Promethazine 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

Promethazine Hydrochloride contains NLT 97.0% and NMT 101.5% of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl), calculated on the dried basis.

[Note—Throughout the following procedures, protect the samples, the Reference Standards, and the solutions containing them, by conducting the procedures without delay under subdued light or using low-actinic glassware.]

2 IDENTIFICATION

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

B. Identification Tests—General 〈191〉, Chloride

C. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

Procedure

Diluent: Dissolve 8.2 mL of hydrochloric acid in 1000 mL of water.

Mobile phase: Acetonitrile, water, and triethylamine (850:270:1)

System suitability stock solution:

1.2 mg/mL of USP Promethazine Related Compound B RS in Diluent. Sonicate to dissolve.

Standard solution:

0.1 mg/mL of USP Promethazine Hydrochloride RS in Diluent. Sonicate to dissolve.

System suitability solution:

0.09 mg/mL of USP Promethazine Hydrochloride RS and 0.12 mg/mL of USP Promethazine Related Compound B RS in Diluent from the Standard solution and System suitability stock solution, respectively

Sample solution:

0.1 mg/mL of Promethazine Hydrochloride in Diluent. Sonicate to dissolve.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 30-cm; 10-µm packing L1

Flow rate: 2.5 mL/min

Injection volume: 20 µL

Run time: NLT 2.5 times the retention time of promethazine

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for promethazine related compound B and promethazine are 0.82 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.5 between promethazine and promethazine related compound B, System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl) in the portion of Promethazine 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 Promethazine Hydrochloride RS in the Standard solution (mg/mL)

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

Acceptance criteria: 97.0%–101.5% on the dried basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Change to read:

Organic Impurities

Diluent: Methanol and triethylamine (999:1)

Buffer: 3.7 g/L of ammonium acetate in water

Solution A: Acetonitrile and Buffer (300:700)

Solution B: Acetonitrile

Mobile phase: See Table 1.

System suitability stock solution:

0.5 mg/mL of USP Promethazine Related Compound B RS in Diluent

Standard stock solution:

0.5 mg/mL of USP Promethazine Hydrochloride RS in Diluent

System suitability solution:

5 µg/mL each of USP Promethazine Hydrochloride RS and USP Promethazine Related Compound B RS from the Standard stock solution and System suitability stock solution, respectively▲, in Diluent▲ (ERR 1-Sep-2022)

Standard solution:

5 µg/mL of USP Promethazine Hydrochloride RS from the Standard stock solution▲in Diluent▲ (ERR 1-Sep-2022)

Sensitivity solution:

0.25 µg/mL of USP Promethazine Hydrochloride RS from the Standard solution▲in Diluent▲ (ERR 1-Sep-2022)

Sample solution:

0.5 mg/mL of Promethazine Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 234 and 249 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Column temperature: 30°

Flow rate: 1.4 mL/min

Injection volume: 15 µL

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

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

Suitability requirements

Resolution: NLT 5.0 between promethazine and promethazine related compound B, System suitability solution

Relative standard deviation: NMT 3.0% at 234 and 249 nm, Standard solution

Signal-to-noise ratio: NLT 10 at 234 and 249 nm, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of promethazine sulfoxide in the portion of Promethazine Hydrochloride taken:

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

rᵤ = peak response of promethazine sulfoxide at 234 nm from the Sample solution

rₛ = peak response of promethazine hydrochloride at 234 nm from the Standard solution

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

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

F = relative response factor (see Table 2)

Calculate the percentage of all other impurities in the portion of Promethazine Hydrochloride taken:

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

rᵤ = peak response of each impurity at 249 nm from the Sample solution

rₛ = peak response of promethazine hydrochloride at 249 nm from the Standard solution

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

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

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

Disregard peaks that are less than 0.05%.

a N,N-Dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine sulfoxide.

b N-Methyl-1-(10H-phenothiazin-10-yl)propan-2-amine.

5 SPECIFIC TESTS

pH 〈791〉

Sample solution: 50 mg/mL of Promethazine Hydrochloride

Acceptance criteria: 4.0–5.0

Loss on Drying 〈731〉

Analysis: Dry at 105° for 4 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers.

USP Reference Standards 〈11〉

USP Promethazine Hydrochloride RS

USP Promethazine Related Compound B RS

Isopromethazine hydrochloride;

N,N-Dimethyl-2-(10H-phenothiazin-10-yl)propan-1-amine hydrochloride.

C₁₇H₂₀N₂S · HCl 320.88