Promethazine Hydrochloride Tablets

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 Tablets contain NLT 95.0% and NMT 110.0% of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl).

[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

2.1 A.

Standard solution: In a separator, dissolve 50 mg of USP Promethazine Hydrochloride RS in 40 mL of dilute hydrochloric acid (1 in 1000).

Sample solution: Shake a quantity of powdered Tablets, equivalent to 50 mg of promethazine hydrochloride, with 30 mL of chloroform, and filter into a beaker. Evaporate the chloroform, dissolve the residue in 40 mL of dilute hydrochloric acid (1 in 1000), and transfer the liquid to a separator.

Analysis: Separately treat the Sample solution and the Standard solution as follows. Add 2 mL of 1 N sodium hydroxide and 15 mL of carbon disulfide to the separators, and shake for 2 min. Centrifuge if necessary to clarify the lower phase, and pass through a dry filter, collecting the filtrate from each separator in a small flask provided with a glass stopper. Reduce the volume of the carbon disulfide extracts to 4–5 mL, and proceed as directed in Identification—Organic Nitrogenous Bases 〈181〉, beginning with “Determine the absorption spectra”.

Acceptance criteria: Meet the requirements

2.2 B. 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

3.1 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 stock solution: Nominally 2.5–5.0 mg/mL of promethazine hydrochloride prepared as follows. Transfer 20 Tablets to a volumetric flask of an appropriate size and add 50% of the flask volume of Diluent. Sonicate with swirling for NLT 20 min, or until the Tablets have fully disintegrated. Shake the flask for NLT 15 min and dilute with Diluent to volume.

Sample solution: Nominally 0.1 mg/mL of promethazine hydrochloride in Diluent from the Sample stock solution. Pass a portion through a filter of 0.45-µm pore size and use the clear filtrate.

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 the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

C_U = nominal concentration of promethazine hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 95.0%–110.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

Test 1

Medium: 0.01 N hydrochloric acid; 900 mL

Apparatus 1: 100 rpm

Time: 45 min

Standard solution: Prepare a solution with a known concentration of USP Promethazine Hydrochloride RS in Medium.

Sample solution: A filtered portion of the solution under test, suitably diluted with Medium

Instrumental conditions

Mode: UV

Analytical wavelength: Absorption maximum at about 249 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl) dissolved:

Result = (A_U/A_S) × (C_S/C_U) × D × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

C_U = nominal concentration of promethazine hydrochloride in the Sample solution (mg/mL)

D = dilution factor for the Sample solution

Tolerances: NLT 75% (Q) of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2.

Medium: 0.01 N hydrochloric acid; 900 mL

Apparatus 1: 100 rpm

Time: 15 min

Standard solution: (L/900) mg/mL of USP Promethazine Hydrochloride RS in Medium, where L is the label claim (mg/Tablet)

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.

Instrumental conditions

Mode: UV

Analytical wavelength: Absorption maximum at about 249 nm

Cell: 0.2 cm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl) dissolved:

Result = (A_U/A_S) × C × V × (1/L) × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S · HCl) is dissolved.

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

5.1 Organic Impurities

Diluent: Methanol and triethylamine (999:1)

Buffer: 3.7 g/L of ammonium acetate in water

Solution A: Buffer and acetonitrile (700:300)

Solution B: Acetonitrile

Mobile phase: See Table 1.

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: Nominally 0.5 mg/mL of promethazine hydrochloride from powdered Tablets (NLT 20) prepared as follows. Transfer a quantity of powdered Tablets, equivalent to 50 mg of promethazine hydrochloride, to a volumetric flask of appropriate size and add 75% of the flask volume of Diluent. Shake the flask for NLT 5 min and dilute with Diluent to volume. Pass a portion through a suitable filter.

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 Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

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

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

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

C_U = nominal concentration of promethazine hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Calculate the percentage of all other degradation products in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100

r_U = peak response of each degradation product at 249 nm from the Sample solution

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

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

C_U = nominal 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%.

Table 2

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

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

ᶜ This is a process impurity and is included for identification only. It is not to be reported and not to be included in the total degradation products.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers. Store at controlled room temperature.

Labeling: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used.

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