Promethazine and Phenylephrine Hydrochloride and Codeine Phosphate 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)

DOWNLOAD PDF HERE

1 DEFINITION 

Promethazine and Phenylephrine Hydrochloride and Codeine Phosphate Oral Solution contains NLT 90.0% and NMT 110.0% of the labeled amount of promethazine hydrochloride (C₁₇H₂₀N₂S.HCl), phenylephrine hydrochloride (C₉H₁₃NO₂.HCl), and codeine phosphate (C₁₈H₂₁NO₃.H₃PO₄. ½H O). It may contain suitable preservatives. 

2 IDENTIFICATION 

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

3 ASSAY

 Procedure 

At all times, protect the sample and the Standard solutions by using low-actinic glassware. 

Solution A: Dissolve 2.0 g of monobasic potassium phosphate and 1.0 g of heptanesulfonic 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 heptanesulfonic acid sodium salt monohydrate in 500 mL of water, and carefully 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, 1.4 mg/mL of USP Phenylephrine Hydrochloride RS, and 2.8 mg/mL of USP Codeine Phosphate 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 in 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, 0.28 mg/mL of USP Codeine Phosphate 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: Equivalent to 0.18 mg/mL, based on the label claim, of promethazine hydrochloride in Solution A 

Phenylephrine hydrochloride sample solution: Equivalent to 0.14 mg/mL, based on the label claim, of phenylephrine hydrochloride in Solution A 

Codeine phosphate sample solution: Equivalent to 0.28 mg/mL, based on the label claim, of codeine phosphate 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 promethazine, phenylephrine, and codeine 

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)

Samples: Standard solution and Codeine phosphate sample solution 

Calculate the percentage of the labeled amount of codeine phosphate (C₁₈H₂₁NO₃.H₃PO₄. ½H O) in the portion of sample taken: 

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) ×100 

r_U = pcodeine peak response from the Codeine phosphate sample solution  

r_S = codeine peak response from the Standard solution 

C_S = concentration of USP Codeine Phosphate RS, on the dried basis, in the Standard solution (mg/mL) 

C_U = nominal concentration of codeine phosphate in the Codeine phosphate sample solution (mg/mL) 

M_r1 = molecular weight of codeine phosphate, 406.37 

M_r2 = molecular weight of anhydrous codeine phosphate, 397.37 

Acceptance criteria: 90.0%–110.0% for promethazine hydrochloride, phenylephrine hydrochloride, and codeine phosphate 

4 IMPURITIES 

Organic Impurities, Procedure 1 

At all times, protect the sample and the 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, prepared from Standard solution. Prepare at time of use. Sample solution: 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: 2 times the retention time of promethazine, Standard solution; 6 times the retention time of promethazine, Sample solution 

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 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-Methylphenothiazine. 

Organic Impurities, Procedure 2 

At all times, protect the sample and the Standard solutions by using low-actinic glassware. 

Solution A, Solution B, Mobile phase, Standard stock solution B, Codeine phosphate sample solution, and Phenylephrine hydrochloride sample solution: Proceed 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 to a 50-mL volumetric flask and diluting with Solution A to volume. 

Sensitivity solution: 0.18 µg/mL of USP Promethazine Hydrochloride RS in Solution A, prepared from Standard stock solution A. Prepare at time of use. 

Promethazine hydrochloride sample solution: Proceed as directed in the Assay. Use this solution to determine promethazine related compounds and species 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 

Sample: 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, and 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: Phenylephrine hydrochloride sample solution and Standard solution 

Identify the phenylephrine impurities using the relative retention times listed in Table 3. Calculate the percentage of each phenylephrine impurity in the portion of sample taken: 

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

r_U = peak response of each impurity 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 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 each promethazine impurity, unspecified impurity, and Unidentified impurity in the portion of sample taken: 

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

r_U = peak response of each impurity 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 Promethazine hydrochloride sample solution (µg/mL) 

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

Samples: Codeine phosphate sample solution and Standard solution 

Identify the codeine impurities using the relative retention times given in Table 4. Calculate the percentage of each codeine impurity in the portion of sample taken: 

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

r_U = peak response of each impurity 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 codeine phosphate in the Codeine phosphate sample solution (µg/mL) 

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

Acceptance criteria: See Table 3 and 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 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 

a Morphinan-6-ol, 7-8-didehydro-4,5-epoxy-3-methoxy-17-methyl,17-oxide-(5α,6α). 

b Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-(5α,6α). 

c Morphinan-6-one, 7-8-didehydro-4,5-epoxy-3-methoxy-17-methyl-(5α). 

d Codeine synthetic impurity. Do not quantitate. 

e 10H-Phenothiazine sulfoxide. 

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

g 10-Methyl-10H-phenothiazine sulfoxide. 

h 1H-Phenothiazin-1-one. 

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

j Promethazine synthetic impurity. Do not quantify. 

k Includes phenothiazine and methylphenothiazine from Procedure 1. 

5 SPECIFIC TESTS 

Microbial Enumeration Tests 〈61〉and Tests for Specified Microorganisms 〈62〉: The total aerobic microbial count does not exceed 102 cfu/mL. The total yeasts and molds count does not exceed 101 cfu/mL. It meets the requirements of the test for absence of Escherichia coli. pH 〈791〉: 3.7–4.7 

Alcohol Determination, Method II 〈611〉(if present): 90.0%–110.0% of the labeled amount of C₂H₅OH 

Deliverable Volume 〈698〉: Meets the requirements 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight, light-resistant containers, and store at controlled room temperature. USP Reference Standards 〈11〉 

USP Codeine Phosphate RS 

USP Methylparaben RS 

USP Phenylephrine Hydrochloride RS 

USP Promethazine Hydrochloride RS 

USP Propylparaben RS 

USP Sodium Benzoate RS