Promethazine Hydrochloride Oral Solution

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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To view the Notice from the Expert Committee that posted in conjunction with this accelerated revision, please click www.uspnf.com/rb promethazine-hcl-os-20231027. 

1 DEFINITION 

Promethazine Hydrochloride Oral Solution contains NLT 90.0% 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 

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

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

3 ASSAY 

Procedure 

Buffer: 3.7 g/L of ammonium acetate in water 

Solution A: Acetonitrile and Buffer (30:70) 

Solution B: Acetonitrile 

Mobile phase: See Table 1. 

Table 1 

Diluent: 0.1% triethylamine in methanol 

System suitability solution: 1.0 µg/mL each of USP Promethazine Hydrochloride RS and USP Promethazine Related Compound B RS in Diluent 

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

Sample solution: Nominally 0.05 mg/mL of promethazine hydrochloride from a volume of Oral Solution in Diluent. Centrifuge for 10 min and use the supernatant. 

[Note—Sonication may be used in the preparation of the System suitability solution, Standard solution, and Sample solution.] Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 254 nm. For Identification test B, use a diode array detector in the range of 200–400 nm. 

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

Temperatures 

Autosampler: 4° 

Column: 30° 

Flow rate: 1.4 mL/min 

Injection volume: 15 µL 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—The relative retention times for promethazine and promethazine related compound B are 1.0 and 1.3, respectively.] Suitability requirements 

Resolution: NLT 5.0 between promethazine and promethazine related compound B peaks, System suitability solution Tailing factor: NMT 2.0, Standard solution 

Relative standard deviation: NMT 1.0%, 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 Oral Solution 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: 90.0%–110.0% 

4 IMPURITIES 

Change to read: 

Organic Impurities 

Buffer, Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay. Standard solution: 1.0 µg/mL each of USP Promethazine Hydrochloride RS and USP Promethazine Related Compound B RS in Diluent Sample solution: Nominally 500 µg/mL of promethazine hydrochloride from a volume of Oral Solution in Diluent. Centrifuge for 10 min and use the supernatant. 

[Note—Sonication may be used in the preparation of the Standard solution and the Sample solution.] 

System suitability 

Sample: Standard solution 

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

Suitability requirements 

Resolution: NLT 5.0 between promethazine and promethazine related compound B peaks 

Relative standard deviation: NMT 5.0% for promethazine 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of each degradation product in the portion of Oral Solution taken: 

Result = (r_U/r ) × (C /C_U) × (1/F) × 100 

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

r_S = peak response of promethazine from the Standard solution 

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

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

F = relative response factor (see Table 2) 

Acceptance criteria: See Table 2. Disregard peaks 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 which is controlled in the drug substance and is included in the table for identification only. d 10H-Phenothiazine. 

5 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