{"id":29475,"date":"2025-11-10T16:53:39","date_gmt":"2025-11-10T09:53:39","guid":{"rendered":"https:\/\/nhathuocngocanh.com\/bp\/?p=29475"},"modified":"2025-11-10T16:53:39","modified_gmt":"2025-11-10T09:53:39","slug":"remifentanil-hydrochloride","status":"publish","type":"post","link":"https:\/\/nhathuocngocanh.com\/bp\/remifentanil-hydrochloride\/","title":{"rendered":"Remifentanil Hydrochloride"},"content":{"rendered":"

Edition: BP 2025 (Ph. Eur. 11.6 update)<\/p>\n

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

Opioid receptor agonist; analgesic.<\/p>\n

DEFINITION<\/h2>\n
Methyl 1-(3-methoxy-3-oxopropyl)-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate hydrochloride.<\/p>\n
Content<\/strong><\/p>\n
97.0 per cent to 102.0 per cent (dried substance).<\/p>\n
CHARACTERS<\/h2>\n
Appearance<\/h3>\n
White or almost white, crystalline powder.<\/p>\n
Solubility<\/h3>\n
Freely soluble in water, soluble in acetonitrile and in methanol, sparingly soluble in ethanol (96 per cent).<\/p>\n
IDENTIFICATION<\/h2>\n
A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison\u00a0 remifentanil hydrochloride CRS.<\/p>\n
B. It gives reaction (a) of chlorides (2.3.1).<\/p>\n
TESTS<\/h2>\n
Appearance of solution<\/h3>\n
The solution is clear (2.2.1) and colourless (2.2.2, Method II). Dissolve 0.5 g in water R and dilute to 50.0 mL with the same solvent.<\/p>\n
Related substances<\/h3>\n
Liquid chromatography (2.2.29). Prepare the solutions immediately before use and keep them at not more than 5 \u00b0C.<\/p>\n
Buffer solution Dissolve 6.0 g of anhydrous sodium dihydrogen phosphate R in 950 mL of water for chromatography R, adjust to pH 3.0 with phosphoric acid R and dilute to 1000 mL with water for chromatography R.<\/p>\n
Test solution (a) Dissolve 30.0 mg of the substance to be examined in mobile phase B and dilute to 20.0 mL with mobile phase B.<\/p>\n
Test solution (b)\u00a0 Dilute 1.0 mL of test solution (a) to 20.0 mL with mobile phase B.<\/p>\n
Reference solution (a) Dissolve 3 mg of remifentanil impurity mixture CRS (containing impurities A, B, C, E, L, N and O) in mobile phase B and dilute to 2 mL with mobile phase B.<\/p>\n
Reference solution (b)\u00a0 Dilute 1.0 mL of test solution (a) to 100.0 mL with mobile phase B. Dilute 1.0 mL of this solution to 10.0 mL with mobile phase B.<\/p>\n
Reference solution (c) Dissolve 30.0 mg of remifentanil hydrochloride CRS in mobile phase B and dilute to 20.0 mL with mobile phase B. Dilute 1.0 mL of the solution to 20.0 mL with mobile phase B.<\/p>\n
Column:<\/p>\n
\u2014 size: l = 0.10 m, \u00d8 = 2.1 mm;<\/p>\n
\u2014 stationary phase: end-capped octadecylphenylsilyl silica gel for chromatography R (2 \u00b5m);<\/p>\n
\u2014 temperature: 40 \u00b0C.<\/p>\n
Mobile phase:<\/p>\n
\u2014 mobile phase A: acetonitrile R1, methanol R2, buffer solution (1:9:90 V\/V\/V);<\/p>\n
\u2014 mobile phase B: acetonitrile R1, buffer solution, methanol R2 (12:40:48 V\/V\/V);<\/p>\n\n\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
0 – 8<\/td>\n 85<\/td>\n 15<\/td>\n<\/tr>\n
8 – 40<\/td>\n 85 \u2192 45<\/td>\n 15 \u2192 55<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Flow rate\u00a0 0.65 mL\/min.<\/p>\n
Detection\u00a0 Spectrophotometer at 210 nm.<\/p>\n
Injection\u00a0 5.0 \u00b5L of test solution (a) and reference solutions (a) and (b).<\/p>\n
Identification of impurities Use the chromatogram supplied with remifentanil impurity mixture CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A, B, C, E, L, N and O.<\/p>\n
Relative retention\u00a0 With reference to remifentanil (retention time = about 10 min): impurity L = about 0.2; impurity O = about 0.40; impurity B = about 0.44; impurity A = about 0.7; impurity C = about 0.80; impurity N = about 0.85; impurity E = about 1.4.<\/p>\n
System suitability\u00a0 Reference solution (a):<\/p>\n
\u2014 resolution: minimum 1.5 between the peaks due to impurities O and B; minimum 2.0 between the peaks due to impurities C and N.<\/p>\n
Calculation of percentage contents:<\/p>\n
\u2014 correction factor: multiply the peak area of impurity L by 1.5;<\/p>\n
\u2014 for each impurity, use the concentration of remifentanil hydrochloride in reference solution (b).<\/p>\n
Limits:<\/p>\n
\u2014 impurity C: maximum 0.5 per cent;<\/p>\n
\u2014 impurity A: maximum 0.2 per cent;<\/p>\n
\u2014 impurities B, E, L: for each impurity, maximum 0.15 per cent;<\/p>\n
\u2014 unspecified impurities: for each impurity, maximum 0.10 per cent;<\/p>\n
\u2014 total: maximum 1.0 per cent;<\/p>\n
\u2014 reporting threshold: 0.05 per cent.<\/p>\n
Methyl acrylate<\/h3>\n
Head-space gas chromatography (2.2.28).<\/p>\n
Internal standard solution Dilute 25.0 \u00b5L of propanol R to 100.0 mL with water for chromatography R. Dilute 50.0 mL of the solution to 1000.0 mL with water for chromatography R.<\/p>\n
Test solution Dissolve 0.100 g of the substance to be examined in the internal standard solution and dilute to 5.0 mL with the internal standard solution.<\/p>\n
Reference solution Dilute 75.0 \u00b5L of methyl acrylate R to 100.0 mL with the internal standard solution. Dilute 10.0 mL of the solution to 100.0 mL with the internal standard solution. Dilute 7.0 mL of this solution to 100.0 mL with the internal standard solution.<\/p>\n
Precolumn:<\/p>\n
\u2014 material: deactivated fused silica;<\/p>\n
\u2014 size: l = 5 m, \u00d8 = 0.25 mm.<\/p>\n
Column:<\/p>\n
\u2014 material: fused silica;<\/p>\n
\u2014 size: l = 60 m, \u00d8 = 0.53 mm;<\/p>\n
\u2014 stationary phase: cyanopropyl(7)phenyl(7)methyl(86)polysiloxane R (film thickness 3 \u00b5m).<\/p>\n
Carrier gas helium for chromatography R. Flow rate 8.3 mL\/min.<\/p>\n
Pressure\u00a0 68.9 kPa.<\/p>\n
Split ratio\u00a0 1:10.<\/p>\n
Static head-space conditions that may be used:<\/p>\n
\u2014 equilibration temperature: 90 \u00b0C;<\/p>\n
\u2014 equilibration time: 5 min;<\/p>\n
\u2014 transfer-line temperature: 180 \u00b0C;<\/p>\n
\u2014 pressurisation time: 2 min;<\/p>\n
\u2014 injection: 6 s or 1 mL;<\/p>\n
\u2014 withdrawal time: 12 s;<\/p>\n
\u2014 shaker: on.<\/p>\n
Temperature:<\/p>\n\n\n\n\n\n\n\n\n
<\/td>\n Time (min)<\/strong><\/td>\n Temperature (\u00b0C)<\/strong><\/td>\n<\/tr>\n
Column<\/td>\n 0 – 35<\/td>\n 35<\/td>\n<\/tr>\n
<\/td>\n 35 – 40<\/td>\n 35 \u2192 210<\/td>\n<\/tr>\n
<\/td>\n 40 – 50<\/td>\n 210<\/td>\n<\/tr>\n
Injection port<\/td>\n 180<\/td>\n<\/tr>\n
Detector<\/td>\n 250<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Detection\u00a0 Flame ionisation.<\/p>\n
Retention time\u00a0 Propanol = about 25 min; methyl acrylate = about 27 min.<\/p>\n
System suitability\u00a0 Reference solution:<\/p>\n
\u2014 resolution: minimum 5.0 between the peaks due to propanol and methyl acrylate. Calculate the content of methyl acrylate, taking its relative density to be 0.955 at 20 \u00b0C. Limit:<\/p>\n
\u2014 methyl acrylate: maximum 250 ppm.<\/p>\n
Loss on drying (2.2.32)<\/strong><\/p>\n
Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 \u00b0C for 3 h.<\/p>\n
Sulfated ash (2.4.14)<\/strong><\/p>\n
Maximum 0.1 per cent, determined on 1.0 g.<\/p>\n
ASSAY<\/h2>\n
Liquid chromatography (2.2.29) as described in the test for related substances with the following modifications.<\/p>\n
Mobile phase:<\/p>\n\n\n\n\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
0 – 8<\/td>\n 85<\/td>\n 15<\/td>\n<\/tr>\n
8 – 12<\/td>\n 85 \u2192 83<\/td>\n 15 \u2192 17<\/td>\n<\/tr>\n
12 – 15<\/td>\n 83 \u2192 15<\/td>\n 17 \u2192 85<\/td>\n<\/tr>\n
15 – 25<\/td>\n 15<\/td>\n 85<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n
Injection\u00a0 Test solution (b) and reference solution (c).<\/p>\n
Retention time\u00a0 Remifentanil = about 11 min.<\/p>\n
System suitability\u00a0 Reference solution (c):<\/p>\n
\u2014 symmetry factor: maximum 2.2 for the peak due to remifentanil.<\/p>\n
Calculate the percentage content of C_{20<\/sub>H_{29<\/sub>ClN_{2<\/sub>O_{5<\/sub> taking into account the assigned content of remifentanil hydrochloride CRS.<\/p>\n}}}}
IMPURITIES<\/h2>\n
Specified impurities\u00a0 A, B, C, E, L.<\/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 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) D, G, H, I, J, K, M, N, O.<\/em><\/p>\n
A. methyl 4-[phenyl(propanoyl)amino]piperidine-4-carboxylate,<\/p>\n
B. methyl 4-[acetyl(phenyl)amino]-1-(3-methoxy-3-oxopropyl)piperidine-4-carboxylate,<\/p>\n
C. 3-[4-(methoxycarbonyl)-4-[phenyl(propanoyl)amino]piperidin-1-yl]propanoic acid,<\/p>\n
D. methyl 4-[butanoyl(phenyl)amino]-1-(3-methoxy-3-oxopropyl)piperidine-4-carboxylate,<\/p>\n
E. methyl 1-(3-methoxy-3-oxopropyl)-4-[(2-methyl-3-oxopentanoyl)(phenyl)amino]piperidine-4-carboxylate,<\/p>\n
G. methyl 1-benzyl-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate,<\/p>\n
H. 1-benzyl-4-(phenylamino)piperidine-4-carbonitrile,<\/p>\n
I. 1-benzyl-4-(phenylamino)piperidine-4-carboxamide,<\/p>\n
J. methyl 1-benzyl-4-(phenylamino)piperidine-4-carboxylate,<\/p>\n
K. methyl 1-methyl-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate,<\/p>\n
L. methyl 3-(2-ethyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-8-yl)propanoate,<\/p>\n
M. methyl 3-[4-cyano-4-(phenylamino)piperidin-1-yl]propanoate,<\/p>\n
N. methyl 3-[4-cyano-4-[phenyl(propanoyl)amino]piperidin-1-yl]propanoate,<\/p>\n
O. N-phenylpropanamide.<\/p>\n","protected":false},"excerpt":{"rendered":"
Edition: BP 2025 (Ph. Eur. 11.6 update) Action and use Opioid receptor agonist; analgesic. DEFINITION Methyl 1-(3-methoxy-3-oxopropyl)-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate hydrochloride. Content 97.0 per cent to 102.0 per cent (dried substance). CHARACTERS Appearance White or almost white, crystalline powder. Solubility Freely soluble in water, soluble in acetonitrile and in methanol, sparingly soluble in ethanol (96 per cent). IDENTIFICATION…<\/p>\n","protected":false},"author":5,"featured_media":29478,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[174],"tags":[],"class_list":["post-29475","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\/29475","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=29475"}],"version-history":[{"count":2,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/29475\/revisions"}],"predecessor-version":[{"id":29495,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/posts\/29475\/revisions\/29495"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media\/29478"}],"wp:attachment":[{"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/media?parent=29475"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/categories?post=29475"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/nhathuocngocanh.com\/bp\/wp-json\/wp\/v2\/tags?post=29475"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}

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

Solubility<\/h3>\nFreely soluble in water, soluble in acetonitrile and in methanol, sparingly soluble in ethanol (96 per cent).<\/p>\n

IDENTIFICATION<\/h2>\nA. Infrared absorption spectrophotometry (2.2.24).<\/p>\nComparison\u00a0 remifentanil hydrochloride CRS.<\/p>\nB. It gives reaction (a) of chlorides (2.3.1).<\/p>\n

TESTS<\/h2>\n

Appearance of solution<\/h3>\nThe solution is clear (2.2.1) and colourless (2.2.2, Method II). Dissolve 0.5 g in water R and dilute to 50.0 mL with the same solvent.<\/p>\n

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

Solubility<\/h3>\n
Freely soluble in water, soluble in acetonitrile and in methanol, sparingly soluble in ethanol (96 per cent).<\/p>\n

IDENTIFICATION<\/h2>\n
A. Infrared absorption spectrophotometry (2.2.24).<\/p>\n
Comparison\u00a0 remifentanil hydrochloride CRS.<\/p>\n
B. It gives reaction (a) of chlorides (2.3.1).<\/p>\n

Appearance of solution<\/h3>\n
The solution is clear (2.2.1) and colourless (2.2.2, Method II). Dissolve 0.5 g in water R and dilute to 50.0 mL with the same solvent.<\/p>\n