Phenylephrine Bitartrate

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

C₉H₁₃NO₂ · C₄H₆O₆ 317.29

Benzenemethanol, 3-hydroxy-α-[(methylamino)methyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (salt);

(R)-(-)-m-Hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrogen tartrate CAS RN®: 17162-39-9; UNII: 27O3Q5ML57.

1 DEFINITION

Phenylephrine Bitartrate contains NLT 98.0% and NMT 102.0% of phenylephrine bitartrate (C₉H₁₃NO₂ · C₄H₆O₆), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

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

B. Identification Tests - General, Tartrate 〈191〉

Sample: The alkaline filtrate from the test for Optical Rotation 〈781S〉, Specific Rotation

Acceptance criteria: The Sample responds positively to the test for Tartrate in Identification Tests - General 〈191〉.

C. 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

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: 0.6 mg/mL of USP Phenylephrine Hydrochloride RS in Diluent

Sample solution: 0.9 mg/mL of Phenylephrine Bitartrate 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: 4 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 bitartrate (C₉H₁₃NO₂ · C₄H₆O₆) in the portion of Phenylephrine Bitartrate taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 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 Bitartrate in the Sample solution (mg/mL)

M_r1 = molecular weight of phenylephrine bitartrate, 317.29

M_r2 = molecular weight of phenylephrine hydrochloride, 203.67

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

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

System suitability solution: 1.0 mg/mL of USP Phenylephrine Hydrochloride RS and 0.9 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

Blank: 0.8 mg/mL of l(+)-tartaric acid in Diluent

Sample solution: 1.56 mg/mL of Phenylephrine Bitartrate in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 215 nm

Column: 4-mm × 5.5-cm; 3-μm packing L1

Column temperature: 45°

Flow rate: 1.5 mL/min

Injection volume: 4 μL

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, Blank, and Sample solution Examine the chromatogram of the Blank for the peaks, and disregard any corresponding peaks observed in the chromatogram of the Sample solution.

Calculate the percentage of norphenylephrine as free base in the portion of Phenylephrine Bitartrate 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 Bitartrate 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 Bitartrate 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 Bitartrate 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 Bitartrate 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 Bitartrate in the Sample solution (mg/mL)

Calculate the percentage of phenylephrine related compound E as free base in the portion of Phenylephrine Bitartrate 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 Bitartrate 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 unspeci

ed impurity in the portion of Phenylephrine Bitartrate taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 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 Bitartrate in the Sample solution (mg/mL)

M_r1 = molecular weight of phenylephrine bitartrate, 317.29

M_r2 = molecular weight of phenylephrine hydrochloride, 203.67

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

Table 2

5 SPECIFIC TESTS

Optical Rotation, Specific Rotation 〈781S〉

Sample solution: Prepare a solution of about 240 mg/mL of Phenylephrine Bitartrate in water. Make the solution slightly alkaline by adding concentrated ammonium hydroxide dropwise. Rub the wall of the vessel with a glass rod so that the base precipitates out. Filter the base under suction, wash with a little water and acetone, and dry at 105° for 2 h. Prepare and measure a 50-mg/mL solution of base precipitate in 1 M hydrochloric acid.

Acceptance criteria: −53° to −57°

pH 〈791〉

Sample solution: 10% w/v aqueous solution

Acceptance criteria: 3.0–4.0

Loss on Drying 〈731〉

Analysis: Dry at 105° to a constant weight.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

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

USP Reference Standards 〈11〉

USP Norphenylephrine Hydrochloride RS

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

C₈H₁₁NO₂ · HCl 189.64

USP Phenylephrine Bitartrate RS

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