Atracurium Besylate

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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Atracurium Besylate

C₆₅H₈₂N₂O₁₈S₂ 1243.48

Isoquinolinium, 2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-, dibenzenesulfonate;

2-(2-Carboxyethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium benzenesulfonate, pentamethylene ester

CAS RN®: 64228-81-5; UNII: 40AX66P76P.

1 DEFINITION

Atracurium besylate contains NLT 96.0% and NMT 102.0% of C₆₅H₈₂N₂O₁₈S₂, calculated on the anhydrous basis.

It contains NLT 5.0% and NMT 6.5% of the trans-trans isomer, NLT 34.5% and NMT 38.5% of the cis-trans isomer, and NLT 55.0% and NMT 60.0% of the cis-cis isomer.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K

B. The retention times of the three main isomeric peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

Procedure

Buffer: 10.2 g of monobasic potassium phosphate in a 1000-mL volumetric flask. Dissolve in 950 mL of water. While stirring, adjust with phosphoric acid to a pH of 3.1, and dilute with water to volume.

Solution A: Acetonitrile, methanol, and Buffer (20:5:75)

Solution B: Acetonitrile, methanol, and Buffer (20:30:50)

Mobile phase: See Table 1.

Standard solution: 1 mg/mL of USP Atracurium Besylate RS in Solution A

Sample solution: 1 mg/mL of Atracurium Besylate in Solution A

Chromatographic system

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm × 25-cm; 5-µm base-deactivated packing L1

Flow rate: 1 mL/min

Injection size: 20 µL

System suitability

Sample: Standard solution

Resolution: NLT 1.5 between the atracurium trans-trans isomer and the cis-trans isomer peaks; NLT 1.5 between the atracurium cis-trans isomer and the cis-cis isomer peaks

Relative standard deviation: NMT 2.0%, for the cis-cis isomer peak

Analysis

Calculate the percentage of atracurium besylate (C₆₅H₈₂N₂O₁₈S₂) in the portion of Atracurium Besylate taken:

Result = (r_U / r_S) × (C_S / C_U) × 100

r_U = sum of the peak responses for the trans-trans isomer, the trans-cis isomer, and the cis-cis isomer from the Sample solution

r_S= sum of the peak responses for the trans-trans isomer, the trans-cis isomer, and the cis-cis isomer from the Standard solution

C_S = concentration of USP Atracurium Besylate RS in the Standard solution (mg/mL)

C_U= concentration of Atracurium Besylate in the Sample solution (mg/mL)

Acceptance criteria: 96.0%–102.0%, calculated on the anhydrous basis. It contains NLT 5.0% and NMT 6.5% of the trans-trans isomer, NLT 34.5% and NMT 38.5% of the cis-trans isomer, and NLT 55.0% and NMT 60.0% of the cis-cis isomer

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.2%

Organic Impurities

Buffer, Solution A, Solution B, Mobile phase, Chromatographic system, and Sample solution: Proceed as directed in the Assay.

Standard solution: 0.01 mg/mL of USP Atracurium Besylate RS in Solution A

System suitability solution: 1 mg/mL of USP Atracurium Besylate RS in Solution A

System suitability

Resolution: NLT 1.5 between the atracurium trans-trans isomer and the cis-trans isomer peaks; NLT 1.5 between the atracurium cis-trans isomer and the cis-cis isomer peaks

Analysis

Calculate the percentage of each impurity in the portion of Atracurium Besylate taken:

Result = (r_U / r_S) × (C_S / C_U)× (1/F) × 100

r_U = peak response for each impurity from the Sample solution

r_S= sum of peak responses due to the atracurium cis-cis, trans-trans, and cis-trans isomers from the Standard solution

C_S = concentration of USP Atracurium Besylate RS in the Standard solution (mg/mL)

C_U= concentration of Atracurium Besylate in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. Disregard any peak less than 0.05%.

a 3-[1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinio]propanoate.

b 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium.

c 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

d trans Isomer of 1-(3,4-dimethoxybenzyl)-2-[3-[(5-hydroxypentyl)oxy]-3-oxopropyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium.

e cis Isomer of 1-(3,4-dimethoxybenzyl)-2-[3-[(5-hydroxypentyl)oxy]-3-oxopropyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium.

f cis-trans Isomer of 1-(3,4-dimethoxybenzyl)-2-[13-[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]-3,11-dioxo-4,10- dioxatridecyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium.

g cis-trans Isomer of 2,2′-[(3-methylpentane-1,5)-diylbis[oxy(3-oxopropane-1,3-diyl)]]bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl1,2,3,4 tetrahydroisoquinolinium].

h cis-trans Isomer of 2,2′-[hexane-1,6-diylbis[oxy(3-oxopropane-1,3-diyl)]]bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium].

i cis-cis Isomer of 1-(3,4-dimethoxybenzyl)-2-[13-[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]-3,11-dioxo-4,10- dioxatridecyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium.

j 2,2′-[(Hexane-1,5)-diylbis(3-oxopropane-1,3-diyl)]]bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro isoquinolinium].

k cis-cis Isomer of 2,2′-[(3-methylpentane-1,5)-diylbis[oxy(3-oxopropane-1,3-diyl)]]bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl1,2,3,4 tetrahydroisoquinolinium].

l cis-cis Isomer of 2,2′-[hexane-1,6-diylbis[oxy(3-oxopropane-1,3-diyl)]]bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro isoquinolinium].

m Pentane-1,5-diyl bis[3-[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propanoate].

n trans Isomer of 1-(3,4-dimethoxybenzyl)-2-(3,11-dioxo-4,10-dioxatridec-12-enyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium

benzenesulfonate.

o cis Isomer of 1-(3,4-dimethoxybenzyl)-2-(3,11-dioxo-4,10-dioxatridec-12-enyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium benzenesulfonate.

p Impurity consists of two isomers that are separated under these conditions; integrate both peaks for the impurity calculations.

Limit of Impurity J (Methyl Benzenesulfonate)

Buffer, Solution A, and Solution B: Prepare as directed in the Assay.

Standard stock solution: 0.2 mg/mL of Impurity J (methyl benzenesulfonate) in acetonitrile

Standard solution: 1 µg/mL of Impurity J (methyl benzenesulfonate) in Solution A from Standard stock solution

Sample solution: 10 mg/mL of Atracurium Besylate in Solution A

Mobile phase: See Table 3.

Mode: LC

Detector: UV 217 nm

Column: 4.6-mm × 25-cm; 5-µm base-deactivated packing L1

Flow rate: 1 mL/min

Injection size: 100 µL

Analysis

Acceptance criteria: NMT 0.01%, the peak response of the Sample solution being NMT that of the Standard solution

5 SPECIFIC TESTS

Water Determination, Method I〈921〉: NMT 5.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers, in a cold place. [Note—Atracurium Besylate is unstable at room temperature.]

USP Reference Standards 〈11〉: USP Atracurium Besylate RS