Almotriptan Malate

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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C₁₇H₂₅N₃O₂S · C₄H₆O₅ 469.55  

Pyrrolidine, 1-[[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]sulfonyl]-, hydroxybutanedioate (1:1); 

1-[({3-[2-(Dimethylamino)ethyl]indol-5-yl}methyl)sulfonyl]pyrrolidine malate (1:1) CAS RN®: 181183-52-8; UNII: PJP312605E. 

1 DEFINITION 

Almotriptan Malate contains NLT 98.0% and NMT 102.0% of almotriptan malate (C₁₇H₂₅N₃O₂S · C₄H₆O₅), calculated on the anhydrous and solvent-free basis. 

2 IDENTIFICATION

Change to read: 

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

Procedure

Buffer: 2.72 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.5.

Mobile phase: Methanol and Buffer (40:60)

System suitability solution: 0.14 mg/mL each of USP Almotriptan Malate RS and USP Almotriptan Related Compound B RS in Mobile phase. Sonication may be used to promote dissolution.

Standard solution: 0.14 mg/mL of USP Almotriptan Malate RS in Mobile phase. Sonication may be used to promote dissolution. Sample solution: 0.14 mg/mL of Almotriptan Malate in Mobile phase. Sonication may be used to promote dissolution. Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 15-cm; 5-µm packing L10

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: NLT 2 times the retention time of almotriptan

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for almotriptan related compound B and almotriptan are 0.7 and 1.0, respectively.] Suitability requirements

Resolution: NLT 2.0 between almotriptan and almotriptan related compound B, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 0.85% for six injections, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of almotriptan malate (C₁₇H₂₅N₃O₂S · C₄H₆O₅) in the portion of Almotriptan Malate taken:

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

r_U = peak response of almotriptan from the Sample solution

r_S = peak response of almotriptan from the Standard solution

C_S = concentration of USP Almotriptan Malate RS in the Standard solution (mg/mL)

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

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.10%

Limit of Almotriptan Related Compound D and Almotriptan N-Dimer

Run buffer: 23.5 g/L of phosphoric acid in water. Adjust with triethanolamine to a pH of 3.0 and pass through a suitable lter of 0.45-µm pore size.

Diluent: Methanol and water (50:50)

Internal standard solution: 0.01 mg/mL of 4-hydroxy-4-phenylpiperidine in Diluent

System suitability solution: 0.005 mg/mL each of USP Almotriptan Related Compound B RS, USP Almotriptan Related Compound D RS, and USP Almotriptan Malate RS in the Internal standard solution. Pass through a suitable lter of 0.45-µm pore size.

Standard stock solution: 0.5 mg/mL of USP Almotriptan Malate RS in Diluent

Standard solution: 0.005 mg/mL of USP Almotriptan Malate RS from the Standard stock solution in the Internal standard solution. Pass through a suitable lter of 0.45-µm pore size.

Sample solution: 2.5 mg/mL of Almotriptan Malate in the Internal standard solution. Sonication may be used to promote dissolution. Pass the solution through a suitable lter of 0.45-µm pore size.

Capillary rinsing procedure: Use separate Run buffer vials for the capillary rinse and sample analysis. Condition the capillary by rinsing with water, 0.1 N sodium hydroxide, water, and the Run buffer before each injection. [Note—It may be suitable to rinse with water, 0.1 N sodium hydroxide, and water using a pressure of 20 psi for NLT 2 min each and then to rinse with the Run buffer using a pressure of 20 psi for NLT 5 min.]

Instrumental conditions Mode: CE

Detector: UV 214 nm

Capillary, Capillary effective length, Capillary temperature, and Voltage: Use parameters described under A or B as indicated in Table 1.

Table 1

Injection sequence: 0.5 psi for 8 s for the Sample solution, followed by 0.5 psi for 1 s for the Run buffer

Run time: NLT 2.5 times the migration time of almotriptan

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for the relative migration times.]

Suitability requirements

Resolution: NLT 2.0 between almotriptan related compound B and almotriptan; NLT 2.0 between almotriptan and almotriptan related compound D, System suitability solution

Relative standard deviation: NMT 5.0% for the ratio of the peak response of almotriptan to the peak response of the internal standard, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the corrected peak response:

Result = (r/m)

r = peak response

m = migration time of the peak (min)

Calculate the percentage of almotriptan related compound D, almotriptan N-dimer, and other impurities in the portion of Almotriptan Malate taken:

Result = (R_U /R_S ) × (C_S /C_U ) × 100

R_U = corrected peak response ratio of the impurity to the internal standard from the Sample solution

R_S = corrected peak response ratio of almotriptan to the internal standard from the Standard solution

C_S = concentration of USP Almotriptan Malate RS in the Standard solution (mg/mL)

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

Acceptance criteria: See Table 2.

Table 2

^a 2-{1-({3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl}methyl)-5-[(pyrrolidin-1-ylsulfonyl)methyl]-1H-indol-3-yl}-N,N-dimethylethan-1-amine.

^b 4-Hydroxy-4-phenylpiperidine.

^c If present, this impurity may not be fully resolved from almotriptan. It is quantied using the test for Organic Impurities.

4.1 Organic Impurities

Buffer: Add 10 mL of triethylamine to every 1000 mL of 0.01 M phosphoric acid. Adjust with phosphoric acid to a pH of 6.5. Mobile phase: Acetonitrile and Buffer (15:85)

System suitability stock solution: 0.5 mg/mL each of USP Almotriptan Related Compound B RS, USP Almotriptan Related Compound C RS, and USP Almotriptan Related Compound D RS in methanol

System suitability solution: 0.005 mg/mL each of USP Almotriptan Related Compound B RS, USP Almotriptan Related Compound C RS, and USP Almotriptan Related Compound D RS from the System suitability stock solution in water

Standard solution: 0.007 mg/mL of USP Almotriptan Malate RS in water

Sample solution: 3.5 mg/mL of Almotriptan Malate in water. Sonication may be used to promote dissolution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 30-cm; 5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 3 times the retention time of almotriptan

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 3 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.0 between almotriptan related compound C and almotriptan related compound D, System suitability solution

Relative standard deviation: NMT 5.0% for six replicate injections, Standard solution

Analysis

Samples: System suitability solution, Standard solution, and Sample solution

Chromatograph the System suitability solution and identify the components on the basis of their relative retention times, as shown in Table 3.

Calculate the percentage of each impurity in the portion of Almotriptan Malate taken:

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

U S S U

r_U = peak response of each impurity from the Sample solution

r_S = peak response of almotriptan from the Standard solution

C_S = concentration of USP Almotriptan Malate RS in the Standard solution (mg/mL)

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

Acceptance criteria: See Table 3.

Table 3

^a This peak is due to the malate counterion; hence it is not an impurity. It is not to be reported or included in the total impurities.

^b This impurity is quantied using the Limit of Almotriptan Related Compound D and Almotriptan N-Dimer test.

^c The sum of all impurities from the test for Organic Impurities and the Limit of Almotriptan Related Compound D and Almotriptan N-Dimer test.

4.2 Limit of Fumaric Acid

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 2.8.

Mobile phase: Methanol and Buffer (5:95)

Standard solution: 0.0085 mg/mL of USP Fumaric Acid RS and 0.0017 mg/mL of USP Maleic Acid RS in water. Sonication may be used to promote dissolution.

Sample solution: 2.8 mg/mL of Almotriptan Malate in water. Sonication may be used to promote dissolution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 5-µm packing L7

Flow rate: 0.7 mL/min

Injection volume: 10 µL

Run time: NLT 1.6 times the retention time of fumaric acid

System suitability

Sample: Standard solution

[Note—See Table 4 for the relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between fumaric acid and maleic acid

Samples: Standard solution and Sample solution

Calculate the percentage of fumaric acid (C₄H₄O₄) in the portion of Almotriptan Malate taken:

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

r_U = peak response of fumaric acid from the Sample solution

r_S = peak response of fumaric acid from the Standard solution

C_S = concentration of USP Fumaric Acid RS in the Standard solution (mg/mL)

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

Table 4

^aIncluded for identication purposes only.

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I, Method Ia: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature.

USP Reference Standards 〈11〉

USP Almotriptan Malate RS

USP Almotriptan Related Compound B RS

2-{5-[(Pyrrolidin-1-ylsulfonyl)methyl]-1H-indol-3-yl}ethanamine hemifumarate.

C₁₅H₂₁N₃O₂S · ½C₄H₄O₄ 365.46

USP Almotriptan Related Compound C RS

N-Methyl-2-{5-[(pyrrolidin-1-ylsulfonyl)methyl]-1H-indol-3-yl}ethanamine.

C₁₆H₂₃N₃O₂S 321.44

USP Almotriptan Related Compound D RS

1-[({3-[2-(Dimethylamino)ethyl]indol-5-yl}methyl)sulfonyl]pyrrolidine N-oxide hydrochloride.

C₁₇H₂₅N₃O₃S · HCl 387.92

USP Fumaric Acid RS

USP Maleic Acid RS