11/27/2020 USP-NF Acetaminophen

Printed on: Fri Nov 27 2020, 10:21:32 am

Printed by: Shruti Kharidia
O cial Status: Currently O cial on 27-Nov-2020
O cial Date: O cial as of 1-May-2020
Document Type: USP
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© 2020 USPC

Acetaminophen

C8H9NO2 151.16
Acetamide, N-(4-hydroxyphenyl)-;
4′-Hydroxyacetanilide [103-90-2]; UNII: 362O9ITL9D.

DEFINITION
Acetaminophen contains NLT 98.0% and NMT 102.0% of acetaminophen (C8H9NO2), calculated on the dried basis.

IDENTIFICATION
Change to read:
• A. ▲SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉, Infrared Spectroscopy: 197K▲ (CN 1-MAY-2020)
• 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
Use low-actinic glassware for preparation of the Sample solution.

L
Solution A: 1.7 g/L of monobasic potassium phosphate and 1.8 g/L of dibasic sodium phosphate, anhydrous
Solution B: Methanol
IA
Mobile phase: See Table 1.

Table 1
IC

Time (min) Solution A (%) Solution B (%)

0.0 99 1

3.0 99 1
FF

7.0 19 81

7.1 99 1

10.0 99 1
O

Standard solution: 0.1 mg/mL of USP Acetaminophen RS in methanol

Sample solution: 0.1 mg/mL of Acetaminophen in methanol
Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 230 nm
Column: 4.6-mm × 10-cm; 3.5-µm packing L7
Column temperature: 35°
Flow rate: 1.0 mL/min
Injection volume: 5 µL
System suitability
Sample: Standard solution
Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 1.0%
Analysis
Samples: Standard solution and Sample solution

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11/27/2020 USP-NF Acetaminophen

Calculate the percentage of acetaminophen (C8H9NO2) in the portion of Acetaminophen 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 Acetaminophen RS in the Standard solution (mg/mL)

CU = concentration of Acetaminophen in the Sample solution (mg/mL)

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

IMPURITIES
• RESIDUE ON IGNITION 〈281〉: NMT 0.1%
• LIMIT OF FREE 4-AMINOPHENOL
Solution A, Solution B, Mobile phase, and Chromatographic system: Proceed as directed in the Assay.
Standard solution: 1.25 µg/mL of USP 4-Aminophenol RS in methanol
Sample solution: 25 mg/mL of Acetaminophen in methanol
System suitability
Sample: Standard solution
[NOTE—The relative retention times for 4-aminophenol and acetaminophen are 0.6 and 1.0, respectively.]
Suitability requirements
Relative standard deviation: NMT 5.0%
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of 4-aminophenol in the portion of Acetaminophen taken:

rU = peak response of 4-aminophenol from the Sample solution

L
Result = (rU/rS) × (CS/CU) × 100
IA
rS = peak response from the Standard solution

CS = concentration of USP 4-Aminophenol RS in the Standard solution (µg/mL)

IC

CU = concentration of Acetaminophen in the Sample solution (µg/mL)

Acceptance criteria: NMT 0.005%

• ORGANIC IMPURITIES
Solution A: Methanol, water, glacial acetic acid (50:950:1)
FF

Solution B: Methanol, water, glacial acetic acid (500:500:1)

Mobile phase: See Table 2.

Table 2
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Time (min) Solution A (%) Solution B (%)

0 82 18

8 82 18

53 0 100

58 0 100

59 82 18

73 82 18

Diluent: Methanol
System suitability solution: 20 µg/mL of USP Acetaminophen RS and 80 µg/mL each of USP Acetaminophen Related Compound B RS
and USP Acetaminophen Related Compound C RS in Diluent
Standard solution: 1.25 µg/mL of USP Acetaminophen Related Compound D RS and 0.25 µg/mL of USP Acetaminophen Related
Compound J RS in Diluent

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11/27/2020 USP-NF Acetaminophen

Sample solution: 25 mg/mL of Acetaminophen in Diluent

Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 254 nm
Column: 4.6-mm × 25-cm; 5-µm packing L7
Flow rate: 0.9 mL/min
Column temperature: 40°
Injection volume: 5 µL
System suitability
Samples: System suitability solution and Standard solution
[NOTE—See Table 3 for relative retention time values.]
Suitability requirements
Tailing factor: NMT 2.0 for acetaminophen related compound D, Standard solution
Resolution: NLT 2.0 between acetaminophen and acetaminophen related compound B; NLT 1.5 between acetaminophen related
compound B and acetaminophen related compound C, System suitability solution
Relative standard deviation: NMT 5.0% for acetaminophen related compound D, Standard solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of acetaminophen related compound J in the portion of Acetaminophen taken:

Result = (rU/rS) × (CS/CU) × 100

rU = peak response of acetaminophen related compound J from the Sample solution

rS = peak response of acetaminophen related compound J from the Standard solution

CS = concentration of USP Acetaminophen Related Compound J RS in the Standard solution (µg/mL)

CU = concentration of Acetaminophen in the Sample solution (µg/mL)L

IA
Calculate the percentage of acetaminophen related compounds B, C, and D and any unspeci ed impurity in the portion of
Acetaminophen taken:

Result = (rU/rS) × (CS/CU) × (1/F) × 100

IC

rU = peak response of each speci ed or unspeci ed impurity from the Sample solution

rS = peak response of acetaminophen related compound D from the Standard solution

CS = concentration of USP Acetaminophen Related Compound D RS in the Standard solution (µg/mL)

FF

CU = concentration of Acetaminophen in the Sample solution (µg/mL)

F = relative response factor for each impurity shown in Table 3

Acceptance criteria: See Table 3. [NOTE—The relative retention times and relative response factors in Table 3 (where applicable) are
calculated relative to those of acetaminophen related compound D.]
O

Table 3

Acceptance Criteria, NMT

Name Relative Retention Time Relative Response Factor (%)

Acetaminophen 0.43 — —

Acetaminophen related
compound Ba 0.67 1.2 0.05

Acetaminophen related
compound Cb 0.71 0.38 0.05

Acetaminophen related
compound Dc 1.0 1.0 0.05

Acetaminophen related —
compound Jd 1.73 0.001

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11/27/2020 USP-NF Acetaminophen

Acceptance Criteria, NMT

Name Relative Retention Time Relative Response Factor (%)

Individual unspeci ed —
impurity 1.0 0.05

Total impurities — — 0.1

a  N-(4-Hydroxyphenyl)propanamide.
b  N-(2-Hydroxyphenyl)acetamide.
c  N-Phenylacetamide.
d  N-(4-Chlorophenyl)acetamide (p-chloroacetanilide).

SPECIFIC TESTS
• LOSS ON DRYING 〈731〉
Analysis: Dry at 105° to constant weight.
Acceptance criteria: NMT 0.5%

ADDITIONAL REQUIREMENTS
• PACKAGING AND STORAGE: Preserve in tight, light-resistant containers, and store at room temperature. Protect from moisture and heat.
• USP REFERENCE STANDARDS 〈11〉
USP Acetaminophen RS
USP Acetaminophen Related Compound B RS
N-(4-Hydroxyphenyl)propanamide.
C9H11NO2 165.19
USP Acetaminophen Related Compound C RS
N-(2-Hydroxyphenyl)acetamide.
C8H9NO2 151.16
USP Acetaminophen Related Compound D RS
N-Phenylacetamide.
C8H9NO 135.17
L
IA
USP Acetaminophen Related Compound J RS
N-(4-Chlorophenyl)acetamide (p-chloroacetanilide).
C8H8ClNO 169.61
USP 4-Aminophenol RS C6H7NO 109.13
IC

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

Topic/Question Contact Expert Committee

FF

ACETAMINOPHEN Clydewyn M. Anthony SM22020 Small Molecules 2

Senior Scienti c Liaison
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Chromatographic Database Information: Chromatographic Database

Most Recently Appeared In:

Pharmacopeial Forum: Volume No. 39(6)

Page Information:

USP43-NF38 - 38
USP42-NF37 - 40
USP41-NF36 - 34

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