{"id":6258,"date":"2025-09-30T13:42:01","date_gmt":"2025-09-30T06:42:01","guid":{"rendered":"https:\/\/nhathuocngocanh.com\/bp\/?p=6258"},"modified":"2025-10-03T10:23:24","modified_gmt":"2025-10-03T03:23:24","slug":"captopril","status":"publish","type":"post","link":"https:\/\/nhathuocngocanh.com\/bp\/captopril\/","title":{"rendered":"Captopril"},"content":{"rendered":"

(Ph. Eur. monograph 1079)<\/p>\n

C_{9<\/sub>H_{15<\/sub>NO_{3<\/sub>S\u00a0 \u00a0 217.3\u00a0 \u00a0 62571-86-2<\/p>\n}}}

Action and use<\/strong><\/p>\n

Angiotensin converting enzyme inhibitor.<\/p>\n

Preparations<\/strong><\/p>\n

Captopril Oral Solution<\/p>\n

Captopril Tablets<\/p>\n

DEFINITION<\/h2>\n
(2S)-1-[(2S)-2-Methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid.<\/p>\n
Content<\/h3>\n
98.0 per cent to 101.5 per cent (dried substance).<\/p>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
White or almost white, crystalline powder.<\/p>\n
Solubility<\/h3>\n
Soluble in water, freely soluble in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides.<\/p>\n
IDENTIFICATION<\/h2>\n
A. Specific optical rotation (see Tests).<\/p>\n
B. Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison: captopril CRS.<\/p>\n
TESTS<\/h2>\n
Solution S<\/h3>\n
Dissolve 0.5 g in carbon dioxide-free water R and dilute to 25 mL with the same solvent.<\/p>\n
Appearance of solution<\/h3>\n
Solution S is clear (2.2.1) and colourless (2.2.2, Method II).<\/p>\n
pH (2.2.3)<\/h3>\n
2.0 to 2.6 for solution S.<\/p>\n
Specific optical rotation (2.2.7)<\/h3>\n
-132 to -127 (dried substance).<\/p>\n
Dissolve 0.250 g in anhydrous ethanol R and dilute to 25.0 mL with the same solvent.<\/p>\n
Impurity F<\/h3>\n
Gas chromatography (2.2.28).<\/p>\n
Reagent solution: Add 2.8 mL of acetyl chloride R dropwise to 17.2 mL of anhydrous methanol R at 0 \u00b0C and mix. Allow to stand for 20 min at room temperature before use.<\/p>\n
Test solution: Introduce 20.0 mg of the substance to be examined into a vial and add 1.0 mL of the reagent solution. Mix and heat at 60 \u00b0C for 30 min.<\/p>\n
Evaporate to dryness under a stream of nitrogen R. Dissolve the residue in 0.5 mL of ethyl acetate R, add 0.5 mL of pentafluoropropionic anhydride R, mix and heat at 60 \u00b0C for 30 min. Evaporate to dryness under a stream of nitrogen R. Dissolve the residue in 1.0 mL of butyl acetate R.<\/p>\n
Reference solution (a): Dissolve the contents of a vial of captopril for system suitability CRS (containing impurity F) in 1 mL of the reagent solution. Prepare as described for the test solution.<\/p>\n
Reference solution (b): Mix 0.25 mL of reference solution (a) and 0.75 mL of butyl acetate R.<\/p>\n
Column:<\/p>\n
\u2014 material: fused silica;<\/p>\n
\u2014 size: l = 25 m, \u00d8 = 0.32 mm;<\/p>\n
\u2014 stationary phase: phenyl(5)methyl(95)polysiloxane R (film thickness 1 \u03bcm).<\/p>\n
Carrier gas helium for chromatography R.<\/p>\n
Flow rate: 1.2 mL\/min.<\/p>\n
Split ratio: 1:20.<\/p>\n
Temperature:<\/p>\n\n\n\n\n\n\n\n\n
<\/td>\n Time<\/strong><\/p>\n
(min)<\/strong><\/td>\n
Temperature<\/strong><\/p>\n
(\u00b0C)<\/strong><\/td>\n<\/tr>\n
Column<\/td>\n 0 – 10<\/td>\n 200<\/td>\n<\/tr>\n
<\/td>\n 10 – 14<\/td>\n 200 \u2192 240<\/td>\n<\/tr>\n
<\/td>\n 14 – 34<\/td>\n 240<\/td>\n<\/tr>\n
Injection port<\/td>\n <\/td>\n 270<\/td>\n<\/tr>\n
Detector<\/td>\n <\/td>\n 300<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Injection port: 270<\/p>\n
Detector: 300<\/p>\n
Detection: Flame ionisation.<\/p>\n
Injection: 1 \u03bcL.<\/p>\n
Relative retention: With reference to captopril (retention time = about 6 min): impurity F = about 0.96.<\/p>\n
System suitability:<\/p>\n
\u2014 resolution: minimum 1.5 between the peaks due to impurity F and captopril in the chromatogram obtained with reference solution (a);<\/p>\n
\u2014 signal-to-noise ratio: minimum 10 for the peak due to impurity F in the chromatogram obtained with reference solution (b).<\/p>\n
Calculate the percentage content of impurity F using the following expression:<\/p>\n
A\/(A+B) \u00d7 100<\/p>\n
A = area of the peak due to impurity F in the chromatogram obtained with the test solution;<\/p>\n
B = area of the peak due to captopril in the chromatogram obtained with the test solution.<\/p>\n
Limit:<\/p>\n
\u2014 impurity F: maximum 0.2 per cent.<\/p>\n
Related substances<\/p>\n
Liquid chromatography (2.2.29).<\/p>\n
Solvent mixture phosphoric acid R, acetonitrile R1, water R (0.08:10:90 V\/V\/V).<\/p>\n
Test solution: Dissolve 0.125 g of the substance to be examined in the solvent mixture and dilute to 25.0 mL with the solvent mixture.<\/p>\n
Reference solution (a): Dissolve 4.0 mg of captopril impurity J CRS, 5.0 mg of captopril impurity B CRS, 5.0 mg of captopril impurity C CRS and 5.0 mg of captopril impurity D CRS in the solvent mixture and dilute to 50.0 mL with the solvent mixture. Dilute 1.0 mL of the solution to 20.0 mL with the solvent mixture. Prepare immediately before use.<\/p>\n
Reference solution (b): Dissolve 5 mg of the substance to be examined and 5 mg of captopril impurity E CRS in
\nacetonitrile R and dilute to 25 mL with the same solvent. Dilute 4 mL of the solution to 50 mL with the solvent mixture.<\/p>\n
Reference solution (c): In order to prepare impurity A in situ, introduce 1.0 mL of the test solution into a volumetric flask and add 230 \u03bcL of 0.05 M iodine. If the solution is not colourless, add 0.1 M sodium thiosulfate dropwise until it becomes colourless, and dilute to 50 mL with the solvent mixture. Dilute 5 mL of this solution to 20 mL with the solvent mixture.<\/p>\n
Reference solution (d): Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.<\/p>\n
Column:<\/p>\n
\u2014 size: l = 0.3 m, \u00d8 = 3.9 mm;<\/p>\n
\u2014 stationary phase: irregular end-capped octadecylsilyl silica gel for chromatography R (10 \u03bcm);<\/p>\n
\u2014 temperature: 50 \u00b0C.<\/p>\n
Mobile phase:<\/p>\n
\u2014 mobile phase A: phosphoric acid R, water for chromatography R (0.08:100 V\/V);<\/p>\n
\u2014 mobile phase B: phosphoric acid R, acetonitrile R1, water for chromatography R (0.08:50:50 V\/V\/V);<\/p>\n\n\n\n\n\n\n
Time<\/strong><\/p>\n
(min)<\/strong><\/td>\n
Mobile phase A<\/strong><\/p>\n
(per cent V\/V)<\/strong><\/td>\n
Mobile phase B<\/strong><\/p>\n
(per cent V\/V)<\/strong><\/td>\n<\/tr>\n
0 – 5<\/td>\n 90<\/td>\n 10<\/td>\n<\/tr>\n
5 – 20<\/td>\n 90 \u2192 50<\/td>\n 10 \u2192 50<\/td>\n<\/tr>\n
20 – 45<\/td>\n 50<\/td>\n 50<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Flow rate: 1.5 mL\/min.<\/p>\n
Detection: Spectrophotometer at 210 nm.<\/p>\n
Injection: 25 \u03bcL.<\/p>\n
Identification of impurities: Use the chromatogram obtained with reference solution (a) to identify the peaks due to impurities B, C, D and J; use the chromatogram obtained with reference solution (b) to identify the peak due to impurity E; use the chromatogram obtained with reference solution (c) to identify the peak due to impurity A.<\/p>\n
Relative retention: With reference to captopril (retention time = about 15 min): impurity C = about 0.6; impurity D = about 0.8; impurity E = about 0.9; impurity B = about 1.17; impurity J = about 1.22; impurity A = about 1.7.<\/p>\n
System suitability:<\/p>\n
\u2014 resolution: minimum 1.5 between the peaks due to impurities B and J in the chromatogram obtained with reference solution (a);<\/p>\n
\u2014 resolution: minimum 2.0 between the peaks due to impurity E and captopril in the chromatogram obtained with reference solution (b).<\/p>\n
Limits:<\/p>\n
\u2014 impurity A: not more than 10 times the area of the principal peak in the chromatogram obtained with reference solution (d) (1.0 per cent);<\/p>\n
\u2014 impurity J: not more than 2.5 times the area of the corresponding peak in the chromatogram obtained with
\nreference solution (a) (0.2 per cent);<\/p>\n
\u2014 impurities B, C, D: for each impurity, not more than 1.5 times the area of the corresponding peak in the chromatogram obtained with reference solution (a) (0.15 per cent);<\/p>\n
\u2014 impurity E: not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (d) (0.15 per cent);<\/p>\n
\u2014 unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (d) (0.10 per cent);<\/p>\n
\u2014 total: maximum 1.2 per cent;<\/p>\n
\u2014 disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (d) (0.05 per cent).<\/p>\n
Loss on drying (2.2.32)<\/h3>\n
Maximum 1.0 per cent, determined on 1.000 g by drying in vacuo at 60 \u00b0C at a pressure not exceeding 0.1 kPa for 3 h.<\/p>\n
Sulfated ash (2.4.14)<\/h3>\n
Maximum 0.2 per cent, determined on 1.0 g.<\/p>\n
ASSAY<\/h2>\n
Dissolve 0.150 g in 30 mL of water R. Titrate with 0.05 M iodine, determining the end-point potentiometrically (2.2.20). Use a combined platinum electrode.<\/p>\n
1 mL of 0.05 M iodine is equivalent to 21.73 mg of C_{9<\/sub>H_{15<\/sub>NO_{3<\/sub>S.<\/p>\n}}}
IMPURITIES<\/h2>\n
Specified impurities A, B, C, D, E, F, J.<\/p>\n
Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other\/unspecified impurities and\/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use) G, H, I, L, M, N, O.<\/p>\n
$\"Captopril\"$ <\/p>\n
A. 1,1\u2032-[disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]]bis[(2S)-pyrrolidine-2-carboxylic] acid (captopril disulfide),<\/p>\n
$\"Captopril\"$ <\/p>\n
B. (2S)-1-[(2S)-3-bromo-2-methylpropanoyl]pyrrolidine-2-carboxylic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
C. (2RS)-2-methyl-3-sulfanylpropanoic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
D. (2RS)-3-bromo-2-methylpropanoic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
E. (2S)-1-(2-methylpropanoyl)pyrrolidine-2-carboxylic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
F. (2S)-1-[(2R)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid (epi-captopril),<\/p>\n
$\"Captopril\"$ <\/p>\n
G. (2RS)-3-(acetylsulfanyl)-2-methylpropanoic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
H. (2S)-1-[(2S)-3-[[(2R)-3-(acetylsulfanyl)-2-methylpropanoyl]sulfanyl]-2-methylpropanoyl]pyrrolidine-2-carboxylic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
I. (2S)-1-[(2S)-3-[[[(2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidin-2-yl]carbonyl]sulfanyl]-2-methylpropanoyl]pyrrolidine-2-carboxylic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
J. (2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]pyrrolidine-2-carboxylic acid (acetylcaptopril),<\/p>\n
$\"Captopril\"$ <\/p>\n
L. 1,1\u2032-[methylenebis[sulfanediyl[(2S)-2-methyl-1-oxopropane-3,1-diyl]]]bis[(2S)-pyrrolidine-2-carboxylic] acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
M. (2S)-1-[(2S)-3-[[(2S)-2-carboxypropyl]disulfanyl]-2-methylpropanoyl]pyrrolidine-2-carboxylic acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
N. 3,3\u2032-disulfanediylbis[(2S)-2-methylpropanoic] acid,<\/p>\n
$\"Captopril\"$ <\/p>\n
O. 1,1\u2032-[propane-2,2-diylbis[sulfanediyl[(2S)-2-methyl-1-oxopropane-3,1-diyl]]]bis[(2S)-pyrrolidine-2-carboxylic] acid.<\/p>\n","protected":false},"excerpt":{"rendered":"
(Ph. Eur. monograph 1079) C9H15NO3S\u00a0 \u00a0 217.3\u00a0 \u00a0 62571-86-2 Action and use Angiotensin converting enzyme inhibitor. Preparations Captopril Oral Solution Captopril Tablets DEFINITION (2S)-1-[(2S)-2-Methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid. Content 98.0 per cent to 101.5 per cent (dried substance). CHARACTERS Appearance White or almost white, crystalline powder. Solubility Soluble in water, freely soluble in methanol and in methylene chloride….<\/p>\n","protected":false},"author":4,"featured_media":6318,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-6258","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicinal-substances"],"acf":[],"_links":{"self":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/6258","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=6258"}],"version-history":[{"count":3,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/6258\/revisions"}],"predecessor-version":[{"id":6685,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/6258\/revisions\/6685"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/6318"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=6258"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=6258"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=6258"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}

Content<\/h3>\n98.0 per cent to 101.5 per cent (dried substance).<\/p>\n

CHARACTERS<\/h2>\n

Appearance<\/h3>\nWhite or almost white, crystalline powder.<\/p>\n

Solubility<\/h3>\nSoluble in water, freely soluble in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides.<\/p>\n

IDENTIFICATION<\/h2>\nA. Specific optical rotation (see Tests).<\/p>\nB. Infrared absorption spectrophotometry (2.2.24).<\/p>\nComparison: captopril CRS.<\/p>\n

TESTS<\/h2>\n

Solution S<\/h3>\nDissolve 0.5 g in carbon dioxide-free water R and dilute to 25 mL with the same solvent.<\/p>\n

Appearance of solution<\/h3>\nSolution S is clear (2.2.1) and colourless (2.2.2, Method II).<\/p>\n

pH (2.2.3)<\/h3>\n2.0 to 2.6 for solution S.<\/p>\n

Specific optical rotation (2.2.7)<\/h3>\n-132 to -127 (dried substance).<\/p>\nDissolve 0.250 g in anhydrous ethanol R and dilute to 25.0 mL with the same solvent.<\/p>\n

Loss on drying (2.2.32)<\/h3>\nMaximum 1.0 per cent, determined on 1.000 g by drying in vacuo at 60 \u00b0C at a pressure not exceeding 0.1 kPa for 3 h.<\/p>\n

Sulfated ash (2.4.14)<\/h3>\nMaximum 0.2 per cent, determined on 1.0 g.<\/p>\n

ASSAY<\/h2>\nDissolve 0.150 g in 30 mL of water R. Titrate with 0.05 M iodine, determining the end-point potentiometrically (2.2.20). Use a combined platinum electrode.<\/p>\n1 mL of 0.05 M iodine is equivalent to 21.73 mg of C9<\/sub>H15<\/sub>NO3<\/sub>S.<\/p>\n

Content<\/h3>\n
98.0 per cent to 101.5 per cent (dried substance).<\/p>\n

Appearance<\/h3>\n
White or almost white, crystalline powder.<\/p>\n

Solubility<\/h3>\n
Soluble in water, freely soluble in methanol and in methylene chloride. It dissolves in dilute solutions of alkali hydroxides.<\/p>\n

IDENTIFICATION<\/h2>\n
A. Specific optical rotation (see Tests).<\/p>\n
B. Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison: captopril CRS.<\/p>\n

Solution S<\/h3>\n
Dissolve 0.5 g in carbon dioxide-free water R and dilute to 25 mL with the same solvent.<\/p>\n

Appearance of solution<\/h3>\n
Solution S is clear (2.2.1) and colourless (2.2.2, Method II).<\/p>\n

pH (2.2.3)<\/h3>\n
2.0 to 2.6 for solution S.<\/p>\n

Specific optical rotation (2.2.7)<\/h3>\n
-132 to -127 (dried substance).<\/p>\n
Dissolve 0.250 g in anhydrous ethanol R and dilute to 25.0 mL with the same solvent.<\/p>\n

Loss on drying (2.2.32)<\/h3>\n
Maximum 1.0 per cent, determined on 1.000 g by drying in vacuo at 60 \u00b0C at a pressure not exceeding 0.1 kPa for 3 h.<\/p>\n

Sulfated ash (2.4.14)<\/h3>\n
Maximum 0.2 per cent, determined on 1.0 g.<\/p>\n

ASSAY<\/h2>\n
Dissolve 0.150 g in 30 mL of water R. Titrate with 0.05 M iodine, determining the end-point potentiometrically (2.2.20). Use a combined platinum electrode.<\/p>\n
1 mL of 0.05 M iodine is equivalent to 21.73 mg of C_{9<\/sub>H_{15<\/sub>NO_{3<\/sub>S.<\/p>\n}}}