Cetirizine Hydrochloride
(se tir' i zeen hye'' droe klor' ide).
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C21H25ClN2O3·2HCl 461.81
(±)-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, dihydrochloride;    
(±)-[2-[4-(p-Chloro--phenylbenzyl)-1-piperazinyl]ethoxy]acetic acid, dihydrochloride     [83881-52-1].
DEFINITION
Cetirizine Hydrochloride contains NLT 98.0% and NMT 102.0% of C21H25ClN2O3·2HCl, calculated on the dried basis.
IDENTIFICATION
•  B. Identification Test—General, Chloride 191: Meets the requirements
ASSAY
•  Procedure
Mobile phase:  Acetonitrile, water, and 1 M sulfuric acid (93:6.6:0.4)
Standard solution:  0.5 mg/mL USP Cetirizine Hydrochloride RS in Mobile phase
Sample solution:  0.5 mg/mL Cetirizine Hydrochloride in Mobile phase
Chromatographic system 
Mode:  LC
Detector:  UV 230 nm
Column:  4.6-mm × 25-cm; 5-µm packing L3
Flow rate:  1 mL/min
Injection size:  10 µL
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 percentage of C21H25ClN2O3·2HCl in the portion of Cetirizine Hydrochloride 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 Cetirizine Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Cetirizine Hydrochloride in the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0% on the dried basis
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.2%
Organic Impurities 
[Note—It is recommended that Test 2 be performed if either cetirizine ethanol (2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}ethanol) or cetirizine acetic acid (2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}acetic acid) may be present in the test substance. ]
•  Procedure 1
Mobile phase and Sample solution:  Proceed as directed in the Assay.
System suitability solution:  4 µg/mL each of USP Cetirizine Hydrochloride RS and USP Cetirizine Related Compound A RS in Mobile phase
Standard solution:  0.5 µg/mL of USP Cetirizine Hydrochloride RS in Mobile phase
Chromatographic system:  Prepare as directed in the Assay.
Run time:  Three times the retention time of cetirizine
System suitability 
Samples:  Standard solution and System suitability solution
Suitability requirements 
Tailing factor:  NMT 2.0 for cetirizine, System suitability solution
Resolution:  NLT 2.0 between cetirizine and cetirizine related compound A, System suitability solution
Relative standard deviation:  NMT 2.0% cetirizine, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Cetirizine hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response for each impurity from the Sample solution
rS== peak response for cetirizine from the Standard solution
CS== concentration of USP Cetirizine Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Cetirizine Hydrochloride in the Sample solution (mg/mL)
F== relative response factor (see Impurity Table 1 for values)
Acceptance criteria:  See Impurity Table 1.
Total impurities:  NMT 0.3%. [Note—Disregard peaks below 0.02%. ]
Impurity Table 1
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
4-CBHa 0.3 1.4 0.1
Dimerb 0.5 1.8 0.1
2-Chlorocetirizinec 0.85 0.49 0.1
Cetirizine related compound Ad 0.9 0.95 0.1
Cetirizine 1.0
Deschlorocetirizinee 1.4 0.45 0.1
CBHPf 1.45 1.6 0.1
Any individual unspecified impurity 1.0 0.1
a  4-Chlorobenzhydrol.
b  1,4-Bis[(4-chlorophenyl)phenylmethyl]piperazine.
c  2-[2-[4-[(2-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid.
d  2-[2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid, ethyl ester (cetirizine ethyl ester).
e  2-[2-[4-(Diphenylmethyl]piperazin-1-yl]ethoxy]acetic acid.
f  1-[(4-Chlorophenyl)phenylmethyl]piperazine.
•  Procedure 2
Solution A:  2 g/L tetrabutyl ammonium hydrogen sulfate and 3 g/L of monobasic sodium phosphate monohydrate in water. Adjust with 1 N sodium hydroxide to a pH of 2.8 ± 0.05.
Solution B:  Methanol
Buffer:  1.4 g/L monobasic sodium phosphate monohydrate and 2.7 g/L of dibasic sodium phosphate heptahydrate. Adjust with either 1 N sodium hydroxide or 10% phosphoric acid to a pH of 6.9 ± 0.1.
Diluent:  Acetonitrile and Buffer (1:1)
Mobile phase:  See the gradient table below.
Time
(min)
Solution A
(%)
Solution B
(%)
Flow Rate
(mL/min)
0 58 42 1.2
40 58 42 1.2
68 20 80 1.5
108 20 80 1.5
110 58 42 1.2
120 58 42 1.2
Standard solution:  2 µg/mL of USP Cetirizine Hydrochloride RS in Diluent
Sample solution:  2 mg/mL cetirizine hydrochloride in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 232 nm
Column:  4.6-mm × 25-cm; 5-µm packing L1
Column temperature:  40
Injection size:  10 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Tailing factor:  NMT 2
Column efficiency:  NLT 6000 theoretical plates
Relative standard deviation:  NMT 5.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Cetirizine Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response for each impurity from the Sample solution
rS== peak response for cetirizine from the Standard solution
CS== concentration of USP Cetirizine Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Cetirizine Hydrochloride in the Sample solution (mg/mL)
F== relative response factor (see Impurity Table 2 for values)
Acceptance criteria:  See Impurity Table 2.
Total impurities:  NMT 0.3%. [Note—Disregard peaks below 0.05%. ]
Impurity Table 2
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
Deschlorocetirizinea 0.35 0.56 0.1
Cetirizine ethanolb 0.53 1.2 0.1
CBHPc 0.66 1.3 0.1
2-Chlorocetirizined 0.70 0.52 0.1
Cetirizine methyl estere 0.81 0.96 0.1
3-Chlorocetirizinef 0.87 0.52 0.1
Cetirizine 1.0
Cetirizine acetic acidg 1.15 0.97 0.1
Cetirizine N-oxideh 1.25 0.81 0.1
4-CBHi 1.55 1.2 0.1
4-Chlorobenzophenonej 1.66 0.50 0.1
Cetirizine dimerk 2.48 1.4 0.1
Any individual unspecified impurity 1.0 0.10
a  2-{2-[4-(Diphenylmethyl)piperazin-1-yl]ethoxy}acetic acid.
b  2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}ethanol.
c  1-[(4-Chlorophenyl)phenylmethyl]piperazine.
d  2-(2-{4-[(2-Chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetic acid.
e  Methyl 2-(2-{4-[(4-chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetate.
f  2-[2-[4-[(3-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid.
g  2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}acetic acid.
h  2-(2-{4-[(4-Chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)acetic acid N1-oxide.
i  4-Chlorobenzhydrol.
j  (4-Chlorophenyl)phenylmethanone.
k  1,4-Bis[(4-chlorophenyl)phenylmethyl]piperazine.
SPECIFIC TESTS
•  pH 791: 1.2-1.8, in an aqueous solution 1 in 20
•  Loss on Drying 731: Dry a sample at 105 to a constant weight: it loses NMT 0.5% of its weight.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers, protected from light and moisture. Store at room temperature.
•  Labeling: Label it to indicate with which impurity procedures the article complies.
•   USP Reference Standards 11
USP Cetirizine Hydrochloride RS Click to View Structure
USP Cetirizine Related Compound A RS
(RS)-2-[2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid ethyl ester dihyrochloride.
    C23H29ClN2O3·2HCl        489.86
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Topic/Question Contact Expert Committee
Monograph Domenick Vicchio, Ph.D.
Senior Scientific Liaison
1-301-998-6828
(SM42010) Monographs - Small Molecules 4
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USP35–NF30 Page 2597