Levocetirizine Dihydrochloride

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₂₁H₂₅ClN₂O₃ · 2HCl 461.81

Acetic acid, [2-[4-[(R)-(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-, dihydrochloride;

(2-{4-[(R)-(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetic acid dihydrochloride CAS RN®: 130018-87-0.

Levocetirizine free base

C₂₁H₂₅ClN₂O₃ 388.89 CAS RN®: 130018-77-8.

1 DEFINITION

Levocetirizine Dihydrochloride contains NLT 98.0% and NMT 102.0% of levocetirizine dihydrochloride (C₂₁H₂₅ClN₂O₃· 2HCl), calculated on the dried basis.

2 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 levocetirizine peak of the System suitability solution, as obtained in the test for Enantiomeric Purity.

C. Identification Tests—General 〈191〉, Chloride: Meets the requirements

3 ASSAY

3.1 Procedure

Mobile phase: Acetonitrile, water, and 1 M sulfuric acid TS (93: 6.6: 0.4)

Standard solution: 0.05 mg/mL of USP Levocetirizine Dihydrochloride RS in Mobile phase

Sample solution: 0.05 mg/mL of Levocetirizine Dihydrochloride in Mobile phase

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-μm packing L3

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 20 μL

3.3 System suitability

Sample: Standard solution

3.4 Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

3.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of levocetirizine dihydrochloride (C₂₁H₂₅ClN₂O₃ · 2HCl) in the portion of Levocetirizine Dihydrochloride taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of levocetirizine from the Sample solution

r_S = peak response of levocetirizine from the Standard solution

C_S = concentration of USP Levocetirizine Dihydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Levocetirizine Dihydrochloride in the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.2%

4.1 Organic Impurities

Mobile phase: Acetonitrile, water, and 1 M sulfuric acid TS (93:6.6:0.4)

System suitability solution: 0.2 mg/mL of USP Levocetirizine Dihydrochloride RS and 0.2 μg/mL each of USP Levocetirizine Amide RS and USP Chlorobenzhydryl Piperazine RS in Mobile phase. Use the solution within 16 h.

Standard solution: 0.2 μg/mL each of USP Levocetirizine Dihydrochloride RS, USP Levocetirizine Amide RS, and USP Chlorobenzhydryl Piperazine RS in Mobile phase. Use the solution within 16 h.

Sample solution: 200 μg/mL of Levocetirizine Dihydrochloride in Mobile phase. Use the solution within 16 h.

4.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-μm packing L3

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 20 μL

Run time: NLT 3 times the retention time of levocetirizine

4.3 System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 1 for the relative retention times.]

4.4 Suitability requirements

Resolution: NLT 3.0 between levocetirizine and chlorobenzhydryl piperazine, System suitability solution

Tailing factor: NMT 2.0 for levocetirizine, System suitability solution

Relative standard deviation: NMT 5.0% for levocetirizine, Standard solution

4.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of levocetirizine amide or chlorobenzhydryl piperazine in the portion of Levocetirizine Dihydrochloride taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of levocetirizine amide or chlorobenzhydryl piperazine from the Sample solution

r_S = peak response of levocetirizine amide or chlorobenzhydryl piperazine from the Standard solution

C_S = concentration of USP Levocetirizine Amide RS or USP Chlorobenzhydryl Piperazine RS in the Standard solution (μg/mL)

C_U = concentration of Levocetirizine Dihydrochloride in the Sample solution (μg/mL)

Calculate the percentage of any unspecified impurity in the portion of Levocetirizine Dihydrochloride taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of any unspecified impurity from the Sample solution

r_S = peak response of levocetirizine from the Standard solution

C_S = concentration of USP Levocetirizine Dihydrochloride RS in the Standard solution (μg/mL)

C_U = concentration of Levocetirizine Dihydrochloride in the Sample solution (μg/mL)

Acceptance criteria: See Table 1.

Table 1

Enantiomeric Purity

Protect solutions containing levocetirizine from direct exposure to light.

Buffer: 1.5 g/L of ammonium acetate in water. Adjust with glacial acetic acid to a pH of 4.8.

Mobile phase: Acetonitrile and Buffer (30:70)

System suitability solution: 0.5 mg/mL of USP Cetirizine Hydrochloride RS in water

Sample solution: 0.5 mg/mL of Levocetirizine Dihydrochloride in water

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-μm packing L90. [Note—A suitable guard column may be used.]

Column temperature: 30°

Flow rate: 0.5 mL/min

Injection volume: 20 μL

Run time: NLT 1.8 times the retention time of levocetirizine

System suitability

Sample: System suitability solution

[Note—The relative retention times for the S-enantiomer (of cetirizine) and levocetirizine, which is the R-enantiomer (of cetirizine), are about 0.83 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.4 between the S-enantiomer and levocetirizine

Tailing factor: NMT 2.0 for levocetirizine

Relative standard deviation: NMT 1.5% each for levocetirizine and the S-enantiomer

Analysis

Sample: Sample solution

Calculate the percentage of the S-enantiomer in the portion of Levocetirizine Dihydrochloride taken:

Result = (r_U/r_T ) × 100

r_U = peak response of the S-enantiomer from the Sample solution

r_T = sum of the peak responses of the S-enantiomer and levocetirizine from the Sample solution

Acceptance criteria: NMT 2.0% of the S-enantiomer

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry at 105° to constant weight.

Acceptance criteria: NMT 1.0%

pH 〈791〉

Sample solution: 50 mg/mL of Levocetirizine Dihydrochloride in water

Acceptance criteria: 1.2–1.8

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, protected from light at controlled room temperature.

USP Reference Standards 〈11〉

USP Cetirizine Hydrochloride RS

USP Chlorobenzhydryl Piperazine RS

(R)-1-[(4-Chlorophenyl)phenylmethyl]piperazine.

C₁₇H₁₉ClN₂ 286.80

USP Levocetirizine Amide RS

(R)-2-(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)acetamide.

C₂₁H₂₆ClN₃O₂ 387.90

USP Levocetirizine Dihydrochloride RS