Penicillin antibacterial.<\/p>\n
Ph Eur<\/p>\n
\n
DEFINITION<\/h2>\n
Sodium (2S,5R,6R)-6-[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia- 1-azabicyclo[3.2.0]heptane-2-carboxylate.<\/p>\n
Semi-synthetic product derived from a fermentation product.<\/p>\n
Content<\/strong><\/p>\n 95.5 per cent to 102.0 per cent (anhydrous substance).<\/p>\n The manufacturing process is evaluated to determine the potential presence of N,N-dimethylaniline. Where necessary, the manufacturing process is validated to demonstrate that the piperacillin sodium complies with the following test:<\/p>\n N,N-Dimethylaniline (2.4.26, Method A) Maximum 20 ppm.<\/p>\n White or almost white, hygroscopic powder.<\/p>\n Freely soluble in water and in methanol, practically insoluble in ethyl acetate.<\/p>\n A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n Preparation Dissolve 0.250 g in water R, add 0.5 mL of dilute hydrochloric acid R and 5 mL of ethyl acetate R; stir and allow to stand for 10 min in iced water. Filter the crystals through a small sintered-glass filter (40), applying suction. Wash with 5 mL of water R and 5 mL of ethyl acetate R, then dry in an oven at 60 \u00b0C for 60 min.<\/p>\n Comparison\u00a0 piperacillin CRS.<\/p>\n B. It gives reaction (a) of sodium (2.3.1).<\/p>\n Dissolve 2.50 g in carbon dioxide-free water R and dilute to 25 mL with the same solvent.<\/p>\n Solution S is clear (2.2.1) and its absorbance (2.2.25) at 430 nm is not greater than 0.10.<\/p>\n pH (2.2.3)<\/strong><\/p>\n 5.0 to 7.0 for solution S.<\/p>\n Liquid chromatography (2.2.29).<\/p>\n Test solution\u00a0 Dissolve 0.120 g of the substance to be examined in water R and dilute to 20.0 mL with the same solvent.<\/p>\n Reference solution (a)\u00a0 Dilute 1.0 mL of the test solution to 100.0 mL with mobile phase B.<\/p>\n Reference solution (b) Dissolve 6 mg of piperacillin impurity I CRS in mobile phase B and dilute to 20 mL with mobile phase B.<\/p>\n Reference solution (c) Dissolve 6 mg of anhydrous ampicillin CRS (impurity A) in mobile phase B and dilute to 20 mL with mobile phase B.<\/p>\n Reference solution (d) To 2 mL of reference solution (b), add 1 mL of reference solution (c) and dilute to 10 mL with mobile phase B.<\/p>\n Reference solution (e) Dissolve 6 mg of piperacillin for peak identification CRS (containing impurities A, B, C, D, E, F, G, I, J, K, L, M, O, P, Q, R, S and T) in mobile phase B and dilute to 1 mL with mobile phase B.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.25 m, \u00d8 = 4.6 mm;<\/p>\n \u2014 stationary phase: end-capped octadecylsilyl amorphous organosilica polymer for chromatography R (5 \u00b5m);<\/p>\n \u2014 temperature: 40 \u00b0C.<\/p>\n Mobile phase:<\/p>\n \u2014 mobile phase A: mix 3 mL of a 320 g\/L solution of tetrabutylammonium hydroxide R, 100 mL of a 27.6 g\/L solution of sodium dihydrogen phosphate R, 275 mL of methanol R1 and 622 mL of water for chromatography R; adjust the apparent pH to 5.5 with phosphoric acid R;<\/p>\n \u2014 mobile phase B: mix 3 mL of a 320 g\/L solution of tetrabutylammonium hydroxide R, 100 mL of a 27.6 g\/L solution of sodium dihydrogen phosphate R, 282 mL of water for chromatography R and 615 mL of methanol R1; adjust the apparent pH to 5.5 with phosphoric acid R;<\/p>\n Flow rate\u00a0 1.0 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 220 nm.<\/p>\n Autosampler\u00a0 Set at 4 \u00b0C.<\/p>\n Injection\u00a0 10 \u00b5L of the test solution and reference solutions (a), (d) and (e).<\/p>\n Identification of impurities Use the chromatogram supplied with piperacillin for peak identification CRS and the chromatogram obtained with reference solution (e) to identify the peaks due to impurities A, B, C, D, E, F, G, I, J, K, L, M, O, P, Q, R, S and T.<\/p>\n Relative retention\u00a0 With reference to piperacillin (retention time = about 54 min): impurity E = about 0.05; impurity I = about 0.12; impurity A = about 0.14; impurity G = about 0.30; impurity J = about 0.36; impurity F = about 0.57; impurity K = about 0.60; impurity L = about 0.65; impurity B (isomer 1) = about 0.71; impurity M = about 0.75; impurity B (isomer 2) = about 0.83; impurity C (isomer 1) = about 0.87; impurity C (isomer 2) = about 0.92; impurity O = about 1.23; impurity P = about 1.26; impurity Q = about 1.31; impurity R = about 1.36; impurity S = about 1.38; impurity T = about 1.41; impurity D = about 1.54.<\/p>\n System suitability\u00a0 Reference solution (d):<\/p>\n \u2014 resolution: minimum 1.5 between the peaks due to impurities I and A.<\/p>\n Calculation of percentage contents:<\/p>\n \u2014 correction factors: multiply the peak areas of the following impurities by the corresponding correction factor: impurity A = 1.3; impurity E = 0.4; impurity I = 3.2;<\/p>\n \u2014 for each impurity, use the concentration of piperacillin sodium in reference solution (a).<\/p>\n Limits:<\/p>\n \u2014 impurity G: maximum 1.5 per cent;<\/p>\n \u2014 impurities B (sum of isomers), D: for each impurity, maximum 1.0 per cent;<\/p>\n \u2014 impurity F: maximum 0.8 per cent;<\/p>\n \u2014 impurity C (sum of isomers): maximum 0.7 per cent;<\/p>\n \u2014 impurity S: maximum 0.5 per cent;<\/p>\n \u2014 impurities L, T: for each impurity, maximum 0.3 per cent;<\/p>\n \u2014 impurities A, E, I, J, K, M, O, P, Q, R: for each impurity, maximum 0.2 per cent;<\/p>\n \u2014 any other impurity: for each impurity, maximum 0.15 per cent;<\/p>\n \u2014 total: maximum 2.5 per cent;<\/p>\n \u2014 reporting threshold: 0.05 per cent.<\/p>\n Water (2.5.12)<\/strong><\/p>\n Maximum 2.0 per cent, determined on 0.500 g.<\/p>\n Liquid chromatography (2.2.29).<\/p>\n Solvent mixture\u00a0 acetonitrile R, 31.2 g\/L solution of sodium dihydrogen phosphate R (25:75 V\/V).<\/p>\n Test solution Dissolve 0.100 g of the substance to be examined in the solvent mixture and dilute to 50.0 mL with the solvent mixture. Dilute 5.0 mL of the solution to 50.0 mL with the solvent mixture.<\/p>\n Reference solution (a) Dissolve 50.0 mg of piperacillin CRS in the solvent mixture and dilute to 50.0 mL with the solvent mixture. Dilute 10.0 mL of the solution to 50.0 mL with the solvent mixture.<\/p>\n Reference solution (b) Dissolve 0.1 g of the substance to be examined in the solvent mixture and dilute to 50 mL with the solvent mixture.<\/p>\n Reference solution (c) Dissolve 5 mg of piperacillin impurity N CRS in the solvent mixture and dilute to 25 mL with the solvent mixture.<\/p>\n Reference solution (d) To 5 mL of reference solution (b), add 0.1 mL of reference solution (c) and dilute to 50 mL with the solvent mixture.<\/p>\n Column:<\/p>\n \u2014 size: l = 0.15 m, \u00d8 = 4.6 mm;<\/p>\n \u2014 stationary phase: end-capped octadecylsilyl amorphous organosilica polymer for chromatography R (3.5 \u00b5m);<\/p>\n \u2014 temperature: 40 \u00b0C.<\/p>\n Mobile phase:<\/p>\n \u2014 mobile phase A: mix 24 mL of an 80 g\/L solution of tetrabutylammonium hydroxide R, 200 mL of acetonitrile for chromatography R, 200 mL of a 31.2 g\/L solution of sodium dihydrogen phosphate R and 576 mL of water for chromatography R; adjust the apparent pH to 5.5 with dilute phosphoric acid R or dilute sodium hydroxide solution R;<\/p>\n \u2014 mobile phase B: mix 24 mL of an 80 g\/L solution of tetrabutylammonium hydroxide R, 126 mL of water for chromatography R, 200 mL of a 31.2 g\/L solution of sodium dihydrogen phosphate R and 650 mL of acetonitrile for chromatography R; adjust the apparent pH to 5.5 with dilute phosphoric acid R or dilute sodium hydroxide solution R;<\/p>\n Flow rate\u00a0 1.0 mL\/min.<\/p>\n Detection\u00a0 Spectrophotometer at 220 nm.<\/p>\n Injection\u00a0 10 \u00b5L of the test solution and reference solutions (a) and (d).<\/p>\n Relative retention\u00a0 With reference to piperacillin (retention time = about 13 min): impurity N = about 0.96.<\/p>\n System suitability\u00a0 Reference solution (d):<\/p>\n \u2014 resolution: minimum 1.5 between the peaks due to impurity N and piperacillin.<\/p>\n Calculate the percentage content of C23<\/sub>H26<\/sub>N5<\/sub>NaO7<\/sub>S using the chromatogram obtained with reference solution (a) and taking into account the assigned content of piperacillin CRS and a conversion factor of 1.042.<\/p>\n In an airtight container. If the substance is sterile, the container is also sterile and tamper-evident.<\/p>\n The label states, where applicable, that the substance is suitable for use in the manufacture of parenteral preparations.<\/p>\n Specified impurities\u00a0 A, B, C, D, E, F, G, I, J, K, L, M, O, P, Q, R, S, T.<\/em><\/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. 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) H, N.<\/em><\/p>\n A. (2S,5R,6R)-6-[(2R)-2-amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (ampicillin),<\/p>\n B. (2\u039e,4S)-2-[(\u039e)-carboxy[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]methyl]-5,5-dimethyl- 1,3-thiazolidine-4-carboxylic acid (penicilloic acids of piperacillin),<\/p>\n C. (2\u039e,4S)-2-[[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]methyl]-5,5-dimethyl-1,3- thiazolidine-4-carboxylic acid (penilloic acids of piperacillin),<\/p>\n D. (2S,5R,6R)-6-[(2R)-2-[(2S,5R,6R)-6-[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]-3,3- dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxamido]-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-\u00a0 azabicyclo[3.2.0]heptane-2-carboxylic acid (piperacillinylampicillin),<\/p>\n E. 1-ethylpiperazine-2,3-dione,<\/p>\n F. (2\u039e,4S)-3-acetyl-2-[(\u039e)-carboxy[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]methyl]-5,5- dimethyl-1,3-thiazolidine-4-carboxylic acid (acetylated penicilloic acids of piperacillin),<\/p>\n G. (R)-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)phenylacetic acid,<\/p>\n H. (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (6-aminopenicillanic acid),<\/p>\n I. (2S)-2-formamido-3-methyl-3-sulfanylbutanoic acid (N-formylpenicillamine),<\/p>\n J. [(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]acetic acid,<\/p>\n K. (2\u039e)-2-[[(E)-[2-[(R)-[(4-ethyl-2,3-dioxopiperazine-1-carboxamido)phenylmethyl]-5-oxo-1,3-oxazol-4(5H)- ylidene]methyl]amino]-3-methyl-3-sulfanylbutanoic acid (penicillenic acid),<\/p>\n L. unknown structure,<\/p>\n M. (2S,5R,6R)-6-[(2R)-2-[[[2-[ethyl(oxalo)amino]ethyl]carbamoyl]amino]-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid,<\/p>\n N. (2S,5R,6R)-6-[(2S)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid (L-piperacillin),<\/p>\n O. unknown structure,<\/p>\n P. (2S,5R,6R)-6-[(2R)-2-[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]-2- phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,<\/p>\n Q. unknown structure,<\/p>\n R. (2S,5R,6R)-6-[(2R)-2-[(2\u039e)-2-[(2\u039e,4S)-4-carboxy-5,5-dimethyl-1,3-thiazolidin-2-yl]-2-[(2R)-2-(4-ethyl-2,3- dioxopiperazine-1-carboxamido)-2-phenylacetamido]acetamido]-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]heptane-2-carboxylic acid,<\/p>\n S. (2S,5R,6R)-6-[(2S,5R,6R)-6-[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7- oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic\u00a0 acid,<\/p>\n T. (2\u039e,4S)-2-[(\u039e)-carboxy[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]methyl]-3- [(2S,5R,6R)-6-[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carbonyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid.<\/p>\n Ph Eur<\/p>\n","protected":false},"excerpt":{"rendered":" Edition: BP 2025 (Ph. Eur. 11.6 update) Action and use Penicillin antibacterial. Ph Eur DEFINITION Sodium (2S,5R,6R)-6-[(2R)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia- 1-azabicyclo[3.2.0]heptane-2-carboxylate. Semi-synthetic product derived from a fermentation product. Content 95.5 per cent to 102.0 per cent (anhydrous substance). PRODUCTION The manufacturing process is evaluated to determine the potential presence of N,N-dimethylaniline. Where necessary, the manufacturing process is validated…<\/p>\n","protected":false},"author":5,"featured_media":27112,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-27111","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\/27111","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\/5"}],"replies":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/comments?post=27111"}],"version-history":[{"count":4,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/27111\/revisions"}],"predecessor-version":[{"id":27613,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/27111\/revisions\/27613"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/27112"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=27111"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=27111"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=27111"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}PRODUCTION<\/h2>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
Solubility<\/h3>\n
IDENTIFICATION<\/h2>\n
TESTS<\/h2>\n
Solution S<\/h3>\n
Appearance of solution<\/h3>\n
Related substances<\/h3>\n
\n\n
\n Time (min)<\/strong><\/td>\n Mobile phase A (per cent V\/V)<\/strong><\/td>\n Mobile phase B (per cent V\/V)<\/strong><\/td>\n<\/tr>\n \n 0 – 6<\/td>\n 100<\/td>\n 0<\/td>\n<\/tr>\n \n 6 – 55<\/td>\n 100 \u2192 71<\/td>\n 0 \u2192 29<\/td>\n<\/tr>\n \n 55 – 73<\/td>\n 71 \u2192 10<\/td>\n 29 \u2192 90<\/td>\n<\/tr>\n \n 73 – 85<\/td>\n 10<\/td>\n 90<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n ASSAY<\/h2>\n
\n\n
\n Time (min)<\/strong><\/td>\n Mobile phase A (per cent V\/V)<\/strong><\/td>\n Mobile phase B (per cent V\/V)<\/strong><\/td>\n<\/tr>\n \n 0 – 3.5<\/td>\n 100<\/td>\n 0<\/td>\n<\/tr>\n \n 3.5 – 4<\/td>\n 100 \u2192 92<\/td>\n 0 \u2192 8<\/td>\n<\/tr>\n \n 4 – 14<\/td>\n 92 \u2192 86<\/td>\n 8 \u2192 14<\/td>\n<\/tr>\n \n 14 – 15<\/td>\n 86 \u2192 0<\/td>\n 14 \u2192 100<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n STORAGE<\/h2>\n
LABELLING<\/h2>\n
IMPURITIES<\/h2>\n
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