Zolmitriptan Nasal Spray

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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1 DEFINITION

Zolmitriptan Nasal Spray is an aqueous solution of zolmitriptan, supplied in a form suitable for nasal administration. It contains NLT 90.0% and NMT 110.0% of the labeled amount of zolmitriptan (C₁₆H₂₁N₃O₂).

2 IDENTIFICATION

Change to read:

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

Standard: Add 300 μL of a solution of 2.5 mg/mL of USP Zolmitriptan RS in methylene chloride to about 200 mg of dried potassium bromide. Allow the mixture to dry. Grind the residue.

Sample: Add the contents of NLT 5 units of Nasal Spray to a container with 3 mL of 0.1 M sodium hydroxide. Extract into a sufficient volume of methylene chloride to obtain a final concentration of about 1.0–2.5 mg/mL of zolmitriptan in the extract. Dry the extract over anhydrous sodium sulfate. Add a suitable volume of the extract containing about 0.8 mg of zolmitriptan to about 200 mg of dried potassium bromide. Allow the mixture to dry. Grind the residue.

Acceptance criteria: Meets the requirements

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

Diluent: 0.02 M hydrochloric acid

Mobile phase: Acetonitrile and water (135:865). Add 1 mL of trifluoroacetic acid and 0.25 mL of triethylamine to each liter of the mixture.

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

Standard solution: 0.025 mg/mL of USP Zolmitriptan RS from Standard stock solution and Mobile phase

System suitability stock solution: 0.005 mg/mL each of USP Zolmitriptan Related Compound E RS and USP Zolmitriptan Related Compound G RS in Mobile phase

System suitability solution: Dilute 1 mL of System suitability stock solution with 9 mL of Standard solution.

Sample stock solution: Nominally 0.5 mg/mL of zolmitriptan prepared as follows. Discharge the contents of NLT 10 units of Nasal Spray to a suitable container. Transfer an amount of the composite solution containing about 5 mg of zolmitriptan to a 10-mL volumetric flask. Dilute with Diluent to volume.

Sample solution: Nominally 0.025 mg/mL of zolmitriptan from Sample stock solution in Mobile phase

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 15-cm; 3-μm packing L1

Column temperature: 40°

Flow rate: 1.6 mL/min

Injection volume: 20 μL

Run time: NLT 3 times the retention time of zolmitriptan

System suitability

Samples: Standard solution and System suitability solution

[Note - See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 4.0 between zolmitriptan and zolmitriptan related compound E, System suitability solution

Tailing factor: NMT 2.0 for zolmitriptan, Standard solution

Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of zolmitriptan (C₁₆H₂₁N₃O₂) in the portion of Nasal Spray taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

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

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Delivered Dose Uniformity

Diluent, Mobile phase, Standard solution, and System suitability solution: Prepare as directed in the Assay.

Sample solution: Nominally 0.025 mg/mL of zolmitriptan prepared as follows. Discharge the contents of a single unit into a suitable volumetric flask. Dilute with Mobile phase to volume.

Repeat this procedure with 9 additional units.

Chromatographic system and System suitability: Proceed as directed in the Assay.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of zolmitriptan in each dose of Nasal Spray taken:

Result = (r_U/r_S) × C_S × V × (1/L) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

V = volume of the Sample solution

L = label claim of zolmitriptan (mg/dose)

Acceptance criteria

Tier 1

1. The mean of 10 units is within 85.0%–115.0% of the labeled amount of zolmitriptan (C₁₆H₂₁N₃O₂).

2. NMT 1 dosage unit outside of 80%–120% of the labeled amount of zolmitriptan (C₁₆H₂₁N₃O₂)

3. None outside of 75%–125% of the labeled amount of zolmitriptan (C₁₆H₂₁N₃O₂) for 10 units

If criterion 2 in Tier 1 cannot be met, proceed to Tier 2.

Tier 2: Test an additional 20 units. All 30 results (including the results from Tier 1) meet the following acceptance criteria.

1. NMT 3 of the 30 dosage units outside of 80%–120% of the labeled amount of zolmitriptan (C₁₆H₂₁N₃O₂)

2. None of the 30 dosage units are outside of 75%–125% of the labeled amount of zolmitriptan (C₁₆H₂₁N₃O₂).

5 IMPURITIES

Organic Impurities

Diluent, Mobile phase, Standard solution, System suitability solution, and Sample stock solution: Prepare as directed in the Assay.

Sensitivity solution: 0.1 μg/mL of USP Zolmitriptan RS in Mobile phase from Standard solution

Sample solution: Nominally 0.1 mg/mL of zolmitriptan from Sample stock solution in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm × 15-cm; 3-μm packing L1

Column temperature: 40°

Flow rate: 1.6 mL/min

Injection volume: 20 μL

Run time: NLT 8 times the retention time of zolmitriptan

System suitability

Samples: System suitability solution and Sensitivity solution

[Note - See Table 1 for the relative retention times.]

Suitability requirements

Resolution: NLT 4.0 between zolmitriptan and zolmitriptan related compound E, System suitability solution

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

Analysis

Sample: Sample solution

Calculate the percentage of each degradation product in the portion of Nasal Spray taken:

Result = (r_I/r_U) × 100

r_I = peak response of each degradation product from the Sample solution

r_U = peak response of zolmitriptan from the Sample solution

Acceptance criteria: See Table 1. The reporting threshold is 0.1%.

Table 1

^a Process impurity; included for peak identification and/or resolution check only; controlled in the drug substance. Not to be included in total degradation products.

^b(4S)-4-({3-[2-(Dimethylamino)ethyl]-3-hydroxy-2-oxoindolin-5-yl}methyl)oxazolidin-2-one.

^c 3a-Hydroxy-1,1-dimethyl-5-{[(S)-2-oxooxazolidin-4-yl]methyl}-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-1-ium; may also be known as (4S)-4-[(8b-Hydroxy-3,3-dimethyl-1,2,3a,4-tetrahydropyrrolo[2,3-b]indol-3-ium-7-yl)methyl]oxazolidin-2-one.

^d(S)-N-(Hydroxymethyl)-N,N-dimethyl-2-{5-[(2-oxooxazolidin-4-yl)methyl]-1H-indol-3-yl}ethan-1-aminium; may also be known as (4S)-4-[[3-(2-Dimethylaminoethyl)-1-(hydroxymethyl)indol-5-yl]methyl]oxazolidin-2-one.

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

^f (S)-4-({3-[2-(Dimethylamino)ethyl]-1-[(3-[2-(dimethylamino)ethyl]-5-{[(S)-2-oxooxazolidin-4-yl]methyl}-1H-indol-2-yl)methyl]-1H-indol-5-yl}methyl)oxazolidin-2-one.

6 SPECIFIC TESTS

pH 〈791〉: 4.7–5.3

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉

Total aerobic viable count: ≤102 cfu/mL

Total combined yeasts and molds count: ≤101 cfu/mL

Bile-tolerant Gram-negative bacteria per mL: NMT 10

Tests for the absence of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli: Meets the requirements

7 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in a tight, light-resistant container. Store at controlled room temperature.

USP Reference Standards 〈11〉

USP Zolmitriptan RS

USP Zolmitriptan Related Compound E RS

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

C₁₆H₂₁N₃O₂ 303.36

USP Zolmitriptan Related Compound G RS

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

C₁₀H₁₂N₂O₂ 192.21