Hydroxychloroquine Sulfate

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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C₁₈H₂₆ClN₃O . H₂SO₄ 433.95

Ethanol, 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethyl]amino-, (±)-, sulfate (1:1) (salt);

(±)-2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino]ethanol sulfate (1:1) (salt) CAS RN^®: 747-36-4.

1 DEFINITION

Hydroxychloroquine Sulfate contains NLT 98.0% and NMT 102.0% of hydroxychloroquine sulfate (C₁₈H₂₆ClN₃O . H₂SO₄), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (Official 1-Jun-2021)

Change to read:

B. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K or 197A (Official 1-Jun-2021)

C. Identification Tests—General 〈191〉, Chemical Identification Tests, Sulfate

Sample solution: 10 mg/mL of Hydroxychloroquine Sulfate in water

Acceptance criteria: Meets the requirements

3 ASSAY

Change to read:

3.1 PROCEDURE

Solution A: Acetonitrile, water, and phosphoric acid (100:900:2)

Solution B: Acetonitrile, water, and phosphoric acid (800:200:1)

Mobile phase: Solution A and Solution B (97:3)

Standard solution: 0.01 mg/mL of USP Hydroxychloroquine Sulfate RS in Solution A prepared as follows. Transfer a suitable quantity of USP Hydroxychloroquine Sulfate RS to a suitable volumetric flask and add about 75% of the flask volume of Solution A. Sonicate for NLT 5 min or until solids are dissolved. Dilute with Solution A to volume.

Sample solution: 0.01 mg/mL of Hydroxychloroquine Sulfate in Solution A prepared as follows. Transfer a suitable quantity of Hydroxychloroquine Sulfate to a suitable volumetric flask and add about 75% of the flask volume of Solution A. Sonicate for NLT 5 min or until solids are dissolved. Dilute with Solution A to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 2.0-mm × 10-cm; 2-µm packing L1

Column temperature: 35°

Flow rate: 0.8 mL/min

Injection volume: 3 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of hydroxychloroquine sulfate (C₁₈H₂₆ClN₃O . H₂SO₄) in the portion of Hydroxychloroquine Sulfate taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of hydroxychloroquine from the Sample solution

r_S = peak response of hydroxychloroquine from the Standard solution

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

C_U = concentration of Hydroxychloroquine Sulfate in the Sample solution (mg/mL) (Official 1-Jun-2021)

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

4 IMPURITIES

Delete the following:

4.1 ORDINARY IMPURITIES (466)

Standard solution: Prepare in 10% water in methanol.

Sample solution: Prepare in 10% water in methanol.

Eluant: A mixture of alcohol, water, and ammonium hydroxide (80:16:4)

Visualization: 1

Acceptance criteria: Meets the requirements (Official 1-Jun-2021)

Add the following:

4.2 ORGANIC IMPURITIES

Solution A and Solution B: Prepare as directed in the Assay.

Mobile phase: See Table 1.

Table 1

Standard stock solution: Use the Standard solution from the Assay.

Standard solution: 0.001 mg/mL of USP Hydroxychloroquine Sulfate RS in Solution A from the Standard stock solution.

Sample solution: 0.1 mg/mL of Hydroxychloroquine Sulfate in Solution A prepared as follows. Transfer a suitable quantity of Hydroxychloroquine Sulfate to a suitable volumetric flask and add about 75% of the flask volume of Solution A. Sonicate for NLT 5 min or until solids are dissolved. Dilute with Solution A to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 2.0-mm × 10-cm; 2-µm packing L1

Column temperature: 35°

Flow rate: 0.8 mL/min

Injection volume: 2 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Hydroxychloroquine Sulfate taken:

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

r_U = peak response of any individual impurity from the Sample solution

r_S = peak response of hydroxychloroquine from the Standard solution

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

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

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

The reporting threshold is 0.05%.

Table 2

ᵃ 2-({4-[(7-Chloroquinolin-4-yl)amino]pentyl}amino)ethan-1-ol.

ᵇ 2-({4-[(7-Chloroquinolin-4-yl)amino]pentyl}ethylamino)ethyl acetate. This process impurity may be present if acetic acid or acetates are used in the synthesis.

ᶜ 2-({4-[(7-Chloroquinolin-4-yl)amino]pentyl}ethylamino)ethyl hydrogen sulfate.

ᵈ 4,7-Dichloroquinoline.

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry at 105° for 2 h.

Acceptance criteria: NMT 2.0%

6 ADDITIONAL REQUIREMENTS

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

USP REFERENCE STANDARDS (11)

USP Hydroxychloroquine Sulfate RS