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Quetiapine Tablets

DEFINITION

Quetiapine Tablets contain an amount of quetiapine fumarate equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of quetiapine (C21H25N3O2S).

IDENTIFICATION

• A. Infrared Absorption

197F

Standard solution: Dissolve 10 mg of quetiapine fumarate in 10 mL of acetone. Sonicate for 10 min. Filter and evaporate the solvent. Dissolve the residue in 2 mL of chloroform. Filter and use 20 µL of the filtrate for analysis.

Sample solution: Finely powder 10 Tablets. Dissolve an amount of the powder equivalent to 10 mg of quetiapine fumarate in 10 mL of acetone, avoiding large pieces of Tablet coating, if any. Sonicate for 10 min. Filter and evaporate the solvent. Dissolve the residue in 2 mL of chloroform. Filter and use 20 µL of the filtrate for analysis.

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

ASSAY

• Procedure

Buffer: 1.4 g/L of monobasic potassium phosphate in water. To 1 L of this solution add 1 mL of triethylamine, and adjust with dilute phosphoric acid to a pH of 6.5 (1 in 10, v/v).

Mobile phase: Acetonitrile and Buffer (35:65)

Standard solution: 0.1 mg/mL of USP Quetiapine Fumarate RS in Mobile phase

Sample stock solution: Nominally 2.0 mg/mL of quetiapine prepared as follows. Transfer NLT 5 Tablets to a suitable volumetric flask. Add water to fill 5% of the final volume, and sonicate to disperse the Tablets. Add Mobile phase to fill 60% of the final volume, and sonicate for 30 min with intermittent shaking. Dilute with Mobile phase to volume. Centrifuge for 5 min. Pass a portion of the solution through a suitable filter of 0.45-µm pore size.

Sample solution: Nominally 0.1 mg/mL of quetiapine prepared by diluting an aliquot of the Sample stock solution with Mobile phase

Chromatographic system

(See Chromatography

621

, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 20 µL

Run time: 2 times the retention time of quetiapine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

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

Result = (rU/rS) × (CS/CU) × N × (Mr1/Mr2) × 100

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)
CU	=	= nominal concentration of quetiapine in the Sample solution (mg/mL)
N	=	= number of moles of quetiapine/mole of quetiapine fumarate, 2
Mr1	=	= molecular weight of quetiapine free base, 383.51
Mr2	=	= molecular weight of quetiapine fumarate, 883.09

Acceptance criteria: 90.0%–110.0%

PERFORMANCE TESTS

• Dissolution

711

Test 1

Medium: Water; 900 mL, deaerated

Apparatus 2: 50 rpm

Time: 30 min

Buffer: 1.4 g/L of monobasic potassium phosphate in water. To 1 L of this solution add 1 mL of triethylamine, and adjust with dilute phosphoric acid to a pH of 6.0 (1 in 10).

Mobile phase: Acetonitrile and Buffer (35:65)

Standard stock solution: 3.3 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Dissolve the Standard first in methanol using 10% of the final volume, and dilute with Medium to volume.

Standard solution: 0.03 mg/mL of USP Quetiapine Fumarate RS in Medium from the Standard stock solution

Sample solution: Pass a portion of the solution through a suitable filter of 0.45-µm pore size. Dilute with Medium to a concentration similar to that of the Standard solution.

Chromatographic system

(See Chromatography

621

, System Suitability.)

Mode: LC

Detector: UV 225 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Flow rate: 2 mL/min

Injection volume: 50 µL

Run time: 1.5 times the retention time of quetiapine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quetiapine (C21H25N3O2S) dissolved:

Result = (rU/rS) × CS × V × N × (Mr1/Mr2) × (1/L) × 100

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)
V	=	= volume of Medium, 900 mL
N	=	= number of moles of quetiapine/mole of quetiapine fumarate, 2
Mr1	=	= molecular weight of quetiapine free base, 383.51
Mr2	=	= molecular weight of quetiapine fumarate, 883.09
L	=	= label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of quetiapine (C21H25N3O2S) is dissolved.

Test 2

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

Medium: 1 g/L of sodium chloride in water; 900 mL, deaerated

Apparatus 2: 50 rpm

Time: 20 min

Standard stock solution: 1.3 mg/mL of USP Quetiapine Fumarate RS prepared as follows. Transfer a suitable quantity of USP Quetiapine Fumarate RS to a suitable volumetric flask. Dissolve in about 25% of the flask volume of methanol. Dilute with Medium to volume.

Standard solution: (L/900) mg/mL of USP Quetiapine Fumarate RS from a suitable volume of Standard stock solution in Medium, where L is the label claim in mg/Tablet.

Sample solution: Pass a portion of solution under test through a suitable filter.

Blank: Medium

Instrumental conditions

Mode: UV

Analytical wavelength: 290 nm with background correction at 490 nm

Cell: See Table 1.

Table 1

Label claim, L (mg/Tablet)	Cell (cm)
25	1.0
50	1.0
100	0.5
150	0.2
200	0.2
300	0.1
400	0.1

Analysis

Samples: Medium, Standard solution, and Sample solution

Calculate the percentage of the labeled amount of quetiapine (C21H25N3O2S) dissolved:

Result = (AU/AS) × CS × V × N × (Mr1/Mr2) × (1/L) × 100

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)
V	=	= volume of Medium, 900 mL
N	=	= number of moles of quetiapine/mole of quetiapine fumarate, 2
Mr1	=	= molecular weight of quetiapine free base, 383.51
Mr2	=	= molecular weight of quetiapine fumarate, 883.09
L	=	= label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of quetiapine (C21H25N3O2S) is dissolved.

Test 3

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

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Times

For Tablets labeled to contain 25 mg: 30 min

For Tablets labeled to contain 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg: 45 min

Standard solution: 0.34 mg/mL of USP Quetiapine Fumarate RS in 0.1 N hydrochloric acid

Dilute standard solution: 0.06 mg/mL of USP Quetiapine Fumarate RS from the Standard solution in 0.1 N hydrochloric acid

Sample solution: Withdraw a suitable portion of the solution under test. Transfer 9 mL of the portion to a 10-mL volumetric flask, and dilute with 1 N hydrochloric acid to volume. Pass a portion of the resulting solution through a suitable filter of 0.45-µm pore size, and discard the first 2 mL.

Instrumental conditions

Mode: UV

Analytical wavelength: 282 nm

Cells

For Tablets labeled to contain 25 mg or 50 mg: 0.5 cm

For Tablets labeled to contain 10 0mg, 200 mg, 300 mg, or 400 mg: 0.1 cm

Blank: 0.1 N hydrochloric acid

Analysis

Samples: Standard solution, Dilute standard solution, Sample solution, and Blank

For Tablets labeled to contain 25 mg or 50 mg

Calculate the percentage of the labeled amount of quetiapine (C21H25N3O2S) dissolved:

Result = (AU/AS) × CS × D × N × (Mr1/Mr2) × V × (1/L) × 100

AU	=	= absorbance of the Sample solution
AS	=	= absorbance of the Dilute standard solution
CS	=	= concentration of USP Quetiapine Fumarate RS in the Dilute standard solution (mg/mL)
D	=	= dilution factor, 1.1
N	=	= number of moles of quetiapine/mole of quetiapine fumarate, 2
Mr1	=	= molecular weight of quetiapine free base, 383.51
Mr2	=	= molecular weight of quetiapine fumarate, 883.09
V	=	= volume of Medium, 900 mL
L	=	= label claim (mg/Tablet)

For Tablets labeled to contain 100 mg, 200 mg, 300 mg, or 400 mg

Calculate the percentage of the labeled amount of quetiapine (C21H25N3O2S) dissolved:

Result = (AU/AS) × CS × D × N × (Mr1/Mr2) × V × (1/L) × 100

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, 1.1
N	=	= number of moles of quetiapine/mole of quetiapine fumarate, 2
Mr1	=	= molecular weight of quetiapine free base, 383.51
Mr2	=	= molecular weight of quetiapine fumarate, 883.09
V	=	= volume of Medium, 900 mL
L	=	= label claim (mg/Tablet)

Tolerances:

For Tablets labeled to contain 25 mg: NLT 75% (Q) of the labeled amount of quetiapine (C21H25N3O2S) is dissolved.

For Tablets labeled to contain 100 mg, 200 mg, 300 mg, or 400 mg: NLT 70% (Q) of the labeled amount of quetiapine (C21H25N3O2S) is dissolved.

• Uniformity of Dosage Units

905

: Meet the requirements

IMPURITIES

• Organic Impurities

Buffer: Dissolve 0.8 g of anhydrous dibasic sodium phosphate and 0.6 g of potassium dihydrogen orthophosphate in 1 L of water.

Solution A: Acetonitrile and Buffer (10:90). Adjust with dilute phosphoric acid (1 in 10, v/v) to a pH of 6.7.

Solution B: Acetonitrile

Diluent: Acetonitrile and Solution A (65:35)

Mobile phase: See Table 2.

Table 2

Time (min)	Solution A (%)	Solution B (%)
0	80	20
20	75	25
30	65	35
35	35	65
55	25	75
56	80	20
65	80	20

System suitability solution: 0.5 mg/mL of USP Quetiapine System Suitability RS in Diluent prepared as follows. Transfer the required quantity of USP Quetiapine System Suitability RS to a suitable volumetric flask. Add 70% of the flask volume and sonicate to dissolve. Dilute with Diluent to volume.

Standard solution: 1.2 µg/mL of USP Quetiapine Fumarate RS in Diluent. Sonication may be used to aid in dissolution.

Sample solution: Nominally 0.5 mg/mL of quetiapine in Diluent from a portion of weighed and crushed Tablets (NLT 10). Sonicate for 10 min with intermittent shaking.

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: 45

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between quetiapine desthoxy and quetiapine peaks, System suitability solution

Tailing factor: NMT 1.5 for the quetiapine peak, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual degradation product in the portion of Tablets taken:

Result = (rU/rS) × (CS/CU) × N × (Mr1/Mr2) × 100

rU	=	= peak response of each individual 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	=	= nominal concentration of quetiapine in the Sample solution (mg/mL)
N	=	= number of moles of quetiapine/mole of quetiapine fumarate, 2
Mr1	=	= molecular weight of quetiapine free base, 383.51
Mr2	=	= molecular weight of quetiapine fumarate, 883.09

Acceptance criteria: See Table 3. Disregard any peak with an area below 0.05% in the Sample solution.

Table 3

Name	Relative Retention Time	Acceptance Criteria, NMT (%)
Quetiapine N-oxidea	0.28	0.2
Quetiapine related compound B	0.39	0.2
Quetiapine related compound G	0.69	0.2
Quetiapine desethoxyb,c	0.88	—
Quetiapine	1.0	—
Bis(dibenzothiazepinyl) piperazineb,d	2.0	—
Any individual unspecified degradation product	—	0.2
Total impurities	—	0.5
a 4-(Dibenzo[b,f][1,4]thiazepin-11-yl)-1-[2-(2-hydroxyethoxy)ethyl]piperazine 1-oxide. b Process impurities controlled in the drug substance. Included for identification purposes only. Not reported for the drug product and not included in the total impurities. c 2-[4-(Dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl]ethanol. d 1,4-Bis(dibenzo[b,f][1,4]thiazepin-11-yl)piperazine.

ADDITIONAL REQUIREMENTS

• Packaging and Storage: Preserve in well-closed containers, and 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

USP Quetiapine Fumarate RS

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

USP38

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question	Contact	Expert Committee
Monograph	Ravi Ravichandran, Ph.D. Principal Scientific Liaison (301) 816-8330	(SM42010) Monographs - Small Molecules 4
711	Margareth R.C. Marques, Ph.D. Senior Scientific Liaison (301) 816-8106	(GCDF2010) General Chapters - Dosage Forms
Reference Standards	RS Technical Services 1-301-816-8129 rstech@usp.org

USP38–NF33 Page 5104

Pharmacopeial Forum: Volume No. 39(6)