Promethazine and Phenylephrine 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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Status: Currently Ocial on 16-Feb-2025 

Ocial Date: Ocial as of 01-May-2019 

Document Type: USP Monographs 

DocId: GUID-F0B9F64F-3D46-4BE3-A6E4-E2A23EA22C7D_2_en-US 

DOI: https://doi.org/10.31003/USPNF_M70200_02_01 

DOI Ref: 2hhs2 

© 2025 USPC 

Do not distribute 

Promethazine and Phenylephrine Hydrochloride Oral Solution 

1 DEFINITION 

Promethazine and Phenylephrine Hydrochloride Oral Solution contains NLT 90.0% and NMT 110.0% of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S.HCl), phenylephrine hydrochloride (C₉H₁₃NO₂.HCl). It may contain suitable preservatives. 

2 IDENTIFICATION 

A. The retention times of the promethazine and phenylephrine peaks of the Sample solutions correspond to those of the Standard solution, as obtained in the Assay. 

Add the following: 

B. The UV absorption spectrum of both promethazine and phenylephrine peaks of the Sample solution exhibits maxima and minima at the same wavelengths as those of the Standard solution, as obtained in the Assay.

ASSAY Procedure 

Protect the sample and Standard solutions by using low-actinic glassware. 

Solution A: Dissolve 2.0 g of monobasic potassium phosphate and 1.0 g of heptane sulfonic acid sodium salt monohydrate in 950 mL of water, and carefully add 50 mL of acetonitrile. Adjust with phosphoric acid to an apparent pH of 3.0. 

Solution B: Dissolve 2.0 g of monobasic potassium phosphate and 1.0 g of heptane sulfonic acid sodium salt monohydrate in 500 mL of water, and add 500 mL of acetonitrile. Adjust with phosphoric acid to an apparent pH of 3.0. 

Mobile phase: See Table 1. 

Table 1 

Standard stock solution A: 1.8 mg/mL of USP Promethazine Hydrochloride RS and 1.4 mg/mL of USP Phenylephrine Hydrochloride RS in Solution A 

Standard stock solution B: 1.4 mg/mL of USP Sodium Benzoate RS, 2.5 mg/mL of USP Methylparaben RS, and 0.28 mg/mL of USP Propylparaben RS. Prepare by dissolving appropriate quantities of USP Methylparaben RS, USP Propylparaben RS, and USP Sodium Benzoate RS into a volume of acetonitrile equivalent to 40% of the total volume of the flask and diluting with Solution A to volume. 

Standard solution: 0.18 mg/mL of USP Promethazine Hydrochloride RS, 0.14 mg/mL of USP Phenylephrine Hydrochloride RS, 0.14 mg/mL of USP Sodium Benzoate RS, 0.25 mg/mL of USP Methylparaben RS, and 0.028 mg/mL of USP Propylparaben RS. Prepare by adding 5.0 mL each of Standard stock solution A and Standard stock solution B to a 50-mL volumetric flask and diluting with Solution A to volume. 

Promethazine hydrochloride sample solution: Nominally equivalent to 0.18 mg/mL of promethazine hydrochloride in Solution A Phenylephrine hydrochloride sample solution: Nominally equivalent to 0.14 mg/mL of phenylephrine hydrochloride in Solution A Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 280 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L1 

Column temperature: 40° 

Flow rate: 1.5 mL/min 

Injection volume: 15 µL 

System suitability 

Sample: Standard solution 

[Note—The relative retention times for benzoate, methylparaben, and propylparaben are 0.59, 0.64, and 1.05, respectively.] Suitability requirements 

Resolution: NLT 4.5 between benzoate and methylparaben; NLT 1.5 between promethazine and propylparaben Relative standard deviation: NMT 2.0% for both promethazine and phenylephrine 

Analysis 

Samples: Standard solution and Promethazine hydrochloride sample solution 

Calculate the percentage of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S.HCl) in the portion of sample taken:

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = promethazine peak response from the Promethazine hydrochloride sample solution

r_S = promethazine 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 Promethazine hydrochloride sample solution (mg/mL)

Samples: Standard solution and Phenylephrine hydrochloride sample solution 

Calculate the percentage of the labeled amount of phenylephrine hydrochloride (C₉H₁₃NO₂.HCl) in the portion of sample taken:

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = phenylephrine peak response from the Phenylephrine hydrochloride sample solution 

r_S = phenylephrine peak response from the Standard solution 

C_S = cconcentration of USP Phenylephrine Hydrochloride RS in the Standard solution (mg/mL) 

C_U = nominal concentration of phenylephrine hydrochloride in the Phenylephrine hydrochloride sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% for both promethazine hydrochloride and phenylephrine hydrochloride 

3 IMPURITIES 

Change to read: 

Organic Impurities, Procedure 1 

Protect the sample and Standard solutions by using low-actinic glassware. 

Solution C: Dissolve 4.36 g of dibasic potassium phosphate in 1 L of water, add 2.0 mL of triethylamine, and adjust with phosphoric acid to a pH of 6.4. 

5 N phosphoric acid: Dilute 12 mL of phosphoric acid with water to 100 mL. 

Diluent: Methanol, water, and 5 N phosphoric acid (5:95:1) 

Mobile phase: Acetonitrile, methanol, and Solution C (30:20:50) 

Standard solution: 3.5 µg/mL of USP Promethazine Hydrochloride RS in Diluent 

Sensitivity solution: 0.18 µg/mL of USP Promethazine Hydrochloride RS in Diluent from the Standard solution. Prepare at time of use. Promethazine hydrochloride sample solution: Nominally equivalent to 175 µg/mL of promethazine hydrochloride in Diluent Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 254 nm 

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

Flow rate: 1.5 mL/min 

Injection volume: 10 µL 

Run time: NLT  2 times the retention time of promethazine for Standards; NLT  6 times the retention time of promethazine for samples 

System suitability 

Samples: Standard solution and Sensitivity solution 

Suitability requirements 

Tailing factor: NMT 1.5 for promethazine, Standard solution 

Relative standard deviation: NMT 7.5% for promethazine, Standard solution 

Signal-to-noise ratio: NLT 10 for promethazine, Sensitivity solution 

Analysis 

Samples: Standard solution and Promethazine hydrochloride sample solution 

Calculate the percentage of each impurity in the portion of Oral Solution taken: 

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

r_U = impurity peak response from the Sample solution 

r_S = promethazine hydrochloride peak response 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 for each impurity (see Table 2) Acceptance criteria: See Table 2. 

Table 2 

^a 10-Methyl-10H-phenothiazine.  

Change to read: 

Organic Impurities, Procedure 2 

Protect the sample and Standard solutions by using low-actinic glassware. 

Solution A, Solution B, Mobile phase, Standard stock solution B, and Phenylephrine hydrochloride sample solution: Prepare as directed in the Assay. 

Standard stock solution A: 88 µg/mL of USP Promethazine Hydrochloride RS in Solution A 

Standard solution: 8.8 µg/mL of USP Promethazine Hydrochloride RS, 140 µg/mL of USP Sodium Benzoate RS, 250 µg/mL of USP Methylparaben RS, and 28 µg/mL of USP Propylparaben RS. Prepare by adding 5.0 mL of Standard stock solution A and 5.0 mL of Standard stock solution B into a 50-mL volumetric flask, and dilute with Solution A to volume. 

Sensitivity solution: 0.18 µg/mL of USP Promethazine Hydrochloride RS in Solution A from Standard stock solution A. Prepare at time of use. Promethazine hydrochloride sample solution: Prepare as directed in the Assay. Use this solution to determine the promethazine related compounds and specified and unknown impurities. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 280 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L1 

Column temperature: 40° 

Flow rate: 1.5 mL/min 

Injection volume: 50 µL 

System suitability 

Samples: Standard solution and Sensitivity solution 

[Note—The relative retention times for benzoate, methylparaben, and propylparaben are 0.59, 0.64, and 1.05, respectively.] Suitability requirements 

Resolution: NLT 4.5 between benzoate and methylparaben; NLT 1.5 between promethazine and propylparaben, Standard solution Relative standard deviation: NMT 7.5% for promethazine, Standard solution 

Signal-to-noise ratio: NLT 10 for promethazine, Sensitivity solution 

Analysis 

Samples: Standard solution and Phenylephrine hydrochloride sample solution 

Identify the phenylephrine impurities using the relative retention times given in Table 3. 

Calculate the percentage of each phenylephrine impurity in the portion of Oral Solution taken: 

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

r_U = peak response of the impurity from the Phenylephrine hydrochloride sample solution

r_S = peak response of promethazine hydrochloride from the Standard solution

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

C_U = nominal concentration of phenylephrine hydrochloride in the Phenylephrine hydrochloride sample solution (µg/mL)

F = relative response factor for each impurity (see Table 3) 

Samples: Standard solution and Promethazine hydrochloride sample solution 

Using the data in Table 4, calculate the percentage of promethazine specified and unidentified impurities and any unspecified impurities in the portion of Oral Solution taken: 

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

r_U = peak response of the impurity from the promethazine hydrochloride sample solution

r_S = peak response of promethazine hydrochloride from the Standard solution

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

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

F = relative response factor for each impurity (see Table 4) 

Acceptance criteria 

Individual impurities: See Table 2, Table 3, and Table 4. 

Total impurities: NMT 16.0%. Sum of the total phenylephrine impurities from Table 3 and total promethazine impurities from Table 4. Table 3 

a 3-Hydroxy-1-methyl-2,3-dihydro-1H-indole-5,6-dione.

b (R)-3-(2-Amino-1-hydroxyethyl)phenol. 

c 7-Hydroxy-1-methyl-1H-indole-3,5,6(2H)-trione. 

d 4-Hydroxy-1-methyl-1H-indole-3,5,6(2H)-trione, and two (R)-  3-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl] (methyl)amino}benzene-1,2-diol isomers. 

e (R)-3-{2-[Benzyl(methyl)amino]-1-hydroxyethyl}phenol. 

f Phenylephrine synthetic impurity. Do not quantify. 

Table 4 

a10H-Phenothiazine sulfoxide.

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

c 10-Methyl-10H-phenothiazine sulfoxide. 

d 1H-Phenothiazin-1-one. 

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

f Promethazine synthetic impurity. Do not quantify. 

g Includes phenothiazine and methylphenothiazine from Procedure 1. 

4 SPECIFIC TESTS 

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉: The total aerobic microbial limit does not exceed 102 cfu/mL. The total yeasts and molds count does not exceed 10 cfu/mL. It meets the requirements for absence of Escherichia coli. pH 〈791〉: 3.7–4.7 

Alcohol Determination 〈611〉, Procedures, Method II—Gas Chromatographic Method (if present): 90.0%–110.0% of the labeled quantity of alcohol (C₂H₅OH ). 

Deliverable Volume 〈698〉: Meets the requirements 

5 ADDITIONAL REQUIREMENTS 

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

USP Reference Standards 〈11〉 

USP Methylparaben RS 

USP Phenylephrine Hydrochloride RS 

USP Promethazine Hydrochloride RS 

USP Propylparaben RS 

USP Sodium Benzoate RS