Quetiapine Fumarate

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

Quetiapine Fumarate contains NLT 98.0% and NMT 102.0% of quetiapine fumarate [(C₂₁H₂₅N₃O₂S) · C₄H₄O₄], calculated on the dried basis.

2 IDENTIFICATION

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

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: 2.6 g/L of dibasic ammonium phosphate. Adjust with phosphoric acid to a pH of 6.5.

Mobile phase: Methanol, acetonitrile, and Buffer (54:7:39)

System suitability solution: 1.0 mg/mL of USP Quetiapine System Suitability RS in Mobile phase

Standard stock solution: 0.16 mg/mL of USP Quetiapine Fumarate RS in Mobile phase

Standard solution: 0.08 mg/mL of USP Quetiapine Fumarate RS from Standard stock solution in Mobile phase

Sample stock solution: 0.16 mg/mL of Quetiapine Fumarate in Mobile phase

Sample solution: 0.08 mg/mL of Quetiapine Fumarate from Sample stock solution in Mobile phase

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

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

Flow rate: 1.3 mL/min

Injection volume: 50 µL

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for quetiapine desethoxy and quetiapine are about 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.5 between the quetiapine desethoxy and quetiapine peaks, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of quetiapine fumarate [(C₂₁H₂₅N₃O₂S) · C₄H₄O₄] in the portion of Quetiapine Fumarate taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from the Standard solution

Cₛ = concentration of USP Quetiapine Fumarate RS in the Standard solution (mg/mL)

Cᵤ = concentration of Quetiapine Fumarate in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the dried basis

4 IMPURITIES

 Residue on Ignition 〈281〉:

NMT 0.1%

Change to read:

Organic Impurities

Buffer: 3.1 g/L of ammonium acetate in water. Add 2 mL of 25% ammonium hydroxide to each 1 L of solution.

The pH of the resulting solution is NLT 9.2.

Solution A: Acetonitrile and Buffer (25:75)

Solution B: Acetonitrile

Diluent: Solution A and Solution B (86:14)

Mobile phase: See Table 1.

Peak identification solution:

1 µg/mL of USP Quetiapine Fumarate RS,

10 µg/mL of USP Quetiapine Related Compound B RS,

2 µg/mL of USP Quetiapine Related Compound G RS in Diluent

System suitability solution: 1 mg/mL of USP Quetiapine System Suitability RS in Diluent

Standard solution: 0.001 mg/mL of USP Quetiapine Fumarate RS in Diluent

Sample solution: 1.0 mg/mL of Quetiapine Fumarate in Solution A

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 250 nm

Column: 4.6-mm × 15-cm; 3.5-µm packing L7

Column temperature: 45°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Samples: Peak identification solution, System suitability solution, and Standard solution

[Note—See Table 2 for relative retention times.

Quetiapine related compound B will be the largest peak in the Peak identification solution chromatogram.]

Suitability requirements

• Resolution:

– NLT 4.0 between the quetiapine desethoxy and quetiapine peaks, System suitability solution

– NLT 3.0 between quetiapine related compound B and quetiapine related compound G, System suitability solution

• Tailing factor: NMT 2.0, Standard solution

• Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Quetiapine Fumarate taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1 / F) × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of quetiapine from the Standard solution

Cₛ = concentration of USP Quetiapine Fumarate RS in the Standard solution (mg/mL)

Cᵤ = concentration of Quetiapine Fumarate in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria:

See Table 2.

Disregard peaks below 0.05% or with retention times less than 2 min.

Footnotes:

ᵃ Peak due to counter ion, included for peak identification purposes. Not to be included in total impurities.

ᵇ Process impurity specific to manufacturing process.

ᶜ 4-(Dibenzo[b,f][1,4]thiazepin-11-yl)-1,1-bis[2-(2-hydroxyethoxy)ethyl]piperazin-1-ium.

ᵈ 2-[4-(Dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl]ethanol.

ᵉ ▲2-[2-(2-{2-[4-(Dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl]ethoxy}ethoxy)ethoxy]ethan-1-ol.▲ (CN 1-Dec-2024)

ᶠ 11-(4-Ethylpiperazin-1-yl)dibenzo[b,f][1,4]thiazepine.

ᵍ 1,4-Bis(dibenzo[b,f][1,4]thiazepin-11-yl)piperazine.

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° to constant weight.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage:

Preserve in well-closed containers, protected from light.

Change to read:

USP Reference Standards 〈11〉

USP Quetiapine Fumarate RS

USP Quetiapine Related Compound B RS

▲11-(Piperazin-1-yl)dibenzo[b,f][1,4]thiazepine dihydrochloride.

C₁₇H₁₇N₃S · 2HCl 368.32▲ (CN 1-Dec-2024)

USP Quetiapine Related Compound G RS

Dibenzo[b,f][1,4]thiazepin-11(10H)-one.

C₁₃H₉NOS 227.28

USP Quetiapine System Suitability RS

It contains quetiapine fumarate and NLT 0.1% of each of the following impurities:

Quetiapine related compound B: 11-(Piperazin-1-yl)dibenzo[b,f][1,4]thiazepine

Quetiapine related compound G: Dibenzo[b,f][1,4]thiazepin-11(10H)-one

Quetiapine desethoxy: 2-[4-(Dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl]ethanol