Interim Revision Announcement

Official May 1, 2014 Acetaminophen 1

. CS = concentration of USP Acetaminophen RS in

the Standard solution (mg/mL)
Acetaminophen 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%
• HEAVY METALS, Method II 〈231〉: NMT 10 ppm
C8H9NO2 151.16
Acetamide, N-(4-hydroxyphenyl)-; Change to read:
4′-Hydroxyacetanilide [103-90-2].
DEFINITION • LIMIT OF FREE •4-AMINOPHENOL• (IRA 1-May-2014)
.

Acetaminophen contains NLT 98.0% and NMT 102.0% of
acetaminophen (C8H9NO2), calculated on the dried basis.
IDENTIFICATION
• A. INFRARED ABSORPTION 〈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.
ASSAY
Solution A, Solution B, Mobile phase, and Chromato-
graphic 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-aminophe-
.

nol• (IRA 1-May-2014) and acetaminophen are 0.6 and 1.0,

respectively.]
Change to read: Suitability requirements
Relative standard deviation: NMT 5.0%
• PROCEDURE Analysis
Use low-actinic glassware for preparation of the Sample Samples: Standard solution and Sample solution
Calculate the percentage of 4-aminophenol •• (IRA 1-May-
solution.
.

2014) in the portion of Acetaminophen taken:

Solution A: 1.7 g/L of monobasic potassium phosphate
and 1.8 g/L of dibasic sodium phosphate, anhydrous Result = (rU/rS) × (CS/CU) × 100
Solution B: Methanol
Mobile phase: See Table 1. rU = peak response of 4-aminophenol from the
Sample solution
Table 1 rS = peak response from the Standard solution
Time Solution A Solution B
CS = concentration of USP 4-Aminophenol RS in
(min) (%) (%)
the Standard solution (µg/mL)
CU = concentration of Acetaminophen in the
0.0 99 1 Sample solution (µg/mL)
3.0 99 1 Acceptance criteria: NMT 0.005%
7.0 19 81
7.1 99 1
Change to read:
10.0 99 1

Standard solution: 0.1 mg/mL of USP Acetaminophen • ORGANIC IMPURITIES

RS in methanol Solution A: Methanol, water, •glacial• (IRA 1-May-2014) ace-
.

Sample solution: 0.1 mg/mL of Acetaminophen in tic acid (50:950:1)

methanol Solution B: Methanol, water, •glacial• (IRA 1-May-2014)
.

Chromatographic system acetic acid (500:500:1)

(See Chromatography 〈621〉, System Suitability.) Mobile phase: See Table 2.
Mode: LC
Detector: •UV 230 nm• (IRA 1-May-2014)
.
Table 2
Column: 4.6-mm × 10-cm; 3.5-µm packing L7 Time Solution A Solution B
Column temperature: 35° (min) (%) (%)
Flow rate: 1.0 mL/min 0 82 18
Injection volume: 5 µL
System suitability 8 82 18
Sample: Standard solution 53 0 100
Suitability requirements 58 0 100
Tailing factor: NMT 2.0 59 82 18
Relative standard deviation: NMT 1.0% 73 82 18
Analysis
Samples: Standard solution and Sample solution Diluent: Methanol
Calculate the percentage of acetaminophen (C8H9NO2) System suitability solution: 20 µg/mL of USP Acet-
in the portion of Acetaminophen taken: aminophen RS and 80 µg/mL each of USP Acetamino-
phen Related Compound B RS and USP Acetamino-
Result = (rU/rS) × (CS/CU) × 100 phen Related Compound C RS in Diluent
Standard solution: 1.25 µg/mL of USP Acetaminophen
rU = peak response from the Sample solution Related Compound D RS and 0.25 µg/mL of USP Acet-
rS = peak response from the Standard solution aminophen Related Compound J RS in Diluent

2014 The United States Pharmacopeial Convention All Rights Reserved.

 Interim Revision Announcement
2 Acetaminophen Official May 1, 2014

Sample solution: 25 mg/mL of Acetaminophen in Table 3

Diluent Relative
Chromatographic system Retention
(See Chromatography 〈621〉, System Suitability.) Time Relative Acceptance
Mode: LC •• Response Criteria,
(IRA 1-May-
Detector: UV 254 nm
.

Name 2014) Factor NMT (%)

Column: 4.6-mm × 25-cm; 5-µm packing L7 Acetaminophen 0.43 — —
Flow rate: 0.9 mL/min
Column temperature: 40°
Acetaminophen re- •1.2•.

(IRA 1-
lated compound Ba 0.67 0.05
Injection volume: 5 µL . May-2014)

System suitability Acetaminophen re-

Samples: System suitability solution and Standard lated compound •0.38•
.

(IRA 1-

solution Cb . 0.71 May-2014) 0.05

[NOTE—See Table 3 for relative retention time values.] Acetaminophen re-
Suitability requirements lated compound
Tailing factor: NMT 2.0 for acetaminophen related Dc . 1.0 1.0 0.05
compound D, Standard solution Acetaminophen re-
—
Resolution: NLT 2.0 between acetaminophen and lated compound Jd 1.73 0.001
•1.0•
.

acetaminophen related compound B; NLT 1.5 be- Individual unspeci- (IRA 1-

tween acetaminophen related compound B and —
.

fied impurity May-2014) 0.05

acetaminophen related compound C, System suitabil- Total impurities — — 0.1
ity solution a N-(4-Hydroxyphenyl)propanamide.
Relative standard deviation: NMT 5.0% for acet- .

b N-(2-Hydroxyphenyl)acetamide.
aminophen related compound D, Standard solution .

c N-Phenylacetamide.
Analysis .

d N-(4-Chlorophenyl)acetamide (p-chloroacetanilide).
Samples: Standard solution and Sample solution • .

Calculate the percentage of acetaminophen related

.

•
.

(IRA 1-May-2014)

compound J in the portion of Acetaminophen taken: SPECIFIC TESTS

• LOSS ON DRYING 〈731〉
Result = (rU/rS) × (CS/CU) × 100 Analysis: Dry at 105° to constant weight.
Acceptance criteria: NMT 0.5%
rU = peak response of acetaminophen related
compound J from the Sample solution ADDITIONAL REQUIREMENTS
rS = peak response of acetaminophen related • PACKAGING AND STORAGE: Preserve in tight, light-resistant
compound J from the Standard solution containers, and store at room temperature. Protect from
CS = concentration of USP Acetaminophen Related moisture and heat.
Compound J RS in the Standard solution • USP REFERENCE STANDARDS 〈11〉
(µg/mL) USP Acetaminophen RS
CU = concentration of Acetaminophen in the USP Acetaminophen Related Compound B RS
Sample solution (µg/mL) N-(4-Hydroxyphenyl)propanamide.
Calculate the percentage of acetaminophen related C9H11NO2 165.19
compounds B, C, and D and any unspecified impurity USP Acetaminophen Related Compound C RS
in the portion of Acetaminophen taken: N-(2-Hydroxyphenyl)acetamide.
C8H9NO2 151.16
Result = (rU/rS) × (CS/CU) × (1/F) × 100 USP Acetaminophen Related Compound D RS
N-Phenylacetamide.
rU = peak response of each specified or unspecified C8H9NO 135.17
impurity from the Sample solution USP Acetaminophen Related Compound J RS
rS = peak response of acetaminophen related N-(4-Chlorophenyl)acetamide (p-chloroacetanilide).
compound D from the Standard solution C8H8ClNO 169.61
CS = concentration of USP Acetaminophen Related USP 4-Aminophenol RS
Compound D RS in the Standard solution C6H7NO 109.13
(µg/mL)
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 re-
.

sponse factors in Table 3 (where applicable) are calcu-

lated relative to those of acetaminophen related com-
pound D.]• (IRA 1-May-2014)

2014 The United States Pharmacopeial Convention All Rights Reserved.