Zolmitriptan

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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C₁₆H₂₁N₃O₂ 287.36

2-Oxazolidinone, 4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-, (S)-;

(S)-4-({3-[2-(Dimethylamino)ethyl]indol-5-yl}methyl)oxazolidin-2-one;

(S)-4-[[3-[2-(Dimethylamino)ethyl]indol-5-yl]methyl]-2-oxazolidinone CAS RN^®: 139264-17-8; UNII: 2FS66TH3YW.

1 DEFINITION

Zolmitriptan contains NLT 97.0% and NMT 102.0% of zolmitriptan (C₁₆H₂₁N₃O₂), 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 migration time of the major peak of the Sample solution corresponds to that of the System suitability solution, as obtained in the test for Limit of Zolmitriptan R-Isomer and Other Impurities.

3 ASSAY

Change to read:

3.1 PROCEDURE

Mobile phase: Acetonitrile and water (135:865). For every liter of the mixture add 1 mL of trifluoroacetic acid and 0.25 mL of triethylamine.

System suitability solution: 0.12 µg/mL of USP Zolmitriptan Related Compound E RS and 25 µg/mL of USP Zolmitriptan RS in Mobile phase

Standard solution: 0.025 mg/mL of USP Zolmitriptan RS in Mobile phase

Sample solution: 0.025 mg/mL of Zolmitriptan in Mobile phase

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.0-mm x 12.5-cm; 5-µm packing 11

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLTA (IRA 1-May-2020) 3 times the retention time of zolmitriptan

3.3 System suitability

Sample: System suitability solution

[NOTE-The relative retention times for zolmitriptan and zolmitriptan related compound E are 1.0 and 1.6, respectively.]

Suitability requirements

Resolution: NLT 5 between zolmitriptan and zolmitriptan related compound E

Tailing factor: NMT 2.0 for zolmitriptan

Relative standard deviation: NMT 0.73% (IRA 1-May-2020)

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of zolmitriptan (C₁₆H₂₁N₃O₂) in the portion of Zolmitriptan taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of zolmitriptan (IRA 1-May-2020) from the Sample solution

r_S = peak response of zolmitriptan (IRA 1-May-2020) from the Standard solution

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

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

Acceptance criteria: 97.0%-102.0% on the anhydrous and solvent-free basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

4.2 LIMIT OF ZOLMITRIPTAN RELATED COMPOUND H

Perform this test only if zolmitriptan related compound H is a known process impurity. If this test is performed, then this is to be included in total impurities.

Standard solution: 0.1 mg/mL of USP Zolmitriptan Related Compound H RS in methanol

Sample solution: 200 mg/mL of Zolmitriptan in methanol

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.32-mm x 15-m; 1-µm coating of dimethylpolysiloxane phase G1

Temperatures

Injection port: 200°

Column: 130°

Detector: 250°

Carrier gas: Helium at 6 mL/min

Injection volume: 3 µL

Injection type: Split, split ratio 10:1

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of zolmitriptan related compound H in the portion of Zolmitriptan taken:

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

r_U = peak response of zolmitriptan related compound H from the Sample solution

r_S = peak response of zolmitriptan related compound H from the Standard solution

C_S = concentration of USP Zolmitriptan Related Compound H.RS in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 0.1% of zolmitriptan related compound H

Change to read:

4.3 LIMIT OF ZOLMITRIPTAN R-ISOMER AND OTHER IMPURITIES

Buffer: 19.1 g/L of sodium borate decahydrate in water. Adjust with phosphoric acid to a pH of 2.2.

Run buffer: 50 mg/mL of hydroxypropyl-B-cyclodextrin in Buffer

Diluent: 0.02 M hydrochloric acid

Internal standard solution: 0.05 mg/mL of tryptamine hydrochloride in Diluent

System suitability solution: 0.01 mg/mL of tryptamine hydrochloride from the Internal standard solution; 1 mg/mL of USP Zolmitriptan RS; and 0.01 mg/mL each of USP Zolmitriptan Related Compound F RS, USP Zolmitriptan Related Compound G RS, and USP Zolmitriptan R-Isomer RS in Diluent

Standard solution: 0.01 mg/mL of tryptamine hydrochloride from Internal standard solution and 0.001 mg/mL of USP Zolmitriptan RS in Diluent

Sample solution: 0.01 mg/mL of tryptamine hydrochloride from Internal standard solution and 1 mg/mL of Zolmitriptan in Diluent. Filter the solution and protect from light.

Capillary rinsing procedure: Use separate Run buffer vials for the capillary rinse and sample analysis. Condition the capillary by rinsing with 0.1 N sodium hydroxide followed by Run buffer before each injection. [NOTE-It may be suitable to rinse with 0.1 N sodium hydroxide using a pressure of 20 psi for NLT 1 min and then to rinse with Run buffer using a pressure of 20 psi for NLT 3 min.]

Electrophoretic system

Mode: CE

Detector: UV 200 nm

Column: 75-µm (ID) x 50-cm effective length, 60-cm total-length capillary uncoated fused-silica

Capillary temperature: 25°

Injection pressure: 0.5 psi for 5 s

Applied voltage: 15 kV

Run time: NLT 1.5 times the migration time of zolmitriptan

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative migration time for tryptamine is 0.78; (IRA 1-May-2020) see Table 1 for the other (IRA 1-May-2020) relative migration times.]

Suitability requirements

Resolution: NLT 1.5 between zolmitriptan and zolmitriptan R-isomer, (IRA 1-May-2020) System suitability solution

Relative standard deviation: NMT 15% (IRA 1-May-2020) for the peak response ratio of zolmitriptan and tryptamine, (IRA 1-May-2020) Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the corrected peak responses:

Result = r/m

r = peak response

m = migration time of the peak (min)

Calculate the percentage of each impurity in the portion of Zolmitriptan taken:

Result = (R_U/R_S) x (C_S/C_U) x (1/F) × 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 zolmitriptan to the internal standard from the Standard solution

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

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

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. Disregard the peak due to zolmitriptan related compound E. The reporting threshold is 0.10%.

Table 1

Change to read:

4.4 ORGANIC IMPURITIES

Mobile phase: Acetonitrile and water (135:865). For every liter of the mixture add 1 mL of trifluoroacetic acid and 0.25 mL of triethylamine.

System suitability solution: 0.5 µg/mL of USP Zolmitriptan Related Compound E RS and 0.1 mg/mL of USP Zolmitriptan RS in Mobile phase

Sample solution: 0.1 mg/mL of Zolmitriptan in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.0-mm x 12.5-cm; 5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 6 times the retention time of zolmitriptan

System suitability

Sample: System suitability solution

[NOTE-See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 5 between zolmitriptan and zolmitriptan related compound E (IRA 1-May-2020)

Tailing factor: NMT 3.0 for zolmitriptan

Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Zolmitriptan taken:

Result = (r_U/r_T) x 100

r_U = peak response of each impurity from the Sample solution

r_T = sum of the peak responses from the Sample solution

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

^a (S)-2-Amino-3-{3-[2-(dimethylamino)ethyl]-1H-indol-5-yl}propan-1-ol.

^b Included for identification purposes only. Not reported here as it is monitored under the Limit of Zolmitriptan R-Isomer and Other Impurities test. Not to be included in total impurities.

^c Includes all impurities except zolmitriptan related compound F. Also includes zolmitriptan related compound H from the test for Limit of Zolmitriptan Related Compound H if it is a known process impurity, as well as impurities from the test for Limit of Zolmitriptan R-Isomer and Other Impurities with the exception of zolmitriptan related compound F.

5 SPECIFIC TESTS

WATER DETERMINATION (921), Method I, Method la: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in well-closed containers. Store at room temperature.

Change to read:

6.2 USP REFERENCE STANDARDS (11)

USP Zolmitriptan RS

USP Zolmitriptan R-Isomer RS

(R)-4-({3-[2-(Dimethylamino)ethyl]indol-5-yl}methyl)oxazolidin-2-one;

Also known as (IRA 1-May-2020) (R)-4-[[3-[2-(Dimethylamino) ethyl]indol-5-yl]methyl]-2-oxazolidinone.

C₁₆H₂₁N₃O₂ 287.36

USP Zolmitriptan Related Compound E RS

(S)-N,N-Dimethyl-2-{5-[(2-oxooxazolidin-4-yl)methyl]-1H-indol-3-yl}ethanamine oxide.

C₁₆H₂₁N₃O₃ 303.36

USP Zolmitriptan Related Compound F RS

2,2'-[4-(Dimethylamino)butane-1,1-diyl]bis{5-[(S)-(2-oxooxazolidin-4-yl)methyl]-3-(2-dimethylaminoethyl)indole}.

C₃₈H₅₃N₇O₄ 671.89 (IRA 1-May-2020)

USP Zolmitriptan Related Compound G RS

(S)-4-(4-Aminobenzyl)oxazolidin-2-one.

C₁₀H₁₂N₂O₂ 192.22 (IRA 1-May-2020)

USP Zolmitriptan Related Compound H RS

4,4-Diethoxy-N,N-dimethylbutan-1-amine.

C₁₀H₂₃NO₂ 189.30