Chlorpheniramine Maleate
(klor'' fen ir' a meen mal' ee ate).
C16H19ClN2 · C4H4O4 390.86
2-Pyridinepropanamine, 𝛾 -(4-chlorophenyl)-N,N-dimethyl-, (Z)-2-butenedioate
(1:1);
2-[p-Chloro-α-[2-(dimethylamino)ethyl]benzyl] pyridine maleate (1:1) [113-
92-8].
UNII: V1Q0O9OJ9Z
UNII: 3U6IO1965U
DEFINITION
Chlorpheniramine Maleate contains NLT 98.0% and NMT 102.0% of
chlorpheniramine maleate (C16H19ClN2 · C4H4O4 ), calculated on the dried basis.
IDENTIFICATION
• A. INFRARED ABSORPTION 〈197K〉
• B. The retention times of the maleic acid and chlorpheniramine peaks of the Sample
solution correspond to those of the Standard solution, as obtained in the Assay.
ASSAY
• PROCEDURE
Solution A: 5.44 g/L of monobasic potassium phosphate. Adjust with phosphoric
acid to a pH of 3.0.
Solution B: Acetonitrile
Diluent: Acetonitrile and Solution A (5:95)
System suitability stock solution: 0.02 mg/mL each of USP Pheniramine Maleate
RS, USP Chlorpheniramine Related Compound B RS, and USP Chlorpheniramine
Related Compound C RS in Diluent. Sonicate for 1 min.
System suitability solution: 0.5 mg/mL of USP Chlorpheniramine Maleate RS and 2
µg/mL each of USP Pheniramine Maleate RS, USP Chlorpheniramine Related
Compound B RS, and USP Chlorpheniramine Related Compound C RS in Diluent,
prepared as follows. Transfer 5.0 mg of USP Chlorpheniramine Maleate RS to a
10-mL volumetric flask, add 5 mL of Diluent and 1.0 mL of the System suitability
stock solution, and dilute with Diluent to volume. Sonicate for 1 min.
Standard solution: 0.5 mg/mL of USP Chlorpheniramine Maleate RS in Diluent.
Sonicate for 1 min.
Sample solution: 0.5 mg/mL of Chlorpheniramine Maleate in Diluent. Sonicate for
1 min.
Mobile phase: See Table 1.
Table 1
Time Solution A Solution B
(min) (%) (%)
0 95 5
1 95 5
20 70 30
30 70 30
31 95 5
40 95 5
Chromatographic system
(See Chromatography 〈621〉 , System Suitability.)
Mode: LC
Detector: UV 225 nm
Column: 4.6-mm × 25-cm; 5-µm packing L1
Column temperature: 30°
Flow rate: 1 mL/min
Injection volume: 10 µL
System suitability
Samples: System suitability solution and Standard solution
Suitability requirements
[NOTE— The relative retention times of maleic acid, chlorpheniramine related
compound C, and chlorpheniramine are 0.18, 0.94 and 1.0, respectively. ]
Resolution: NLT 1.5 between chlorpheniramine related compound C and
chlorpheniramine; and NLT 2.0 between chlorpheniramine related compound B
and pheniramine, System suitability solution
Tailing factor: NMT 2.0 for chlorpheniramine, Standard solution
Relative standard deviation: NMT 0.73% for chlorpheniramine, Standard solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of chlorpheniramine maleate (C16H19ClN2 · C4H4O4 ) in the
portion of Chlorpheniramine Maleate taken:
Result = ( r U / r S ) × ( C S / C U ) × 100
rU = peak response of chlorpheniramine from the Sample solution
rS = peak response of chlorpheniramine from the Standard solution
CS = concentration of USP Chlorpheniramine Maleate RS in the Standard
solution (mg/mL)
C U = concentration of Chlorpheniramine Maleate in the Sample solution
(mg/mL)
Acceptance criteria: 98.0%–102.0% on the dried basis
IMPURITIES
• RESIDUE ON IGNITION 〈281〉 : NMT 0.2%
• ORGANIC IMPURITIES
Solution A, Solution B, Diluent, System suitability solution, Mobile phase, and
Chromatographic system: Proceed as directed in the Assay.
Standard solution: 1.4 µg/mL of USP Chlorpheniramine Maleate RS in Diluent,
equivalent to 1.0 µg/mL of chlorpheniramine. Sonicate for 1 min.
Sensitivity solution: 0.28 µg/mL of USP Chlorpheniramine Maleate RS in Diluent
Sample solution: 0.5 mg/mL of Chlorpheniramine Maleate in Diluent. Sonicate for
1 min.
System suitability
Samples: System suitability solution, Standard solution, and Sensitivity solution
Suitability requirements
Resolution: NLT 1.5 between chlorpheniramine related compound C and
chlorpheniramine; and NLT 2.0 between the chlorpheniramine related compound
B and pheniramine, System suitability solution
Relative standard deviation: NMT 5.0% for chlorpheniramine, Standard solution
Signal-to-noise ratio: NLT 10 for chlorpheniramine, Sensitivity solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Chlorpheniramine
Maleate taken:
Result = ( r U / r S ) × ( C S / C U ) × (1/F) × 100
rU = peak response of each impurity from the Sample solution
rS = peak response of chlorpheniramine from the Standard solution
CS = concentration of chlorpheniramine from the Standard solution (mg/mL)
CU = concentration of Chlorpheniramine Maleate in the Sample solution
(mg/mL)
F = relative response factor (see Table 2)
Acceptance criteria: See Table 2. Disregard peaks having areas less than 0.05%
that of chlorpheniramine.
Table 2
Relative Relative Acceptance
Retention Response Criteria,
Name Time Factor NMT (%)
Maleic acida 0.18 — —
Diamine analogb 0.37 0.73 0.2
Chlorpheniramine
related compound Bc 0.49 0.77 0.1
Pheniramined 0.57 — —
Chlorpheniramine
related compound Ce 0.97 1.0 0.1
Chlorpheniramine 1.0 — —
Chlorpheniramine
nitrilef 1.19 1.0 0.1
Any other unspecified impurity — 1.0 0.10
Total impurities — — 0.5
a
Salt counter ion is included in the table for identification purposes only.
b
2-(4-Chlorophenyl)-4-(dimethylamino)-2-[2-(dimethylamino)ethyl]butanenitrile.
c
Di(pyridin-2-yl)amine.
Relative Relative Acceptance
Retention Response Criteria,
Name Time Factor NMT (%)
d
Used only to establish the system suitability.
e
3-(4-Chlorophenyl)-N-methyl-3-(pyridin-2-yl)propan-1-amine.
f
2-(4-Chlorophenyl)-4-(dimethylamino)-2-(pyridin-2-yl)butanenitrile.
SPECIFIC TESTS
• OPTICAL ROTATION 〈781〉
Sample: 100 mg/mL in water at 20°
Acceptance criteria: –0.10° to +0.10°
• LOSS ON DRYING 〈731〉
Analysis: Dry at 105° for 3 h.
Acceptance criteria: NMT 0.5%
ADDITIONAL REQUIREMENTS
• PACKAGING AND STORAGE: Preserve in tight, light-resistant containers.
• USP REFERENCE STANDARDS 〈11〉
USP Chlorpheniramine Maleate RS
USP Chlorpheniramine Related Compound B RS
Di(pyridin-2-yl)amine.
C10H9N3 171.20
USP Chlorpheniramine Related Compound C RS
3-(4-Chlorophenyl-N-methyl-3-(pyridin-2-yl)propan-1-amine.
C15H17ClN2 260.76
USP Pheniramine Maleate RS
Auxiliary Information— Please check for your question in the FAQs before
contacting USP.
Topic/Question Contact Expert Committee
Monograph Richard Nguyen (CHM62015) Chemical
Medicines Monographs 6
(301) 816-8170
〈197〉 Edmond Biba, Ph.D. (GCCA2015) General
Chapters-Chemical
Scientific Liaison Analysis 2015
Topic/Question Contact Expert Committee
(301) 230-3270
〈281〉 Antonio Hernandez- (GCPA2015) General
Cardoso, M.Sc. Chapters-Physical
Senior Scientific Analysis 2015
Liaison
(301) 816-8308
〈781〉 Antonio Hernandez- (GCPA2015) General
Cardoso, M.Sc. Chapters-Physical
Senior Scientific Analysis 2015
Liaison
(301) 816-8308
〈731〉 Antonio Hernandez- (GCPA2015) General
Cardoso, M.Sc. Chapters-Physical
Senior Scientific Analysis 2015
Liaison
(301) 816-8308
Reference RS Technical
Standards Services
1-301-816-8129
rstech@usp.org
USP40–NF35 Page 3385
Previously Appeared In:
Pharmacopeial Forum: Volume No. 38(6)
