Methyldopa

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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C₁₀H₁₃NO₄ . 1½H₂O 238.24

C₁₀H₁₃NO₄ 211.22

L-Tyrosine, 3-hydroxy-a-methyl-, sesquihydrate;

L-3-(3,4-Dihydroxyphenyl)-2-methylalanine sesquihydrate CAS RN^®: 41372-08-1; UNII: 56LH93261Y.

Anhydrous CAS RN^®: 555-30-6; UNII: M4R0H12F6M.

1 DEFINITION

Methyldopa contains NLT 98.0% and NMT 102.0% of methyldopa (C₁₀H₁₃NO₄), calculated on the anhydrous basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197A or 197K

B. 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

3.1 PROCEDURE

[NOTE-Freshly prepare the Standard solution and Sample solution before use.]

Buffer: 0.1 M monobasic sodium phosphate. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Buffer and methanol (850:150)

Diluent: 0.1 N hydrochloric acid

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

Sample solution: 0.4 mg/mL of Methyldopa in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm

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

Flow rate: 1.0 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: 0.9-1.5

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of methyldopa (C₁₀H₁₃NO₄) in the portion of Methyldopa taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of methyldopa from the Sample solution

r_S = peak response of methyldopa from the Standard solution

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

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

Acceptance criteria: 98.0%-102.0% on the anhydrous basis

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1%

ORGANIC IMPURITIES

[NOTE-Freshly prepare the Standard solution and Sample solution before use.]

Buffer, Mobile phase, and Diluent: Prepare as directed in the Assay.

System suitability solution: 4 µg/mL of USP Methyldopa RS and 6 µg/mL each of USP 3-0-Methylmethyldopa RS, USP Methyldopa Related Compound B RS, and USP Methyldopa Related Compound C RS in Diluent

Standard solution: 4 µg/mL of USP Methyldopa RS in Diluent

Sample solution: 4 mg/mL of Methyldopa in Diluent

Chromatographic system: Proceed as directed in the Assay, except for the Run time.

Run time: NLT 6 times the retention time of methyldopa

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between methyldopa related compound B and methyldopa related compound C, System suitability solution

Relative standard deviation: NMT 5%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Methyldopa taken:

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of methyldopa from the Standard solution

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

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

Acceptance criteria: See Table 1. Disregard any peaks below 0.03%.

Table 1

^a (S)-2-Amino-3-(4-hydroxy-3-methoxyphenyl)-2-methylpropanoic acid.

^b (S)-2-Amino-3-(4-methoxyphenyl)-2-methylpropanoic acid.

^c (S)-2-Amino-3-(3,4-dimethoxyphenyl)-2-methylpropanoic acid.

5 SPECIFIC TESTS

OPTICAL ROTATION (781S), Procedures, Specific Rotation

Sample solution: 44 mg/mL, in a solvent that is a solution of aluminum chloride hexahydrate in water (2 in 3) that previously has been treated with activated charcoal, filtered, and adjusted with 0.25 N sodium hydroxide to a pH of 1.5

Acceptance criteria: -25° to -28°

ACIDITY

Sample solution: Dissolve 1.0 g in carbon dioxide-free water with the aid of heat, and add 1 drop of methyl red TS.

Analysis: Titrate the Sample solution with 0.10 N sodium hydroxide to a yellow endpoint.

Acceptance criteria: NMT 0.50 mL is required.

WATER DETERMINATION (921), Method I: 10.0%~13.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed, light-resistant containers.

Change to read:

USP REFERENCE STANDARDS (11)

USP Methyldopa RS

USP Methyldopa Related Compound B RS

(S)-2-Amino-3-(4-methoxyphenyl)-2-methylpropanoic acid hydrochloride.

C₁₁H₁₅NO₃ . HCl 245.70

USP Methyldopa Related Compound C RS

(S)-2-Amino-3-(3,4-dimethoxyphenyl)-2-methylpropanoic acid hydrochloride.

C₁₂H₁₇NO₄ . HCl 275.73

USP 3-O-Methylmethyldopa RS

(S)-2-Amino-3-(4-hydroxy-3-methoxyphenyl)-2-methylpropanoic acid monohydrate. (CN 1-Aug-2023)

C₁₁H₁₅NO₄ . H₂O 243.26 (CN 1-Aug-2023)