Hydroxyzine Hydrochloride

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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1 DEFINITION

Hydroxyzine Hydrochloride contains NLT 98.0% and NMT 102.0% of hydroxyzine hydrochloride (C₂₁H₂₇ClN₂O₂ · 2HCl), calculated on the anhydrous basis.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 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.

Change to read:

C.

Sample solution: 2.5 mg/mL of Hydroxyzine Hydrochloride in water

Analysis: To 10 mL of the Sample solution, add 2 drops of nitric acid and 1 mL of silver nitrate TS.

Acceptance criteria: A curdy, white precipitate, insoluble in 2 N nitric acid ▲TS▲ (USP 1-May-2022) but soluble in 6 N ammonium hydroxide, separates (presence of chloride).

3 ASSAY

Procedure

Solution A: Trifluoroacetic acid and water (0.1:99.9)

Solution B: Trifluoroacetic acid and acetonitrile (0.05:99.95)

Mobile phase: See Table 1.

Diluent: Acetonitrile and water (30:70)

Standard solution: 0.05 mg/mL of USP Hydroxyzine Hydrochloride RS in Diluent

Sample solution: 0.05 mg/mL of Hydroxyzine Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 2.1-mm × 15-cm; 1.8-µm packing L1

Flow rate: 0.3 mL/min

Injection volume: 2 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of hydroxyzine hydrochloride (C₂₁H₂₇ClN₂O₂ · 2HCl) in the portion of Hydroxyzine Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of hydroxyzine from the Sample solution

rₛ = peak response of hydroxyzine from the Standard solution

Cₛ = concentration of USP Hydroxyzine Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = concentration of Hydroxyzine Hydrochloride in the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.5%

Change to read:

Organic Impurities

Solution A, Solution B, Mobile phase, and Diluent: Prepare as directed in the Assay.

Standard solution: 1.5 µg/mL each of USP Hydroxyzine Hydrochloride RS, USP Hydroxyzine Related Compound A RS, and USP 4-Chlorobenzophenone RS in Diluent

Sample solution: 500 µg/mL of Hydroxyzine Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detectors

Decloxizine, hydroxyzine related compound A, and hydroxyzine: UV 230 nm

4-Chlorobenzophenone: UV 254 nm

Column: 2.1-mm × 15-cm; 1.8-µm packing L1

Flow rate: 0.3 mL/min

Injection volume: 2 µL

System suitability

Sample: Standard solution

[Note—See Table 2 for the relative retention times.]

Suitability requirements

Resolution: NLT 5.0 between hydroxyzine related compound A and hydroxyzine

Relative standard deviation: NMT 3.0% for hydroxyzine related compound A, hydroxyzine, and 4-chlorobenzophenone

Analysis

Samples: Standard solution and Sample solution

For impurities detected at UV 230 nm

Calculate the percentage of hydroxyzine related compound A in the portion of Hydroxyzine Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of hydroxyzine related compound A from the Sample solution

rₛ = peak response of hydroxyzine related compound A from the Standard solution

Cₛ = concentration of USP Hydroxyzine Related Compound A RS in the Standard solution (µg/mL)

Cᵤ = concentration of Hydroxyzine Hydrochloride in the Sample solution (µg/mL)

Calculate the percentage of decloxizine or any individual unspecified impurity in the portion of Hydroxyzine Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1/F) × 100

rᵤ = peak response of decloxizine or any other individual impurity from the Sample solution

rₛ = peak response of hydroxyzine from the Standard solution

Cₛ = concentration of USP Hydroxyzine Hydrochloride RS in the Standard solution (µg/mL)

Cᵤ = concentration of Hydroxyzine Hydrochloride in the Sample solution (µg/mL)

F = relative response factor (see Table 2)

For 4-chlorobenzophenone detected at UV 254 nm

Calculate the percentage of 4-chlorobenzophenone in the portion of Hydroxyzine Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response of 4-chlorobenzophenone from the Sample solution

rₛ = peak response of 4-chlorobenzophenone from the Standard solution

Cₛ = concentration of USP 4-Chlorobenzophenone RS in the Standard solution (µg/mL)

Cᵤ = concentration of Hydroxyzine Hydrochloride in the Sample solution (µg/mL)

Acceptance criteria: See Table 2. ▲The reporting threshold is 0.05%.▲ (USP 1-May-2022)

Table 2

ᵃ 2-[2-(4-Benzhydrylpiperazin-1-yl)ethoxy]ethanol; also known as

2-{2-[4-(diphenylmethyl)piperazin-1-yl]ethoxy}ethanol.

5 SPECIFIC TESTS

Change to read:

Water Determination 〈921〉, ▲Method I:▲ (USP 1-May-2022) NMT 5.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature. Protect from light.

USP Reference Standards 〈11〉

USP 4-Chlorobenzophenone RS

4-Chlorobenzophenone.

C₁₃H₉ClO 216.66

USP Hydroxyzine Hydrochloride RS

USP Hydroxyzine Related Compound A RS

1-[(4-Chlorophenyl)phenylmethyl]piperazine;

Also known as p-Chlorobenzhydrylpiperazine.

C₁₇H₁₉ClN₂ 286.80