Montelukast Sodium

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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C₃₅H₃₅CINNaO₃S            608.17

Cyclopropaneacetic acid, 1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]-, sodium salt, [R-,(E)]-;

Sodium 1-[[[(R)-m-[(E)-2-(7-chloro-2-quinolyl) vinyl]-a-[o-(1-hydroxy-1-methylethyl)phenethyl benzyl thio]-methyl]cyclopropaneacetate CAS RN^®: 151767-02-1; UNII: U103J18SFL.

C₃₅H₃₅CINNO₃S             586.18

Montelukast CAS RN^®: 158966-92-8; UNII: MHM278SD3E.

1 DEFINITION

Montelukast Sodium contains NLT 98.0% and NMT 102.0% of CH 35 35 anhydrous and solvent-free basis.

2 IDENTIFICATION

Change to read:

A. ^▲SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 1974, 197K, or 197MA _{▲(CN 1-May-2020)}

B. IDENTIFICATION TESTS GENERAL, Sodium (191)

Sample: 100 mg

Analysis: Ignite the Sample in a crucible until an almost white residue is obtained. Take up the residue in 2 mL of water, and filter.

Acceptance criteria: The filtrate meets the requirements of test A.

C. Meets the requirements of the test for Enantiomeric Purity.

3 ASSAY

[NOTE-Avoid exposure of the samples to light. Use low-actinic glassware.]

PROCEDURE

Solution A: Add 1.5 mL of trifluoroacetic acid to 1 L of water.

Solution B: Add 1.5 mL of trifluoroacetic acid to 1 L of acetonitrile.

Mobile phase: See Table 1. Return to original conditions and re-equilibrate the column.

Table 1

Diluent: Methanol and water (9:1)

Standard solution: 0.13 mg/mL of USP Montelukast Dicyclohexylamine RS in Diluent

Sample solution: 0.1 mg/mL of Montelukast Sodium in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 238 nm

Column: 4.6-mm x 5-cm; 1.8-µm packing L11

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection size: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of montelukast sodium (C₃₅H₃₅CINNaO₃S) in the portion of Montelukast Sodium taken:

                         Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) ×100

r_U = peak area from the Sample solution

r_S = peak area from the Standard solution

C_S = concentration of the Standard solution (mg/mL)

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

M_r1 = molecular weight of montelukast sodium, 608.17

M_r2 = molecular weight of montelukast dicyclohexylamine, 767.50 

Acceptance criteria: 98.0%-102.0% on the anhydrous and solvent-free basis

4 IMPURITIES

4.1 ORGANIC IMPURITIES

[NOTE-Avoid exposure of the samples to light. Use low-actinic glassware.]

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

Impurity solution: 1 mg/mL of USP Montelukast for Peak Identification RS in Diluent

System suitability solution: Transfer 1 mL of the Impurity solution to a colorless glass vial, and expose to ambient light for approximately 20 min to generate the cis-isomer of montelukast.

Sample solution: 1 mg/mL of Montelukast Sodium in Diluent

Sensitivity solution: 0.5 µg/mL of Montelukast Sodium in Diluent from the Sample solution

System suitability

Samples: System suitability solution and Sensitivity solution

Suitability requirements

Resolution: NLT 2.5 between the cis-isomer and montelukast; NLT 1.5 between montelukast and the methylketone impurity, System suitability solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Montelukast Sodium taken:

                         Result = (r_U/r_T) x 100

r_U = peak response of each impurity from the Sample solution

r_T = sum of all the peak responses from the Sample solution

Acceptance criteria: See Table 2.

Reporting level for impurities: 0.05%

Table 2

* These two impurities are not resolved by the method and need to be integrated together to determine conformance.

^a [1-[[[1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl)phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl sulfinyl]methyl]cyclopropyl acetic acid.

^b [1-[[[(1R)-1-[3-[(Z)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl sulfanyl]methyl]cyclopropyl acetic acid.

^c 1-[[[(1R)-1-[3-[(1R)-1-[[[1-(Carboxymethyl)cyclopropyl]methyl]sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl acetic acid.

^d 1-[[[(1R)-1-[3-[(1S)-1-[[[1-(Carboxymethyl)cyclopropyl]methyl]sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl)phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl acetic acid.

^e [1-[[[(1R)-3-(2-Acetylphenyl)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl]propyl sulfanyl]methyl]cyclopropyl acetic acid.

^f [1-[[[(1R)-1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-methylethenyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetic acid.

4.2 ENANTIOMERIC PURITY

[NOTE-Avoid exposure of the samples to light. Use low-actinic glassware.]

Solution A: 2.3 g/L of ammonium acetate in water. Adjust with glacial acetic acid to a pH of 5.7.

Solution B: Methanol and acetonitrile (60:40)

Mobile phase: See Table 3.

Table 3

Diluent: Acetonitrile and water (1:1)

System suitability solution: 0.1 mg/mL of USP Montelukast Racemate RS in Diluent

Sample solution: 1 mg/mL of Montelukast Sodium in Diluent

Sensitivity solution: 1 µg/mL of Montelukast Sodium in Diluent from the Sample solution

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.0-mm x 15-cm; 5-µm packing L41

Column temperature: 30°

Flow rate: 0.9 mL/min

Injection size: 10 µL

System suitability

Samples: System suitability solution and Sensitivity solution

[NOTE-The relative retention times are 1.0 for montelukast, which is the R-enantiomer, and 0.7 for the S-enantiomer.]

Suitability requirements

Resolution: NLT 2.9 between the S-enantiomer and montelukast, System suitability solution

Signal-to-noise ratio: NLT 10 for the montelukast peak, Sensitivity solution

Analysis

Sample: Sample solution

Calculate the percentage of S-enantiomer in the portion of Montelukast Sodium taken:

                         Result = (r_U/r_T) x 100

r_U = peak response of the S-enantiomer from the Sample solution

r_T = sum of the peak responses of the S-enantiomer and montelukast from the Sample solution

Acceptance criteria: NMT 0.2% of the S-enantiomer

5 SPECIFIC TESTS

WATER DETERMINATION, Method la(921): NMT 4.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers, protected from light. Store at room temperature.

USP REFERENCE STANDARDS (11)

USP Montelukast Sodium RS

USP Montelukast Dicyclohexylamine RS   C₃₅H₃₆CINO₃S · C₁₂H₂₃N          767.50

USP Montelukast Racernate RS

USP Montelukast for Peak Identification RS

(montelukast containing sulfoxide impurity, michael adducts 1 and 2, methylketone impurity, and methylstyrene impurity)