Phenylephrine 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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C₉H₁₃NO₂ · HCl 203.67

Benzenemethanol, 3-hydroxy-α-[(methylamino)methyl]-, hydrochloride (R)-;

(−)-m-Hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride CAS RN®: 61-76-7; UNII: 04JA59TNSJ.

DEFINITION

Phenylephrine Hydrochloride contains NLT 98.0% and NMT 102.0% of phenylephrine hydrochloride (C₉H₁₃NO₂ · HCl), calculated on the dried basis.

1 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K (CN 1-May-2020)

B. Identification Tests - General, Chloride〈191〉

Sample solution: 10 mg/mL

Acceptance criteria: Meets the requirements

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

2 ASSAY

Procedure

Buffer: Dissolve 3.25 g of 1-octanesulfonic acid sodium salt monohydrate in 1 L of water, and adjust with 3 M phosphoric acid to a pH of 2.8.

Solution A: Acetonitrile and Buffer (10:90)

Solution B: Acetonitrile and Buffer (90:10)

Mobile phase: See Table 1.

Table 1

Diluent: Solution A and Solution B (80:20)

Standard solution: 0.4 mg/mL of USP Phenylephrine Hydrochloride RS in Diluent

Sample solution: 0.4 mg/mL of Phenylephrine Hydrochloride in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4.0-mm × 5.5-cm; 3-μm packing L1

Column temperature: 45°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.9

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of phenylephrine hydrochloride (C₉H₁₃NO₂ · HCl) in the portion of Phenylephrine Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of phenylephrine from the Sample solution

r_S = peak response of phenylephrine from the Standard solution

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

C_U = concentration of Phenylephrine Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0% on the dried basis

3 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.2%

Chloride and Sulfate, Sulfate〈221〉

Standard solution: 0.10 mL of 0.020 N sulfuric acid

Sample solution: 50 mg in 25 mL of water

Acceptance criteria: The Sample solution shows no more turbidity than corresponds to that of the Standard solution (0.20%).

Organic Impurities

Buffer, Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 1.0 mg/mL of USP Phenylephrine Hydrochloride RS and 10 μg/mL each of USP Norphenylephrine Hydrochloride RS and USP Phenylephrine Related Compound C RS in Diluent

Standard solution: 0.001 mg/mL each of USP Phenylephrine Hydrochloride RS, USP Norphenylephrine Hydrochloride RS, USP Phenylephrine Related Compound C RS, USP Phenylephrine Related Compound D RS, and USP Phenylephrine Related Compound E RS in Diluent

Sample solution: 1.0 mg/mL of Phenylephrine Hydrochloride in Diluent

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between norphenylephrine and phenylephrine and NLT 1.5 between phenylephrine and phenylephrine related compound C, System suitability solution

Relative standard deviation: NMT 5% for norphenylephrine, phenylephrine, phenylephrine related compound C, phenylephrine related compound D, and phenylephrine related compound E, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of norphenylephrine as free base in the portion of Phenylephrine Hydrochloride taken:

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

r_U = peak response of norphenylephrine from the Sample solution

r_S = peak response of norphenylephrine from the Standard solution

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

C_U = concentration of Phenylephrine Hydrochloride in the Sample solution (mg/mL)

M_r1 = molecular weight of norphenylephrine as free base, 153.18

M_r2 = molecular weight of norphenylephrine as hydrochloride salt, 189.64

Calculate the percentage of phenylephrine related compound C as free base in the portion of Phenylephrine Hydrochloride taken:

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

r_U = peak response of phenylephrine related compound C from the Sample solution

r_S = peak response of phenylephrine related compound C from the Standard solution

C_S = concentration of USP Phenylephrine Related Compound C RS in the Standard solution (mg/mL)

C_U = concentration of Phenylephrine Hydrochloride in the Sample solution (mg/mL)

M_r1 = molecular weight of phenylephrine related compound C as free base, 165.19

M_r2 = molecular weight of phenylephrine related compound C as hydrochloride salt, 201.65

Calculate the percentage of phenylephrine related compound D in the portion of Phenylephrine Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of phenylephrine related compound D from the Sample solution

r_S = peak response of phenylephrine related compound D from the Standard solution

C_S= concentration of USP Phenylephrine Related Compound D RS in the Standard solution (mg/mL)

C_U = concentration of Phenylephrine Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of phenylephrine related compound E as free base in the portion of Phenylephrine Hydrochloride taken:

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

r_U = peak response of phenylephrine related compound E from the Sample solution

r_S = peak response of phenylephrine related compound E from the Standard solution

C_S = concentration of USP Phenylephrine Related Compound E RS in the Standard solution (mg/mL)

C_U = concentration of Phenylephrine Hydrochloride in the Sample solution (mg/mL)

M_r1 = molecular weight of phenylephrine related compound E as free base, 255.31

M_r2 = molecular weight of phenylephrine related compound E as hydrochloride salt, 291.77

Calculate the percentage of any individual unspecified impurity in the portion of Phenylephrine Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each unspecified impurity from the Sample solution

r_S = peak response of phenylephrine from the Standard solution

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

C_U = concentration of Phenylephrine Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: See Table 2. Disregard any peaks below 0.05%.

Table 2

4 SPECIFIC TESTS

Optical Rotation, Specific Rotation〈781S〉

Sample solution: 50 mg/mL in water

Acceptance criteria: −43° to −47°

Loss on Drying 〈731〉

Analysis: Dry at 105° for 2 h.

Acceptance criteria: NMT 1.0%

5 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers. Store at 25°, excursions permitted between 15° and 30°.

USP Reference Standards 〈11〉

USP Norphenylephrine Hydrochloride RS

3-(2-Amino-1-hydroxyethyl)phenol hydrochloride.

C₈H₁₁NO₂ · HCl 189.64

USP Phenylephrine Hydrochloride RS

USP Phenylephrine Related Compound C RS

1-(3-Hydroxyphenyl)-2-(methylamino)ethan-1-one hydrochloride.

C₉H₁₁NO₂ · HCl 201.65

USP Phenylephrine Related Compound D RS

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

C₁₆H₁₉NO₂ 257.33

USP Phenylephrine Related Compound E RS

2-[Benzyl(methyl)amino]-1-(3-hydroxyphenyl)ethan-1-one hydrochloride.

C₁₆H₁₇NO₂ · HCl 291.77