水解，生成水杨酸和醋酸，片剂中加入枸橼酸或酒石酸作稳定剂，不能直接滴定，采用两步中和滴定法。

第一步为中和：于中性乙醇中以氢氧化钠中和样品中所有游离酸至终点（阿司匹林成为钠盐）；

OCOCH 3COOH OH COONa

OCOCH COOH OCOCH 3COONa

中和可能存在的全部酸，阿司匹林也成为钠盐。（氢氧化钠用量可不计）

第二步为水解后的滴定：于得到的中性供试品溶液中，加入过量的碱，加热使乙酰羟基酯水解，剩于的碱用酸回滴定，并将滴定的结果用空白试验校正。

2NaOH + H 2SO 4 → Na 2SO 4 + 2H 2O

四、实验内容

阿司匹林肠溶片

Asipilin Changrong Pian

AspirinEnteric-coated Tablets

本品含阿司匹林（C 9H 8O 4）应为标示量的95.0%～105.0%。

【性状】 本品为肠溶包衣片，出去包依后显白色。

【鉴别】 取本品的细粉适量（约相当于阿司匹林0.1g ），加水10mL ，煮沸，放冷，加三氯化铁试液1滴，即显紫堇色。

【检查】 游离水杨酸 取本品30片，研细，用乙醇30mL 分次研磨，并移入100mL 量瓶中，充分振摇，用水稀释至刻度，摇匀，立即滤过，精密量取续滤液2mL ，置50mL 纳氏比色管中，用水稀释至50mL ，立即加新制的稀硫酸铁铵溶液（取1mol/L 盐酸溶液1mL ，加硫酸铁铵指示液2mL 后再加水适量使成100mL ）3mL ，摇匀，30秒钟内如显色，与对照液（精密量取0.01%水杨酸溶液

4.5mL ，加乙醇3mL ，0.05%酒石酸溶液1mL ，用水稀释至50mL ，再加上述新制的稀硫酸铁铵溶液3mL ，摇匀）比较，不得更深（1.5%）。

【含量测定】 1. 阿司匹林原料药的中和滴定：取本品约0.4g ，精密称定，加中性乙醇20mL 溶解，再加酚酞指示液3滴，用氢氧化钠液（0.1mol/L ）滴定。每1mL 氢氧化钠液（0.1mol/L ）相当于18.05mg 的C 9H 8O 4。

讨论及结果计算

式中，T 为滴定度(mg/mL)；V 为消耗滴定液体积；W 为供试品量；f 为浓度校正系数(f=N’/N ，N’为实际滴定液浓度，N 为标准滴定液浓度)

2.阿司匹林肠溶片的中和滴定：取本品20片，精密称定，计算平均片重，研细，精密称取适量（约相当于阿司匹林0.5g ）置100 mL 量瓶中，加入70 mL 中性乙醇，充分振遥，再用水稀OCOCH 3COOH NaOH OCOCH

3COONa OCOCH

COONa

NaOH OH COONa CH 3COONa OH C O O H

OH C O O N a + 100%T V f W

??=?含量10.1180.218.021T =??=滴定度

释至刻度，摇匀，滤过，精密量取续滤液10mL ，置锥形瓶中，加中性乙醇（对酚酞指示液显中性）20mL ，振摇，使阿司匹林溶解，加酚酞指示液3滴，不断振摇下滴加氢氧化钠滴定液，迅速滴定至粉红色，再精密加入10mL 氢氧化钠滴定液（0.1mol/L ），置水浴上加热15分钟并时时振摇，迅速放冷至室温，用硫酸滴定液（0.05mol/L ）滴定，并将滴定的结果用空白试验校正。每1mL 氢氧化钠滴定液（0.1mol/L ）相当于18.02mg 的C 9H 8O 4。

计算：阿司匹林标示量% =100%W W D T F V)0(V ??????-标示量

V O :空白试验消耗硫酸滴定液的体积（mL ）；

V:供试品消耗硫酸滴定液的体积（mL ）；

F ：硫酸滴定液浓度校正因数； T ：滴定度；

W :平均片重（g ）； W: 供试品片粉取样量（g ）；

D:稀释倍数。

五、注意事项

1. 阿司匹林微溶于水，易溶于醇。为使供试品溶解，及防止在水溶液中滴定时酯的水解，因而采用中性乙醇为溶剂。

2. 中性乙醇的“中性”之意是对本中和法所用指示剂而言的。中和法采用酚酞为指示剂时，中性乙醇的制取方法为：取适量乙醇，加入酚酞指示液3滴，用氢氧化钠液（0.1mol/L ）滴定至淡红色，即得。

3. 本品是弱酸，用强碱滴定时，化学计量点偏碱性，故指示剂选用在碱性区变色的酚酞。为了避免样品的水解，滴定时应使温度在20℃以下，并不断搅拌（防止局部碱度过大）较快滴定。

4.片剂中因含酒石酸或枸橼酸及水解产物（水杨酸、醋酸），因此采用两步滴定法。第一步先中和与供试品共存的酸，此时阿司匹林中和为钠盐；第二步阿司匹林中酯结构水解而消耗碱，而共存酸不干扰测定，供试品中阿司匹林的含量，由水解时消耗的碱量计算。

六、思考题

1. 阿司匹林原料药物与阿司匹林肠溶片在质量检验方面有哪些不同之处？为何不同？

2. 滴定过程中，如何防止阿司匹林水解？

3. 如何配制中性乙醇？为什么要用中性乙醇？

七、参考文献

《中国药典》2010年版二部，283，284，化学工业出版社。

The Analysis of Aspirin and Aspirin Enteric-coated Tablets

Purpose

1. To learn about the procedures and the items for drug analysis.

2. To exercise on the analysis of Aspirin and its Enteric-coated Tablets.

Procedures and methods

Aspirin

( C9H8O4，FW=180.16，[ 50-78-2 ] )

Aspirin is 2 - ( acetyloxy ) – benzoic acid. It contains not less than 99.5% of C9H8O4 .

1.Description White crystals or a white crystalline powder; odourless or with a faint acetic acid odour; taste, faintly sour; gradually hydrolyses in contact with moisture to form salicylic acid and acetic acid; aqueous solution yields an acidic reaction.

Freely soluble in ethanol; soluble in chloroform or ether; slightly soluble in water or anhydrous ether; soluble in solutions of sodium hydroxide or sodium carbonate with decomposition.

2.Identification (1) To about 0.1 g add 10 ml of water, boil and cool. Add 1 drop of ferric chloride TS; a violet colour is produced.

(2) To about 0.5 g add 10 ml of sodium carbonate TS, boil for 2 minutes and cool. Add dilute sulfuric acid in excess; a white precipitate is produced and an odour of acetic acid is perceptible.

(3) The infrared absorption spectrum ( Appendix Ⅳ C ) is concordant with the reference spectrum of aspirin ( Appendix ⅩⅥ ).

3.Clarity of solution A solution of 0.50 g in 10 ml of sodium carbonate TS preheated to about 45℃ is clear.

Salicylic acid Dissolve 0.10 g in 1 ml of ethanol, add cold water to produce 50ml, add immediately 1 ml of freshly prepared dilute ferric ammonium sulfate solution [ to 1 ml of hydrochloric acid solution ( 9→100 ) add 2 ml of ferric ammonium sulfate IS and add water to produce 100 ml ] add mix well; any colour produced in 30 seconds is not more intense than that of a reference preparation ( dissolve 0.1 g of salicylic acid, accurately weighed, in water, add 1 ml of glacial acetic acid, mix well, add water to produce 1000 ml and mix well. Measure accurately 1 ml, add 1 ml of ethanol, 48 ml of water and 1 ml of freshly prepared dilute ferric ammomium sulfate solution and mix well ) ( 0.1% ).

Readily carbonizable substances Carry out the limit test for readily carbonizable substances ( Appendix ⅧK ),using 0.5 g; any colour produced is not more intense than that of a reference preparation ( mix 0.25 ml of standard cobalt chloride CS, 0.25 ml of standard potassium dichromate CS, and 0.40 ml of standard copper sulfate CS, and add water to produce 5 ml ).

Residue on ignition Not more than 0.1% ( Appendix Ⅷ N ).

Heavy metals Dissolve 1.0 g in 23 ml of ethanol, add 2 ml of acetate BS ( pH3.5 ) carry out the limit test for heavy metals ( Appendix Ⅷ H, method 1 ): not more than 0.001%.

4.Assay Dissolve about 0.4 g, accurately weighed, in 20 ml of neutral ethanol ( neutral to phenolphthalein IS ) and add 3 drops of phenolphthalein IS. Titrate with sodium hydroxide (0.1 mol/L)

VS. Each ml of sodium hydroxide (0.1 mol/L) VS is equivalent to 18.02 mg of C9H8O4.

Aspirin Enteric-coated Tablets

Aspirin Enteric-coated Tablets contain not less than 95.0% and not more than 105.0% of the labeled amount of aspirin (C9H8O4).

1.Description Enteric-coated Tablets, with white core.

2.Identification To a quantity of the powdered tablets equivalent to about 0.1 g of aspirin add 10 ml of water, boil, cool and add 1 drop of ferric chloride TS; a violet colour is produced.

3. Salicylic acid Triturate 5 tablets with 30 ml of ethanol in portions and transfer the mixture to a 100 ml volumetric flask, shake thoroughly, dilute with water to volume, mix well, filter immediately. Measure accurately 2 ml of the filtrate in a Nessler cylinder, add water to produce 50 ml, than add immediately 3 ml of freshly prepared dilute ferric ammonium sulfate solution [ to 1 ml of 1 mol/L hydrochloric acid solution, add 2 ml of ferric ammonium sulfate IS and add water to produce 100 ml ], add mix well; any colour produced in 30 seconds is not more intense than that of a reference preparation ( To

4.5 ml of 0.01% salicylic acid solution, accurately measured, add 3 ml of ethanol, 1 ml of 0.05% tartaric acid solution, dilute with water to produce 50 ml, add 3 ml of freshly prepared dilute ferric ammonium sulfate solution and mix well ) ( 1.5% ).

4.Assay Weigh accurately and powder 10 tablets, triturate with divided portions of 70 ml neutral ethanol and transfer to a 100 ml volumetric flask, shake thoroughly, wash the mortar several times with sufficient water, add the combine washings to the flask, dilute with water to volume, mix well and filter. Measure accurately 10 ml of the filtrate equivalent to about 0.3 g of aspirin into a conical flask, add 20 ml of neutral ethanol ( neutral to phenolphthalein IS ), shake well. Add 3 drops of phenolphthalein IS and sodium hydroxide (0.1 mol/L) VS dropwise until the solution becomes pink. Add 40 ml of sodium hydroxide (0.1 mol/L) VS, accurately measured, heat on a water bath for 1 minutes with shaking, cool immediately to room temperature and titrate with sulfuric acid (0.05 mol/L) VS. Perform a bank determination and make any necessary correction. Each ml of sodium hydroxide (0.1 mol/L) VS is equivalent to 18.02 mg of C9H8O4.

5.Strength0.3 g

Discussions

1. What is the difference between the assay of Aspirin and its enteric-coated tablets?

2. How to prevent hydrolysis of aspirin during the titration process?