Quinine Sulfate Capsules

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

Quinine Sulfate Capsules contain amounts of quinine sulfate and dihydroquinine sulfate totaling NLT 90.0% and NMT 110.0% of the labeled amount of quinine sulfate, calculated as (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O.

2 IDENTIFICATION

A.

Sample: Nominally 100 mg of quinine sulfate from the contents of Capsules

Analysis: Shake the Sample with 100 mL of dilute sulfuric acid (1 in 350), and filter.

Acceptance criteria: An appropriate dilution of the filtrate exhibits a vivid blue fluorescence. On the addition of a few drops of hydrochloric acid, the fluorescence disappears.

Delete the following:

B. The R value of the principal spot from the Sample solution corresponds to that from Standard solution A, as obtained in the test for Organic Impurities. (USP 1-May-2021)

Change to read:

B. (USP 1-May-2021) Identification Tests—General 〈191〉, Chemical Identification Tests, Sulfate

Sample: Nominally 20 mg of quinine sulfate from the contents of Capsules

Analysis: Shake the Sample with 10 mL of dilute hydrochloric acid (1 in 100), and filter.

Acceptance criteria: The filtrate meets the requirements.

Change to read:

C. (USP 1-May-2021) 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

Change to read:

3.1 Procedure

Solution A: Add 35.0 mL of methanesulfonic acid to 20.0 mL of glacial acetic acid, and dilute with water to 500 mL.

Solution B: Dissolve 10.0 mL of diethylamine in water to obtain 100 mL of solution.

Mobile phase: Acetonitrile, Solution A, Solution B, and water (100:20:20:860). Adjust with Solution B to a pH of 2.6 if the pH is found to be lower.

System suitability solution: 0.2 mg/mL each of USP Quinine Sulfate RS and dihydroquinine, dissolved in 10% of the final volume of methanol. Dilute with Mobile phase to volume.

Standard solution: 0.2 mg/mL of USP Quinine Sulfate RS in Mobile phase

Sample stock solution: Nominally 1.6 mg/mL of quinine sulfate in methanol prepared as follows. Transfer an amount, equivalent to 160 mg of quinine sulfate from the contents of NLT 20 Capsules, to a 100-mL volumetric flask, add 80 mL of methanol, and shake the flask by mechanical means for 30 min. Dilute with methanol to volume, and filter, discarding the first 10 mL of the filtrate.

Sample solution: Nominally 0.2 mg/mL of quinine sulfate in Mobile phase from the Sample stock solution

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 235 nm

Column: 3.9-mm × 30-cm; 10-µm (USP 1-May-2021) packing L1

Flow rate: 1 mL/min

Injection volume: 50 µL

System suitability

Sample: System suitability solution

[Note—The relative retention times for quinine and dihydroquinine are 1 and 1.5, respectively.]

Suitability requirements

Resolution: NLT 1.2 between quinine and dihydroquinine

Relative standard deviation: NMT 2.0% for the quinine peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quinine sulfate (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O, calculated as the sum of quinine sulfate and dihydroquinine sulfate, in the portion of Capsules taken:

Result = [(r_b,U + r_d,U)/(r_b,S + r_d,S)] × (C_S/C_U) × (M_r1/M_r2) (USP 1-May-2021) × 100

r_b,U = peak response of quinine from the Sample solution

r_d,U = peak response of dihydroquinine from the Sample solution

r_b,S = peak response of quinine from the Standard solution

r_d,S = peak response of dihydroquinine from the Standard solution

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

C_U = nominal concentration of quinine sulfate in the Sample solution (mg/mL)

M_r1 = molecular weight of quinine sulfate, 782.94

M_r2 = molecular weight of anhydrous quinine sulfate, 746.92 (USP 1-May-2021)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 Dissolution 〈711〉

Test 1

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 100 rpm

Time: 45 min

Detector: UV maximum at about 248 nm

Standard solution: Prepare a solution of known concentration of USP Quinine Sulfate RS in Medium.

Sample solution: A filtered portion of the solution under test, suitably diluted with Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quinine sulfate (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O dissolved:

Result = (r_U/r_S) × (C_S/L) × (M_r1/M_r2) × D × V × 100

r_U = absorbance of the Sample solution

r_S = absorbance of the Standard solution

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

L = label claim (mg/Capsule)

M_r1 = molecular weight of quinine sulfate, 782.94

M_r2 = molecular weight of anhydrous quinine sulfate, 746.92

D = dilution factor of the Sample solution, as needed

V = volume of Medium, 900 mL (USP 1-May-2021)

Tolerances: NLT 75% (Q) of the labeled amount of quinine sulfate (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O is dissolved.

Test 2: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2.

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 100 rpm

Time: 30 min

Solution A: Add 7.0 mL of methanesulfonic acid to 4.0 mL of glacial acetic acid, and dilute with water to 100 mL.

Solution B: Dissolve 10.0 mL of diethylamine in water to obtain 100 mL of solution.

Mobile phase: Water, acetonitrile, Solution A, and Solution B (81:15:2:2). Adjust with Solution B to a pH of 3.0.

Standard solution: Prepare a solution of known concentration of USP Quinine Sulfate RS in Medium.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, and suitably dilute with Medium.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 235 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Flow rate: 1.2 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for the quinine peak

Relative standard deviation: NMT 2.0% for the sum of the quinine and dihydroquinine peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quinine sulfate (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O dissolved.

Result = (r_U/r_S) × (C_S/L) × (M_r1/M_r2) × D × V × 100

r_U = sum of the peak responses of quinine and dihydroquinine from the Sample solution

r_S = sum of the peak responses of quinine and dihydroquinine from the Standard solution

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

L = label claim (mg/Capsule)

M_r1 = molecular weight of quinine sulfate, 782.94

M_r2 = molecular weight of anhydrous quinine sulfate, 746.92

D = dilution factor for the Sample solution

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amount of quinine sulfate (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O is dissolved.

Test 3: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3.

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Standard solution: 0.0144 mg/mL of USP Quinine Sulfate RS in Medium

Sample solution: A filtered portion of the solution under test, suitably diluted with Medium

Instrumental conditions

Mode: UV

Analytical wavelength: 248 nm

Cell: 1 cm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of quinine sulfate (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O dissolved:

Result = (r_U/r_S) × (C_S/L) × (M_r1/M_r2) × D × V × 100

r_U = absorbance of the Sample solution

r_S = absorbance of the Standard solution

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

L = label claim (mg/Capsule)

M_r1 = molecular weight of quinine sulfate, 782.94

M_r2 = molecular weight of anhydrous quinine sulfate, 746.92

D = dilution factor of the Sample solution, if necessary

V = volume of Medium, 900 mL

Tolerances: NLT 75% (Q) of the labeled amount of quinine sulfate (C₂₀H₂₄N₂O₂) · H₂SO₄ · 2H₂O is dissolved.

Change to read:

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements

(USP 1-May-2021)

5 IMPURITIES

Delete the following:

5.1 Organic Impurities

Standard stock solution: 6 mg/mL of USP Quinine Sulfate RS in diluted alcohol

Standard solution A: 0.06 mg/mL of USP Quinine Sulfate RS from the Standard stock solution in diluted alcohol

Standard solution B: 0.05 mg/mL of USP Quininone RS (corresponding to 0.06 mg/mL of the sulfate) and 0.10 mg/mL of cinchonidine (corresponding to 0.12 mg/mL of the sulfate) in diluted alcohol

Sample solution: Nominally 6 mg/mL of quinine sulfate in diluted alcohol prepared as follows. Shake the equivalent of 150 mg of quinine sulfate from the contents of Capsules with 25 mL of diluted alcohol for 10 min, and filter.

Chromatographic system

(See Chromatography 〈621〉, General Procedures, Thin-Layer Chromatography.)

Mode: TLC

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 10 µL

Developing solvent system: Chloroform, acetone, and diethylamine (50:40:10). [Note—The solvent chamber being used without previous equilibration.]

Analysis

Samples: Standard solution A, Standard solution B, and Sample solution

Proceed as directed in Chromatography 〈621〉, General Procedures, Thin-Layer Chromatography. Allow the spots to dry, and develop the chromatogram using a solvent chamber without previous equilibration. When the solvent front has moved about 15 cm, remove the plate from the chamber, mark the solvent front, and allow the solvent to evaporate. Locate the spots on the plate by spraying with glacial acetic acid, and examine under long-wavelength UV light.

Acceptance criteria: Any spot produced by the Sample solution at the Rf value of a spot produced by Standard solution B is not greater in size or intensity than that corresponding spot. Apart from these spots and from the spot appearing at the Rf value of quinine sulfate, any additional fluorescent spot is not greater in size or intensity than the spot from Standard solution A. Spray the plate with potassium iodoplatinate TS. Any spot produced by the Sample solution is not greater in size or intensity than a corresponding spot from Standard solution B. (USP 1-May-2021)

Add the following:

5.2 Organic Impurities, Procedure 1

Perform both Organic Impurities, Procedure 1 and Organic Impurities, Procedure 2.

[Note—The Standard solution, Sample solution, and Sensitivity solution are stable for up to 24 h at 10°.]

Mobile phase: 14.25 g of anhydrous potassium phosphate, monobasic in 1800 mL of water, and add 8 mL of hexylamine. Adjust with diluted phosphoric acid to a pH of 2.3 ± 0.01. Add 30 mL of acetonitrile and dilute with water to 2000 mL.

Diluent: Mobile phase

Standard solution: 0.02 mg/mL of USP Quinine Sulfate RS in Diluent. Sonicate in cold water to dissolve completely.

Sensitivity solution: 0.002 mg/mL of USP Quinine Sulfate RS from the Standard solution in Diluent

Sample solution: Nominally 2 mg/mL of quinine sulfate dihydrate in Diluent prepared as follows. Weigh accurately 20 Capsules and transfer the Capsule contents, equivalent to 200 mg of quinine sulfate, into a 100-mL volumetric flask. Add 70 mL of Diluent, and sonicate for about 15 min in cold water with intermittent shaking. Cool to room temperature and dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 316 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Temperatures

Autosampler: 10°

Column: 25°

Flow rate: 1.5 mL/min

Injection volume: 50 µL

Run time: NLT 3 times the retention time of quinine

System suitability

Samples: Standard solution and Sensitivity solution

Suitability requirements

Tailing factor: NMT 2.5, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Sample solution and Standard solution

Calculate the percentage of cinchonidine sulfate and any individual unspecified impurity in the portion of Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × (1/F) × 100

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

r_S = peak response of quinine from the Standard solution

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

C_U = nominal concentration of quinine sulfate in the Sample solution (mg/mL)

M_r1 = molecular weight of quinine sulfate, 782.94

M_r2 = molecular weight of anhydrous quinine sulfate, 746.92

F = relative response factor for each impurity (see Table 1)

Acceptance criteria: See Table 1. The reporting threshold is 0.10%.

Table 1

ᵃ R-Quinolin-4-yl[(2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol sulfate.

ᵇ (R)-(2S,4S,5R)-5-Ethylquinuclidin-2-yl

methanol sulfate.

ᶜ Process impurity included in the table for identification only. Process impurities are controlled in the drug substance and are not to be reported or included in the total impurities for the drug product.

ᵈ S-(6-Methoxyquinolin-4-yl)[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol sulfate dihydrate.

ᵉ S-(1S,2S,4S,5R)-5-Ethylquinuclidin-2-yl

methanol sulfate.

ᶠ R-(2S,4S,5R)-5-Ethylquinuclidin-2-yl

methanol sulfate.

ᵍ Dihydroquinine sulfate is part of the drug substance and not to be included in the total impurities.

ʰ Includes quinicine sulfate and quininone sulfate from Organic Impurities, Procedure 2.

Add the following:

5.3 Organic Impurities, Procedure 2

Organic Impurities, Procedure 2 is applicable only for the impurities quinicine sulfate and quininone sulfate.

[Note—The Standard solution and Sample solution are stable for up to 25 h at 10°.]

Buffer: 2.72 g/L of anhydrous potassium dihydrogen orthophosphate in water. Add 2 mL of triethylamine and adjust with dilute orthophosphoric acid to a pH of 7.0 ± 0.01.

Solution A: Acetonitrile, methanol, and Buffer (23:10:67)

Solution B: Acetonitrile and Buffer (70:30)

Diluent: Solution A

Mobile phase: See Table 2.

Table 2

Standard stock solution: 0.5 mg/mL of USP Quinine Sulfate RS in Diluent. Sonicate in cold water to dissolve completely.

Standard solution: 0.01 mg/mL of USP Quinine Sulfate RS in Diluent from Standard stock solution

Sample solution: Nominally 1 mg/mL of quinine sulfate dihydrate in Diluent prepared as follows. Weigh accurately 20 Capsules and transfer the Capsule contents, equivalent to 100 mg of quinine sulfate, into a 100-mL volumetric flask. Add 70% of the final volume of Diluent, and sonicate for about 15 min in cold water with intermittent shaking. Cool to room temperature and dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 235 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Temperatures

Autosampler: 10°

Column: 50°

Flow rate: 1.2 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.5

Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of quinine from the Standard solution

C_U = concentration of USP Quinine Sulfate RS in the Standard solution (mg/mL)

C_U = nominal concentration of quinine sulfate in the Sample solution (mg/mL)

M_r1 = molecular weight of quinine sulfate, 782.94

M_r2 = molecular weight of anhydrous quinine sulfate, 746.92

F = relative response factor for each impurity (see Table 3)

Acceptance criteria: See Table 3.

Table 3

ᵃ 1-(6-Methoxyquinolin-4-yl)-3-[(3R,4R)-3-vinylpiperidin-4-yl]propan-1-one sulfate.

ᵇ (6-Methoxyquinolin-4-yl)[(2S,4S,5R)-5-vinylquinuclidin-2-yl]methanone sulfate.

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature. (USP 1-May-2021)

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

Change to read:

USP Reference Standards 〈11〉

USP Quinine Sulfate RS

(USP 1-May-2021)