Quetiapine Extended-Release Tablets

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 Extended-Release Tablets contain quetiapine fumarate [(C₂₁H₂₅N₃O₂S) · C₄H₄O₄] equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S).

2 IDENTIFICATION

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

Standard solution:

Transfer 10 mg of USP Quetiapine Fumarate RS to a suitable vial. Add 10 mL of acetone and cap the vial. Sonicate for about 10 min. Allow the solution to equilibrate to room temperature. Evaporate the acetone completely. Add 2 mL of chloroform. Gently swirl for several minutes. Pass through a suitable filter of 0.45-µm pore size. Use the filtrate.

Sample solution:

Grind NLT 10 Tablets. Transfer an amount of powder equivalent to NLT 10 mg of quetiapine fumarate to a suitable vial. Add 10 mL of acetone and cap the vial. Sonicate for about 10 min. Allow the solution to equilibrate to room temperature. Evaporate the acetone completely. Add 2 mL of chloroform. Gently swirl for several minutes. Pass through a suitable filter of 0.45-µm pore size. Use the filtrate.

Acceptance criteria: Meet 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

Buffer:

Dissolve 2.6 g/L of dibasic ammonium phosphate in water.

Mobile phase:

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

Diluent:

Acetonitrile and water (50:50)

System suitability stock solution:

0.05 mg/mL of USP Quetiapine Related Compound H RS in Mobile phase

System suitability solution:

0.005 mg/mL of USP Quetiapine Related Compound H RS and 0.5 mg/mL of USP Quetiapine System Suitability RS in Mobile phase prepared as follows. Transfer 5 mg of USP Quetiapine System Suitability RS to a 10-mL volumetric flask. Add 7 mL of Mobile phase and sonicate to dissolve. Transfer 1 mL of System suitability stock solution to the volumetric flask. Dilute with Mobile phase to volume.

Standard solution:

0.2 mg/mL of USP Quetiapine Fumarate RS in Mobile phase

Sample stock solution:

Transfer NLT 5 Tablets to a homogenizer vessel. Add 50 mL of acetonitrile, swirl to wet, and allow to stand for approximately 10 min. Add an additional 160 mL of Diluent and extract for about 10 min. Transfer the contents of the homogenizer to a 500-mL volumetric flask. Dilute with Diluent to volume. Pass a portion of the solution through a suitable filter of 0.45-µm pore size and use the filtrate.

Sample solution:

Nominally 0.16–0.18 mg/mL of quetiapine from the 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: 30 µL

Run time: NLT 2.5 times the retention time of quetiapine

System suitability

Samples: System suitability solution and Standard solution

[Note—See ▲Table 14▲ (RB 1-Dec-2024) for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between quetiapine related compound G and quetiapine related compound H; NLT 2.0 between the quetiapine desethoxy and quetiapine peaks; System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) in the portion of Tablets taken:

Result = (r₁/r₂) × (Cₛ/Cᵤ) × (Mᵤ/Mₛ) × N × 100

where

r₁ = peak response from the Sample solution

r₂ = peak response from the Standard solution

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

Cᵤ = nominal concentration of quetiapine in the Sample solution (mg/mL)

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

 Dissolution 〈711〉

Test 1

Medium 1:

Citrate buffer, pH 4.8. Dissolve 9.6 g of anhydrous citric acid in 600 mL of water. Add 90 mL of 1 N sodium hydroxide. Dilute with water to 1 L; 900 mL.

Medium 2:

Dissolve 17.9 g of dibasic sodium phosphate dodecahydrate in 400 mL of water. Add 460 mL of 1 N sodium hydroxide VS and dilute with water to 1 L; 100 mL.

[Note—It is recommended to check the pH of the mixture of 90 mL of Medium 1 and 10 mL of Medium 2, which should be between 6.4 and 6.8. If the pH of the mixture is less than 6.4, 10 mL/L of 1 N sodium hydroxide VS may be added to Medium 2. If the pH of the mixture is greater than 6.8, 10 mL/L of 1 N hydrochloric acid VS may be added to Medium 2.]

Start the test with 900 mL of Medium 1. Add 100 mL of Medium 2 to the vessel after 5 h of the test and continue the test.

Apparatus 1: 200 rpm

Times: 1, 6, 12, and 20 h

Diluent:

Medium 1 and Medium 2 (90:10)

Standard solution:

(L/400) mg/mL of USP Quetiapine Fumarate RS in Diluent, where L is the label claim in mg/Tablet

Sample solution:

Pass a suitable portion of the solution under test through a suitable filter.

Instrumental conditions

Mode: UV

Analytical wavelength: About 290 nm

Blank: Diluent

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration, Cᵢ, of quetiapine (C₂₁H₂₅N₃O₂S) in Medium (mg/mL) after time point (i):

Cᵢ = (Aᵤ/Aₛ) × Cₛ × (Mᵤ/Mₛ) × N

where

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

Cₛ = concentration of quetiapine fumarate in the Standard solution (mg/mL)

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

For the 1-h time point:

Result₁ = C₁ × V₁ × (1/L) × 100

For the 6-h time point:

Result₂ = [(C₂ × V₁) + (C₁ × Vₛ)] × (1/L) × 100

For the 12-h time point:

Result₃ = {(C₃ × V₁) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

For the 20-h time point:

Result₄ = {(C₄ × V₁) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in Medium in the portion of sample withdrawn at each time point (mg/mL)

V₁ = volume of Medium, 900 mL for 1 h; 1000 mL for 6-, 12-, and 20-h time points

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 2

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium:

Water; 900 mL

Apparatus 1: 100 rpm

Times: 2, 4, 8, and 24 h

Standard solution:

0.03 mg/mL of USP Quetiapine Fumarate RS in water

Sample solution:

Pass a suitable portion of the solution under test through a suitable filter of 0.45-µm pore size. Discard the first few milliliters of filtrate. Replace the volume withdrawn with an equal volume of Medium. Dilute with Medium to a concentration that is similar to that of the Standard solution.

Instrumental conditions

Mode: UV

Analytical wavelength: 290 nm

Blank: Water

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration, Cᵢ, of quetiapine (C₂₁H₂₅N₃O₂S) in Medium (mg/mL) after each time point (i):

Cᵢ = (Aᵤ/Aₛ) × Cₛ × D × (Mᵤ/Mₛ) × N

where

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

Cₛ = concentration of quetiapine fumarate in the Standard solution (mg/mL)

D = dilution factor for the Sample solution, if needed

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in Medium in the portion of sample withdrawn at each time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 3

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium:

0.1 N hydrochloric acid VS; 900 mL

Apparatus 2: 50 rpm

Times: 1, 4, and 8 h

Standard solution:

USP Quetiapine Fumarate RS, equivalent to (L/900) mg/mL of quetiapine in Medium, where L is the label claim in mg/Tablet

Sample solution:

Pass a suitable portion of the solution under test through a suitable full-flow filter of 10-µm pore size.

Instrumental conditions

Mode: UV

Analytical wavelength: 295 nm

Cell:

For 50-mg Tablets: 10 mm

For 150-, 200-, 300-, and 400-mg Tablets: 1 mm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result = (Aᵤ/Aₛ) × Cₛ × V × (1/L) × (Mᵤ/Mₛ) × N × 100

where

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

Cₛ = concentration of quetiapine fumarate in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 4

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium:

Water; 900 mL

Apparatus 2: 100 rpm

Times: 1, 4, 8, and 16 h

Standard solution:

USP Quetiapine Fumarate RS, equivalent to (L/900) mg/mL of quetiapine in Medium, where L is the label claim in mg/Tablet

Sample solution:

Pass a suitable portion of the solution under test through a suitable filter.

Instrumental conditions

Mode: UV

Analytical wavelength: 250 nm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result = (Aᵤ/Aₛ) × Cₛ × V × (1/L) × (Mᵤ/Mₛ) × N × 100

where

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

Cₛ = concentration of quetiapine fumarate in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Tolerances: See Table 4. The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Table 4

Test 5

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.

Medium, Apparatus 1, Times, Standard solution, Sample solution, Instrumental conditions, and Analysis:

Proceed as directed in Dissolution Test 2.

Tolerances: See Table 5.

Table 5

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 6

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.

Medium:

pH 6.8 phosphate buffer (6.8 g/L of monobasic potassium phosphate and 0.9 g/L of sodium hydroxide in water. Adjust with 1 N sodium hydroxide VS or phosphoric acid to a pH of 6.8, and sonicate for NLT 10 min); 900 mL

Apparatus 2: 100 rpm, with sinker

Times: 1, 4, 8, and 16 h

Mobile phase:

Methanol, trifluoroacetic acid, and water (40:0.1:60)

Standard solution:

0.1 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Transfer an appropriate amount of USP Quetiapine Fumarate RS to a suitable volumetric flask, and add 5% of the final flask volume of methanol. Sonicate to dissolve, then dilute with Medium to volume.

Sample solution:

Pass a suitable portion of the solution under test through a suitable filter of 0.45-µm pore size. Discard the first few milliliters of filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm × 5.0-cm; 5-µm packing L1

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 10 µL

Run time: NLT 2.0 times the retention time of quetiapine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 3.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration, Cᵢ, of quetiapine (C₂₁H₂₅N₃O₂S) in Medium (mg/mL) after each time point (i):

Cᵢ = (rᵤ/rₛ) × Cₛ × (Mᵤ/Mₛ) × N

where

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)

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − Vₛ)] + (C₁ × Vₛ)} × (1/L) × 100

Result₃ = {C₃ × [V − (2 × Vₛ)] + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {C₄ × [V − (3 × Vₛ)] + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in Medium in the portion of sample withdrawn at each time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn from the Medium (mL)

Tolerances: See Table 6.

Table 6

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 7

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.

Acid stage medium:

Citrate buffer, pH 4.8 (9.6 g/L of anhydrous citric acid in water prepared as follows. Transfer a suitable quantity of anhydrous citric acid to an appropriate volumetric flask. Dissolve in 60% of the flask volume of water, then add 9% of the flask volume of 1 N sodium hydroxide VS. Dilute with water to volume); 900 mL, deaerated.

0.05 M phosphate buffer solution:

17.9 g/L of dibasic sodium phosphate dodecahydrate solution prepared as follows. Transfer a suitable amount of dibasic sodium phosphate dodecahydrate to an appropriate volumetric flask containing 40% of the flask volume of water. Add 46% of the flask volume of 1 N sodium hydroxide VS and dilute with water to volume.

Buffer stage medium:

Phosphate buffer, pH 6.6 (add 100 mL of 0.05 M phosphate buffer solution to the Acid stage medium; adjust with 1 N sodium hydroxide VS or 1 N hydrochloric acid VS to obtain a pH of 6.6 ± 0.20, if necessary); 1000 mL

Apparatus 1: 20-mesh basket; 200 rpm

Times: 1 and 4 h in Acid stage medium; 6, 10, and 16 h in Buffer stage medium. The time in the Buffer stage medium includes the time in the Acid stage medium.

Procedure:

Run the test in the Acid stage medium for the times specified. After 5 h, add 100 mL of 0.05 M phosphate buffer solution and continue running the test in Buffer stage medium for the times specified.

Standard stock solution:

1.2 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Transfer an appropriate amount of USP Quetiapine Fumarate RS into a suitable volumetric flask. Add 40% of the flask volume of methanol and sonicate to dissolve. Dilute with water to volume.

Acid stage standard solution:

0.03 mg/mL of USP Quetiapine Fumarate RS from Standard stock solution in Acid stage medium

Buffer stage standard solution:

0.03 mg/mL of USP Quetiapine Fumarate RS from Standard stock solution in Buffer stage medium

Acid stage sample solution:

Pass a portion of the solution under test through a suitable filter, discarding the first portion of filtrate if needed. Dilute the filtrate further with Acid stage medium, if needed. Replace the portion of solution removed from the vessel with an equivalent volume of warmed Acid stage medium.

Buffer stage sample solution:

Pass a portion of the solution under test through a suitable filter, discarding the first portion of filtrate if needed. Dilute the filtrate further with Buffer stage medium, if needed. Replace the portion of solution removed from the vessel with an equivalent volume of warmed Buffer stage medium.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 290 nm

Blank: Acid stage medium or Buffer stage medium

System suitability

Samples: Acid stage standard solution and Buffer stage standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%, Acid stage standard solution and Buffer stage standard solution

Analysis

Samples: Acid stage standard solution and Acid stage sample solution or Buffer stage standard solution and Buffer stage sample solution

Calculate the concentration (Cᵢ) of quetiapine (C₂₁H₂₅N₃O₂S) in the sample withdrawn from the vessel at each time point (i):

Cᵢ = (Aᵤ/Aₛ) × Cₛ × D × (Mᵤ/Mₛ) × N

where

Aᵤ = absorbance of the Acid stage sample solution or Buffer stage sample solution

Aₛ = absorbance of the Acid stage standard solution or Buffer stage standard solution, corresponding to the related sample solution

Cₛ = concentration of quetiapine fumarate in Acid stage standard solution or Buffer stage standard solution (mg/mL)

D = dilution factor for the Acid stage sample solution or Buffer stage sample solution, if needed

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × Vₐ × (1/L) × 100

Result₂ = [(C₂ × Vₐ) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × Vₐ) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {(C₄ × Vₐ) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₅ = {(C₅ × Vₐ) + [(C₄ + C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in Acid stage medium or Buffer stage medium in the portion of sample withdrawn at each time point (mg/mL)

Vₐ = volume of Acid stage medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Acid stage sample solution or Buffer stage sample solution withdrawn from the vessel and replaced with Acid stage medium or Buffer stage medium, respectively (mL)

Vᵦ = volume of Buffer stage medium, 1000 mL

Tolerances: See Table 7.

Table 7

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

▲Test 9: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 9.

Acid stage medium:

Citrate buffer, pH 4.8 (9.6 g/L of anhydrous citric acid prepared as follows. Transfer an appropriate quantity of anhydrous citric acid to a suitable volumetric flask and add 60% of the flask volume of water and dissolve. Then add 9% of the flask volume of 1 N sodium hydroxide VS, and dilute with water to volume. Adjust with 1 N sodium hydroxide VS to obtain a pH of 4.8, if necessary.); 900 mL

0.05 M phosphate buffer solution:

17.9 g/L of dibasic sodium phosphate dodecahydrate prepared as follows. Transfer an appropriate quantity of dibasic sodium phosphate dodecahydrate to a suitable volumetric flask and add 40% of the flask volume of water and dissolve and then add 46% of the flask volume of 1 N sodium hydroxide VS. Dilute with water to volume.

Buffer stage medium:

Phosphate buffer, pH 6.6 (Add 100 mL of 0.05 M phosphate buffer solution to Acid stage medium. Adjust with either 1 N hydrochloric acid VS or 1 N sodium hydroxide VS to obtain a pH of 6.6, if necessary.); 1000 mL

Apparatus 1: 20-mesh basket; 200 rpm

Times: 1 h in Acid stage medium; 6, 12, and 20 h in Buffer stage medium. The time in Buffer stage medium includes the time in Acid stage medium.

Procedure:

Run the test in the Acid stage medium for the times specified. After 5 h, add 100 mL of 0.05 M phosphate buffer solution and continue running the test in Buffer stage medium for the times specified.

Buffer:

To each liter of water, add 8 mL of triethylamine, and adjust with glacial acetic acid to a pH of 4.5.

Mobile phase:

Acetonitrile and Buffer (35:65)

Diluent:

Acetonitrile and water (5:95)

Standard stock solution:

0.75 mg/mL of USP Quetiapine Fumarate RS in Diluent. Sonicate to dissolve.

Standard solution:

(L/900) mg/mL of quetiapine from the Standard stock solution in Buffer stage medium, where L is the label claim of quetiapine in mg/Tablet

Acid stage sample solution:

Pass a portion of the solution under test through a suitable filter.

Buffer stage sample solution:

Pass a portion of the solution under test through a suitable filter.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 292 nm

Column: 4.6-mm × 15.0-cm; 5.0-µm packing L1

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume

For 50-mg Tablets: 20 µL

For 150-, 200-, 300-, and 400-mg Tablets: 10 µL

Run time: NLT 1.7 times the retention time of quetiapine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: 0.8–1.8

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution, Acid stage sample solution, and Buffer stage sample solution

Calculate the concentration (Cᵢ) of quetiapine (C₂₁H₂₅N₃O₂S) in the sample withdrawn from the vessel at each time point (i):

Cᵢ = (rᵤ/rₛ) × Cₛ × (Mᵤ/Mₛ) × N

where

rᵤ = peak response of quetiapine from the Acid stage sample solution or Buffer stage sample solution

rₛ = peak response of quetiapine from the Standard solution

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

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × Vₐ × (1/L) × 100

Result₂ = {[C₂ × (Vᵦ − Vₛ)] + (C₁ × Vₛ)} × (1/L) × 100

Result₃ = {(C₃ × Vᵦ) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {(C₄ × Vᵦ) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in Acid stage medium or Buffer stage medium in the portion of sample withdrawn at each time point (mg/mL)

Vₐ = volume of Acid stage medium, 900 mL

L = label claim (mg/Tablet)

Vᵦ = volume of Buffer stage medium, 1000 mL

Vₛ = volume of the Acid stage sample solution or Buffer stage sample solution withdrawn from the vessel (mL)

Tolerances: See Table 8.

Table 8

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2. ▲(RB 1-Dec-2024)

Test 10

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 10.

Medium:

3.72 g/L potassium chloride in water. Adjust with hydrochloric acid to a pH of 1.2; 900 mL

Apparatus 1: 100 rpm

Times: 1, 4, and 12 h

Standard solution:

0.016 mg/mL of USP Quetiapine Fumarate RS in Medium

Sample solution:

Pass a suitable portion of the solution under test through a suitable filter of 0.45-µm pore size. Discard the first few milliliters of filtrate. Replace the volume withdrawn with an equal volume of Medium. Dilute with Medium, if necessary.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 254 nm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ) of quetiapine (C₂₁H₂₅N₃O₂S) in the sample withdrawn from the vessel at each time point (i):

Cᵢ = (Aᵤ/Aₛ) × Cₛ × D × (Mᵤ/Mₛ) × N

where

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

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

D = dilution factor for the Sample solution, if needed

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in the portion of sample withdrawn at time point (i) (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn from the vessel and replaced with Medium (mL)

Tolerances: See ▲Table 9.

Table 9▲ (RB 1-Dec-2024)

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 11

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 11.

Medium:

0.1 N hydrochloric acid VS; 900 mL

Apparatus 2: 50 rpm

Times: 1, 4, 8, and 16 h

Standard stock solution:

1.5 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Transfer a suitable amount of USP Quetiapine Fumarate RS into an appropriate volumetric flask and add 20% of the flask volume of methanol to dissolve. Dilute with Medium to volume.

Standard solution:

Prepare a solution of USP Quetiapine Fumarate RS at a concentration equivalent to (L/900) mg/mL of quetiapine, from Standard stock solution in Medium, where L is the label claim in mg/Tablet.

Sample solution:

At the times specified, withdraw a portion of the solution under test, centrifuge, and use the supernatant.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 290 nm

Cell:

50-mg Tablets: 1 cm

150-, 200-, 300-, and 400-mg Tablets: 0.1 cm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ) of quetiapine (C₂₁H₂₅N₃O₂S) in the sample withdrawn from the vessel at each time point (i):

Cᵢ = (Aᵤ/Aₛ) × Cₛ × (Mᵤ/Mₛ) × N

where

Aᵤ = absorbance of the Sample solution

Aₛ = absorbance of the Standard solution

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

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − Vₛ)] + (C₁ × Vₛ)} × (1/L) × 100

Result₃ = {C₃ × [V − (2 × Vₛ)] + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {C₄ × [V − (3 × Vₛ)] + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in the portion of sample withdrawn at time point (i) (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn from the vessel (mL)

Tolerances: See ▲Table 10.

Table 10▲ (RB 1-Dec-2024)

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 12

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 12.

Acid stage medium:

Citrate buffer, pH 4.8 (9.6 g/L of anhydrous citric acid in water prepared as follows. Transfer a suitable quantity of anhydrous citric acid to an appropriate volumetric flask. Dissolve in 60% of the flask volume of water, then add 9% of the flask volume of 1 N sodium hydroxide VS. Dilute with water to volume.); 900 mL

0.05 M phosphate buffer solution:

17.9 g/L of dibasic sodium phosphate dodecahydrate solution prepared as follows. Transfer a suitable amount of dibasic sodium phosphate dodecahydrate to an appropriate volumetric flask containing 40% of the flask volume of water. Add 46% of the flask volume of 1 N sodium hydroxide VS and dilute with water to volume. Adjust the pH of the resulting solution with 1 N sodium hydroxide VS or 1 N hydrochloric acid VS, if necessary, so that a mixture of 10 mL of the solution with 90 mL of Acid stage medium has a pH of 6.4–6.8.

Buffer stage medium:

Phosphate buffer, pH 6.6 ± 0.2 (add 100 mL of 0.05 M phosphate buffer solution to the Acid stage medium); 1000 mL

Apparatus 1: 20-mesh basket; 200 rpm

Times: 1 h in Acid stage medium; 6 and 14 h in Buffer stage medium. The time in the Buffer stage medium includes the time in the Acid stage medium.

Procedure:

Run the test in the Acid stage medium for the times specified. After 5 h, add 100 mL of 0.05 M phosphate buffer solution and continue running the test in Buffer stage medium for the times specified.

Standard stock solution:

0.55 mg/mL of USP Quetiapine Fumarate RS in methanol. Sonicate to dissolve.

Standard solution:

0.0275 mg/mL of USP Quetiapine Fumarate RS from Standard stock solution in Buffer stage medium

Acid stage sample solution:

Pass a portion of the solution under test through a suitable filter. Dilute the filtrate further with Buffer stage medium. Replace the portion of solution removed from the vessel with an equivalent volume of Acid stage medium.

Buffer stage sample solution:

Pass a portion of the solution under test through a suitable filter. Dilute the filtrate further with Buffer stage medium. Replace the portion of solution removed from the vessel with an equivalent volume of Buffer stage medium.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 290 nm

Blank: Buffer stage medium

Analysis

Samples: Standard solution, Acid stage sample solution, and Buffer stage sample solution

Calculate the concentration (Cᵢ) of quetiapine (C₂₁H₂₅N₃O₂S) in the sample withdrawn from the vessel at each time point (i):

Cᵢ = (Aᵤ/Aₛ) × Cₛ × D × (Mᵤ/Mₛ) × N

where

Aᵤ = absorbance of the Acid stage sample solution or Buffer stage sample solution

Aₛ = absorbance of the Standard solution

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

D = dilution factor for the Acid stage sample solution or Buffer stage sample solution

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × Vₐ × (1/L) × 100

Result₂ = [(C₂ × Vᵦ) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × Vᵦ) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in Acid stage medium or Buffer stage medium in the portion of sample withdrawn at each time point (mg/mL)

Vₐ = volume of Acid stage medium, 900 mL

L = label claim (mg/Tablet)

Vᵦ = volume of Buffer stage medium, 1000 mL

Vₛ = volume of the Acid stage sample solution or Buffer stage sample solution withdrawn from the vessel and replaced with Acid stage medium or Buffer stage medium, respectively (mL)

Tolerances: See ▲Table 11.

Table 11▲ (RB 1-Dec-2024)

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 13

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 13.

Medium:

0.1 N hydrochloric acid; 1000 mL

Apparatus 1: 20-mesh basket; 100 rpm

Times: 1, 4, and 10 h

Buffer:

Dissolve 7.1 g of sodium phosphate, dibasic, anhydrous in 1 L of water. Adjust with phosphoric acid to a pH of 5.5.

Mobile phase:

Acetonitrile and Buffer (50:50)

Standard stock solution:

0.29 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Transfer an appropriate amount of USP Quetiapine Fumarate RS to a suitable volumetric flask, and add 2.5% of the flask volume of methanol. Sonicate to dissolve and dilute with Medium to volume.

Standard solution:

0.029 mg/mL of USP Quetiapine Fumarate RS from Standard stock solution in Medium. [Note—The concentration is equivalent to 0.025 mg/mL of quetiapine.]

Sample solution:

At the time specified, withdraw a portion of the solution under test and replace with the same volume of Medium. Pass through a suitable filter of 1-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained. Dilute with Medium to a concentration similar to that of the Standard solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Column temperature: 30°

Flow rate: 1.2 mL/min

Injection volume: 20 µL

Run time: NLT 2.0 times the retention time of quetiapine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ) of quetiapine (C₂₁H₂₅N₃O₂S) in the sample withdrawn from the vessel at each time point (i):

Cᵢ = (rᵤ/rₛ) × Cₛ × D × (Mᵤ/Mₛ) × N

where

rᵤ = peak response of quetiapine 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)

D = dilution factor for the Sample solution

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in the portion of sample withdrawn at time point (i) (mg/mL)

V = volume of Medium, 1000 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See ▲Table 12.

Table 12▲ (RB 1-Dec-2024)

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 14

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 14.

Acid stage medium:

Citrate buffer, pH 4.8 (9.6 g/L of citric acid, anhydrous and 3.6 g/L of sodium hydroxide in water. Adjust with 1 M citric acid, anhydrous or 1 M sodium hydroxide to a pH of 4.8.); 900 mL

Buffer stock solution:

7.1 g/L of sodium phosphate, dibasic, anhydrous and 18.4 g/L of sodium hydroxide in water. Determine the volume of this solution required to adjust 900 mL of Acid stage medium to a pH of 6.6.

Buffer solution:

Dilute the measured volume of Buffer stock solution with water to 100 mL, if necessary.

Buffer stage medium:

Phosphate buffer, pH 6.6 (add 100 mL of Buffer solution to the Acid stage medium); 1000 mL

Apparatus 1: 20-mesh basket; 200 rpm

Times: 1 and 4 h in Acid stage medium; 8 and 16 h in Buffer stage medium. The time in the Buffer stage medium includes the time in the Acid stage medium.

Solution A:

Dissolve 1.36 g of potassium phosphate, monobasic in 1 L water. Add 1 mL of triethylamine and adjust with phosphoric acid to a pH of 6.0.

Mobile phase:

Acetonitrile and Solution A (50:50)

Procedure:

Run the test in the Acid stage medium for the times specified. After 5 h, add 100 mL of Buffer solution and continue running the test in Buffer stage medium for the times specified.

Acid stage standard stock solution:

0.62 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Transfer an appropriate amount of USP Quetiapine Fumarate RS into a suitable volumetric flask. Add 10% of the flask volume of methanol and sonicate to dissolve, if necessary. Dilute with Acid stage medium to volume.

Acid stage standard solution:

For Tablets labeled to contain 50 mg: 0.0124 mg/mL of USP Quetiapine Fumarate RS from Acid stage standard stock solution in Acid stage medium

For Tablets labeled to contain 150, 200, 300, and 400 mg: 0.0248 mg/mL of USP Quetiapine Fumarate RS from Acid stage standard stock solution in Acid stage medium

Buffer stage standard stock solution:

0.56 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Transfer an appropriate amount of USP Quetiapine Fumarate RS into a suitable volumetric flask. Add 10% of the flask volume of methanol and sonicate to dissolve. Dilute with Buffer stage medium to volume.

Buffer stage standard solution:

For Tablets labeled to contain 50 mg: 0.0112 mg/mL of USP Quetiapine Fumarate RS from Buffer stage standard stock solution in Buffer stage medium

For Tablets labeled to contain 150, 200, 300, and 400 mg: 0.0224 mg/mL of USP Quetiapine Fumarate RS from Buffer stage standard stock solution in Buffer stage medium

Acid stage sample solution:

At the time specified, withdraw a portion of the solution under test and replace with the same volume of the Acid stage medium. Pass through a suitable filter of 70-µm pore size. Dilute with Acid stage medium to a concentration similar to that of the corresponding Acid stage standard solution. Pass through a suitable filter of 0.45-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained.

Buffer stage sample solution:

At the time specified, withdraw a portion of the solution under test and replace with the same volume of the Buffer stage medium. Pass through a suitable filter of 70-µm pore size. Dilute with Buffer stage medium to a concentration that is similar to that of the corresponding Buffer stage standard solution. Pass through a suitable filter of 0.45-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Column temperature: 35°

Flow rate: 2 mL/min

Injection volume: 10 µL

Run time: NLT 2.7 times the retention time of quetiapine

System suitability

Samples: Acid stage standard solution and Buffer stage standard solution

Suitability requirements

Tailing factor: NMT 2.0 for Acid stage standard solution and Buffer stage standard solution

Relative standard deviation: NMT 2.0% for Acid stage standard solution and Buffer stage standard solution

Analysis

Samples: Acid stage standard solution, Acid stage sample solution, Buffer stage standard solution, and Buffer stage sample solution

Calculate the concentration (Cᵢ) of quetiapine (C₂₁H₂₅N₃O₂S) in the sample withdrawn from the vessel at each time point (i):

Cᵢ = (rᵤ/rₛ) × Cₛ × D × (Mᵤ/Mₛ) × N

where

rᵤ = peak response of quetiapine from the Acid stage sample solution or Buffer stage sample solution

rₛ = peak response of quetiapine from the Acid stage standard solution or Buffer stage standard solution, corresponding to the related sample solution

Cₛ = concentration of USP Quetiapine Fumarate RS in Acid stage standard solution or Buffer stage standard solution (mg/mL)

D = dilution factor for the Acid stage sample solution or Buffer stage sample solution, if needed

Mᵤ = molecular weight of quetiapine free base, 383.51

Mₛ = molecular weight of quetiapine fumarate, 883.09

N = number of moles of quetiapine free base per mole of quetiapine fumarate, 2

Calculate the percentage of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at each time point (i):

Result₁ = C₁ × Vₐ × (1/L) × 100

Result₂ = [(C₂ × Vₐ) + (C₁ × Vₛ)] × (1/L) × 100

Result₃ = {(C₃ × Vᵦ) + [(C₂ + C₁) × Vₛ]} × (1/L) × 100

Result₄ = {(C₄ × Vᵦ) + [(C₃ + C₂ + C₁) × Vₛ]} × (1/L) × 100

where

Cᵢ = concentration of quetiapine in Acid stage medium or Buffer stage medium in the portion of sample withdrawn at each time point (i) (mg/mL)

Vₐ = volume of the Acid stage medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Acid stage sample solution or Buffer stage sample solution withdrawn at each time point and replaced with Acid stage medium or Buffer stage medium, respectively, 10 mL

Vᵦ = volume of Buffer stage medium, 1000 mL

Tolerances: See ▲Table 13.

Table 13▲ (RB 1-Dec-2024)

The percentages of the labeled amount of quetiapine (C₂₁H₂₅N₃O₂S) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Uniformity of Dosage Units 〈905〉

Meet the requirements.

5 IMPURITIES

Organic Impurities

Buffer, Mobile phase, Diluent, System suitability solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

System suitability

Sample: System suitability solution

[Note—See ▲Table 14▲ (RB 1-Dec-2024) for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between quetiapine related compound G and quetiapine related compound H; NLT 2.0 between the quetiapine desethoxy and quetiapine peaks

Analysis

Sample: Sample solution

[Note—See ▲Table 14▲ (RB 1-Dec-2024) for the relative retention times.]

Calculate the percentage of each degradation product in the portion of Tablets taken:

Result = (rᵢ/rₛ) × (1/F) × 100

where

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

rₛ = peak response of quetiapine from the Sample solution

F = relative response factor for the corresponding degradation product from ▲Table 14▲ (RB 1-Dec-2024)

Acceptance criteria: See ▲Table 14.▲ (RB 1-Dec-2024). Disregard peaks less than 0.05%.

▲Table 14▲ (RB 1-Dec-2024)

ᵃ Counter ion peak, not to be included in the total degradation products.

ᵇ Process impurity controlled in the drug substance. Included for identification purposes only. Not reported for the drug product and not included in the total degradation products.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage:

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

Labeling:

When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Quetiapine Fumarate RS

USP Quetiapine Related Compound H RS

4-(Dibenzo[b,f][1,4]thiazepin-11-yl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine 1-oxide.

C H N O S 399.51 (subscripts not available in source text)

USP Quetiapine System Suitability RS

It contains quetiapine fumarate and at least 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