Cetirizine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets
DEFINITION
Cetirizine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of cetirizine hydrochloride (C21H25ClN2O3·2HCl) and pseudoephedrine hydrochloride (C10H15NO·HCl).
IDENTIFICATION
• The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.
ASSAY
• Cetirizine Hydrochloride
Buffer:
3.5 g/L of monobasic ammonium phosphate and 1.0 g/L of tetrabutylammonium bisulfate in water. Adjust with phosphoric acid to a pH of 2.5.
Diluent:
Methanol and Buffer (2:3)
Solution A:
Acetonitrile, methanol, and Buffer (9:2:29)
Solution B:
Acetonitrile
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 100 | 0 |
| 27.0 | 100 | 0 |
| 30.0 | 0 | 100 |
| 30.1 | 100 | 0 |
| 35.0 | 100 | 0 |
Standard stock solution:
0.5 mg/mL of USP Cetirizine Hydrochloride RS in Diluent. [Note—Sonicate to dissolve. ]
Standard solution:
0.025 mg/mL of USP Cetirizine Hydrochloride RS in Diluent from the Standard stock solution
Sample solution:
0.025 mg/mL of cetirizine hydrochloride (from NMT 10 finely powdered Tablets) prepared as follows. Dissolve the Tablets first in methanol, using 22.5% of the final flask volume. Sonicate for NLT 20 min with vigorous swirling every 5 min. To the solution add a volume of Buffer equal to 26% of the final flask volume. Allow the solution to equilibrate to room temperature. Dilute with Diluent to volume. Pass a portion through a membrane filter of 0.45-µm pore size.
Chromatographic system
Mode:
LC
Detector:
UV 230 nm
Column:
4.6-mm × 15-cm; 3.5-µm packing L1
Column temperature:
30
Autosampler temperature:
5
Flow rate:
1mL/min
Injection size:
25 µL
System suitability
Sample:
Standard solution
Suitability requirements
Column efficiency:
NLT 3000 theoretical plates
Tailing factor:
NMT 1.5
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of cetirizine hydrochloride (C21H25ClN2O3·2HCl) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of cetirizine from the Sample solution |
| rS | = | = peak response of cetirizine from the Standard solution |
| CS | = | = concentration of USP Cetirizine Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of cetirizine hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
• Pseudoephedrine Hydrochloride
Buffer:
0.8 g/L of ammonium acetate in water. To 1 L of the solution add 1.0 mL of triethylamine. Adjust with glacial acetic acid to a pH of 4.5.
Mobile phase:
Acetonitrile and Buffer (3:7)
Standard solution:
0.5 mg/mL of USP Pseudoephedrine Hydrochloride RS in Mobile phase. [Note—Sonicate to dissolve. ]
Sample stock solution:
2.4 mg/mL of pseudoephedrine hydrochloride (from 5 finely powdered Tablets) prepared as follows. Dissolve the crushed Tablets first in acetonitrile, using 24% of the final flask volume. Sonicate for NLT 15 min. To the solution add a volume of Buffer equal to 56% of the final flask volume. Sonicate for NLT 15 min. Shake the flask for NLT 10 min. Allow the solution to equilibrate to room temperature. Dilute with Mobile phase to volume. Centrifuge a portion for 15 min to obtain a clear supernatant.
Sample solution:
0.5 mg/mL of pseudoephedrine hydrochloride in Mobile phase, from the Sample stock solution. Pass the solution through a membrane filter of 0.45-µm pore size.
Chromatographic system
Mode:
LC
Detector:
UV 254 nm
Column:
4.6-mm × 15-cm; 5-µm packing L9
Flow rate:
1.5 mL/min
Injection size:
25 µL
Run time:
2 times the retention time of pseudoephedrine
System suitability
Sample:
Standard solution
Suitability requirements
Column efficiency:
NLT 1000 theoretical plates
Tailing factor:
NMT 2.0
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of pseudoephedrine hydrochloride (C10H15NO·HCl) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of pseudoephedrine from the Sample solution |
| rS | = | = peak response of pseudoephedrine from the Standard solution |
| CS | = | = concentration of USP Pseudoephedrine Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of pseudoephedrine hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 
711
711
Medium:
0.1 N hydrochloric acid; 500 mL, deaerated
Apparatus 1:
100 rpm
Time:
30 min for cetirizine hydrochloride and 30 min (used only for adjustments in the calculations), 1, 2, and 6 h for pseudoephedrine hydrochloride
Buffer:
0.77 g/L of ammonium acetate in water. To 1 L of the solution add 1.0 mL of triethylamine. Adjust with glacial acetic acid to a pH of 4.5 ± 0.05.
Mobile phase:
Acetonitrile and Buffer (3:7)
Standard stock solution:
0.5 mg/mL of USP Cetirizine Hydrochloride RS in water
Standard solution:
0.24 mg/mL of USP Pseudoephedrine Hydrochloride RS and 0.01 mg/mL of USP Cetirizine Hydrochloride RS in Medium from the Standard stock solution
Sample solution:
At the times specified, withdraw 5 mL of the solution under test, and pass through a suitable filter of 0.45-µm pore size, discarding the first few mL.
Chromatographic system
Mode:
LC
Detector:
UV, 230 nm for cetirizine hydrochloride, 254 nm for pseudoephedrine hydrochloride
Column:
4.6-mm × 15-cm; 5-µm packing L9
Flow rate:
1.5 mL/min
Injection size:
25 µL
Run time:
2 times the retention time of pseudoephedrine
System suitability
Sample:
Standard solution
Suitability requirements
Tailing factor:
NMT 2.0 for both cetirizine and pseudoephedrine
Relative standard deviation:
NMT 2.0% for both cetirizine and pseudoephedrine
Calculate the percentage of cetirizine hydrochloride dissolved:
Result = (rU/rS) × (CS/L) × V × 100
| rU | = | = peak response of cetirizine from the Sample solution |
| rS | = | = peak response of cetirizine from the Standard solution |
| CS | = | = concentration of cetirizine hydrochloride in the Standard solution (mg/mL) |
| L | = | = cetirizine hydrochloride Tablet label claim (mg) |
| V | = | = volume of Medium, 500 mL |
Calculate the percentage of pseudoephedrine hydrochloride dissolved at each time point:
Q30 = (rU/rS) × (CS/L) × V × 100
Q1 = (Q30 × 5/500) + [(rU/rS) × (CS/L) × 495 × 100]
Q2 = (Q30 × 5/500) + (Q1 × 5/495) + [(rU/rS) × (CS/L) × 490 × 100]
Q6 = (Q30 × 5/500) + (Q1 × 5/495) + (Q2 × 5/490) + [(rU/rS) × (CS/L) × 485 × 100]
| rU | = | = peak response of pseudoephedrine from the Sample solution |
| rS | = | = peak response of pseudoephedrine from the Standard solution |
| CS | = | = concentration of pseudoephedrine hydrochloride in the Standard solution (mg/mL) |
| L | = | = pseudoephedrine hydrochloride Tablet label claim (mg) |
| V | = | = initial volume of Medium, 500 mL |
Tolerances:
NLT 80% (Q) of the labeled amount of cetirizine hydrochloride is dissolved in 30 min. The percentage of the labeled amount of pseudoephedrine hydrochloride dissolved at times specified conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 30%–50% |
| 2 | 50%–70% |
| 6 | NLT 80% |
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure 1: Cetirizine Hydrochloride Related Compounds
Buffer, Diluent, Solution A and Solution B:
Proceed as directed in the Assay for Cetirizine hydrochloride.
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 100 | 0 |
| 27 | 100 | 0 |
| 45 | 60 | 40 |
| 65 | 60 | 40 |
| 65.1 | 100 | 0 |
| 75 | 100 | 0 |
Standard stock solution:
0.5 mg/mL of USP Cetirizine Hydrochloride RS in Diluent. [Note—Sonicate to dissolve. ]
Standard solution:
1 µg/mL of USP Cetirizine Hydrochloride RS in Diluent from the Standard stock solution
Sample stock solution:
0.5 mg/mL of cetirizine hydrochloride (from NMT 10 finely powdered Tablets) prepared as follows. Dissolve the Tablets first in methanol, using 70% of the final flask volume. Sonicate for 15 min, and then shake for 15 min. Allow the solution to cool to room temperature, and dilute with methanol to volume. Centrifuge a portion for 10 min.
Sample solution:
0.2 mg/mL of cetirizine hydrochloride in Buffer, from the Sample stock solution. Pass a portion through a suitable membrane filter of 0.45-µm pore size.
Chromatographic system
Mode:
LC
Detector:
UV 230 nm
Column:
4.6-mm × 15-cm; 3.5-µm packing L1
Column temperature:
30
Autosampler temperature:
5
Flow rate:
1 mL/min
Injection size:
25 µL
System suitability
Sample:
Standard solution
Suitability requirements
Column efficiency:
NLT 1300 theoretical
Tailing factor:
NMT 2.0
Relative standard deviation:
NMT 5.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak response of the individual impurity from the Sample solution |
| rS | = | = peak response of cetirizine from the Standard solution |
| CS | = | = concentration of USP Cetirizine Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of cetirizine hydrochloride in the Sample solution (mg/mL) |
| F | = | = relative response factor (see Impurity Table 1) |
Acceptance criteria:
[Note—Disregard any peak less than 0.05% of the main peak. ]
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 0.8%
Impurity Table 1
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|---|---|---|---|
| Cetirizineethanola | 0.54 | 1.4 | 0.3 |
| Chlorobenzhydryl piperazine (CBHP)b | 0.57 | 1.5 | 0.3 |
| Cetirizine | 1.0 | — | — |
| Cetirizine acetic acidc | 1.30 | 1.1 | 0.3 |
| Cetirizine N-Oxided | 1.47 | 1.2 | 0.3 |
| Any unspecified degradation product | — | 1.0 | 0.2 |
|
a
2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethanol.
b
1-[(4-Chlorophenyl)phenylmethyl]piperazine.
c
2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]acetic acid.
d
2-[4-[(4-Chlorophenyl)phenylmethyl]-1-oxide-1-piperazinyl] ethoxy]acetic
acid. |
|||
• Procedure 2: Pseudoephedrine Hydrochloride Related Compounds
Buffer:
11.2 g/L of monohydrate sodium perchlorate in water. Adjust with hydrochloric acid to a pH of 2.7.
Solution A:
Methanol and Buffer (3:17)
Solution B:
Methanol and Buffer (1:1)
Diluent:
Solution A
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 100 | 0 |
| 10 | 100 | 0 |
| 35 | 28 | 72 |
Standard stock solution:
0.48 mg/mL of USP Pseudoephedrine Hydrochloride RS in Diluent
Standard solution:
4.8 µg/mL of USP Pseudoephedrine Hydrochloride RS in Diluent from the Standard stock solution
System suitability stock solution:
49 µg/mL of ephedrine in Diluent from USP Ephedrine Sulfate RS
System suitability solution:
1.96 µg/mL of ephedrine and 0.46 mg/mL of USP Pseudoephedrine Hydrochloride RS in Standard stock solution from the System suitability stock solution and the Standard stock solution, respectively
Sample stock solution:
2.4 mg/mL of pseudoephedrine hydrochloride (from NMT 25 finely powdered Tablets) prepared as follows. Dissolve the Tablets first in methanol, using 75% of the final flask volume. Sonicate for NLT 15 min, and then shake for 15 min. Allow the solution to cool to room temperature, and dilute with methanol to volume. Centrifuge a portion for 10 min.
Sample solution:
0.48 mg/mL of pseudoephedrine hydrochloride in Diluent, from the Sample stock solution. Pass a portion through a suitable membrane filter of 0.45-µm pore size.
Chromatographic system
Mode:
LC
Detector:
UV 212 nm
Column:
4.6-mm × 25-cm; 4-µm packing L11
Column temperature:
40
Flow rate:
1 mL/min
Injection size:
30 µL
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Resolution:
NLT 1.3 between ephedrine and pseudoephedrine, System suitability solution
Tailing factor:
NMT 1.5, Standard solution
Relative standard deviation:
NMT 3.0%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak response of the individual impurity from the Sample solution |
| rS | = | = peak response of pseudoephedrine from the Standard solution |
| CS | = | = concentration of USP Pseudoephedrine Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of pseudoephedrine hydrochloride in the Sample solution (mg/mL) |
| F | = | = relative response factor (see Impurity Table 2) |
Acceptance criteria
[Note—Disregard any peak less than 0.05% of the main peak. ]
Individual impurities:
See Impurity Table 2.
Total pseudoephedrine related impurities:
NMT 0.5%
Total cetirizine and pseudoephedrine related impurities:
NMT 1.0%
Impurity Table 2
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria, NMT (%) |
|
|---|---|---|---|---|
| Ephedrinea* | 0.95 | — | — | |
| Pseudoephedrine | 1.0 | — | — | |
| Methcathinoneb | 1.1 | 1.1 | 0.2 | |
| Any unspecified degradation product | — | 1.0 | 0.2 | |
|
*
For system suitability and identification purposes.
a
[R-(R*,S*)]-
 -[1-(Methylamino)ethyl]-benzenemethanol.
b
2-Methylamino-1-phenylpropan-1-one.
|
||||
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in well-closed containers. Store at controlled room temperature.
• USP Reference Standards 11
11
USP Cetirizine Hydrochloride RS 
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USP Ephedrine Sulfate RS
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USP Pseudoephedrine Hydrochloride RS
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Domenick Vicchio, Ph.D.
Senior Scientific Liaison 1-301-998-6828 |
(SM42010) Monographs - Small Molecules 4 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2600
Pharmacopeial Forum: Volume No. 36(1) Page 82