Quinidine Gluconate Extended-Release Tablets

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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To view the Notice from the Expert Committee that posted in conjunction with this accelerated revision, please click https://www.uspnf.com/rb-quinidine-gluconate-ert-20211029.

1 DEFINITION

Quinidine Gluconate Extended-Release Tablets contain amounts of quinidine gluconate and dihydroquinidine gluconate totaling NLT 90.0% and NMT 110.0% of the labeled amount of quinidine gluconate, calculated as quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇).

2 IDENTIFICATION

A.

Sample solution: Shake an amount, equivalent to 50 mg of quinidine gluconate from powdered Tablets, with 100 mL of dilute sulfuric acid (1 in 350), and filter.

Acceptance criteria: The filtrate so obtained exhibits a vivid blue fluorescence when viewed under long-wavelength UV light. On the addition of hydrochloric acid, the fluorescence disappears.

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

C. The Rf value of the principal spot of the Sample solution corresponds to that of the Standard solution, as obtained in Organic Impurities.

3 ASSAY

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 prepare a 100-mL 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 found to be lower.

System suitability solution: Transfer 10 mg each of quinidine gluconate and dihydroquinidine hydrochloride to a 50-mL volumetric flask. Dissolve in 5 mL of methanol, and dilute with Mobile phase to volume.

Standard solution: 0.2 mg/mL of USP Quinidine Gluconate RS in Mobile phase.

Sample stock solution: To an amount equivalent to 160 mg of quinidine gluconate from NLT 20 finely powdered Tablets in a 100-mL volumetric flask add 80 mL of a mixture of methanol and water (1:1), and sonicate until evenly dispersed. Cool to room temperature, dilute with a mixture of methanol and water (1:1) to volume, and filter, discarding the first 20 mL of the filtrate.

Sample solution: 0.19 mg/mL of quinidine gluconate in Mobile phase prepared as follows. Transfer 3.0 mL of the Sample stock solution to a 25-mL volumetric flask, and dilute with Mobile phase to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 235 nm

Column: 3- to 5-mm × 25- to 30-cm; packing L1

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for quinidine and dihydroquinidine are 1 and 1.5, respectively, for the System suitability solution.]

Suitability requirements

Resolution: NLT 1.2 between quinidine and dihydroquinidine, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the sum of the percentages of quinidine gluconate and dihydroquinidine gluconate in the Tablets taken:

Result = [(r_B,U + r_D,U)/(r_B,S + r_D,S)] × (C_S/C_U) × 100

r_B,U = peak response of quinidine from the Sample solution

r_D,U = peak response of dihydroquinidine from the Sample solution

r_B,S = peak response of quinidine from the Standard solution

r_D,S = peak response of dihydroquinidine from the Standard solution

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

C_U = nominal concentration of quinidine gluconate in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

Test 1: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 1.

Medium: Add 6.9 g of anhydrous sodium acetate and 0.525 mL of glacial acetic acid to 1 L of water. Adjust with 0.1 N hydrochloric acid or

0.1 N sodium hydroxide to a pH of 5.4; 900 mL.

Apparatus 2: 75 rpm

Times: 1, 2, 4, and 8 h

Standard solution: A known concentration of USP Quinidine Gluconate RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium if necessary, in comparison with the Standard solution concentration.

Instrumental conditions

Mode: UV

Analytical wavelength: 235 nm

Analysis

Samples: Standard solution and Sample solution

Determine the percentage of the labeled amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved from UV absorbances of the Sample solution and Standard solution.

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium: 0.1 N hydrochloric acid; 600 mL

Apparatus 2: 75 rpm

Times: Proceed as directed for Test 1.

Standard solution: A known concentration of USP Quinidine Gluconate RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium if necessary, in comparison with the Standard solution concentration.

Instrumental conditions

Mode: UV

Analytical wavelength: 235 nm

Analysis

Samples: Standard solution and Sample solution

Determine the percentage of the labeled amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved from UV absorbances of the Sample solution and Standard solution.

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 5

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.

Medium: Proceed as directed for Test 1.

Apparatus: Proceed as directed for Test 1, using 8-mesh sinker baskets.¹

Times: 1, 2, and 4 h

Standard solution: USP Quinidine Gluconate RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium, if necessary, in comparison with the Standard solution concentration.

Instrumental conditions

Mode: UV

Analytical wavelength: 235 nm

Analysis

Samples: Standard solution and Sample solution

Determine the amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved from the UV absorbances of the Sample solution and the Standard solution.

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Test 6

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.

Medium: pH 5.4 acetate buffer prepared as follows. Add 6.9 g of anhydrous sodium acetate and 0.53 mL of glacial acetic acid to 1 L of water. Adjust with 0.1 N hydrochloric acid or 0.1 N sodium hydroxide to a pH of 5.4; 900 mL, deaerated.

Apparatus 2: 75 rpm, using 8-mesh sinker baskets¹

Times: 1, 2, 3, and 5 h

Standard solution: 0.012 mg/mL of USP Quinidine Gluconate RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium to a concentration similar to that of the Standard solution.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 235 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (Cᵢ) of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) in the sample withdrawn at each time point (i):

Result_i = (A_U/A_S) × C_S × D

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

D = dilution factor for the Sample solution

Calculate the percentage of the labeled amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_S)] + [C₁ × V_S]} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100

Result₄ = ({C₄ × [V − (3 × V_S)]} + [(C₃ + C₂ + C₁) × V_S]) × (1/L) × 100

C_i = concentration of quinidine gluconate in the portion of sample withdrawn at time point (i) (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at time point (i) (mL)

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

Change to read:

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements (CN 1-Aug-2023)

Procedure for content uniformity

Standard solution: 0.0525 mg/mL of USP Quinidine Gluconate RS in 0.1 N hydrochloric acid

Sample solution: Transfer 1 intact or powdered Tablet to a 250-mL volumetric flask, and add 125 mL of 0.1 N hydrochloric acid. Heat the sample with frequent agitation just to boiling, and cool to room temperature. Dilute with 0.1 N hydrochloric acid to volume, mix, and filter, discarding the first 20 mL of filtrate. If necessary, further dilute quantitatively with 0.1 N hydrochloric acid.

Instrumental conditions

Mode: UV

Cell: 1 cm

Analytical wavelength: 347 nm

Blank: 0.1 N hydrochloric acid

Analysis

Samples: Standard solution, Sample solution, and Blank

Concomitantly determine the absorbances of the Samples.

Calculate the percentage of the labeled amounts of active ingredients, calculated as quinidine gluconate (C₂₀H₂₄N₂O₂ · C₆H₁₂O₇), in the Tablet taken:

Result = (A_U/A_S) × (C_S/C_U) × 100

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

C_U = nominal concentration of quinidine gluconate in the Sample solution (mg/mL)

(CN 1-Aug-2023)

5 IMPURITIES

5.1 Organic Impurities

Standard solution A: 6 mg/mL of USP Quinidine Gluconate RS in diluted alcohol

Standard solution B: 0.06 mg/mL of USP Quinidine Gluconate RS in diluted alcohol from Standard solution A

Standard solution C: 0.04 mg/mL of USP Quininone RS (corresponding to 0.06 mg of the gluconate) in diluted alcohol

Sample solution: Nominally equivalent to 6 mg/mL of quinidine gluconate prepared as follows. Shake a quantity of powdered Tablets, equivalent to about 150 mg of quinidine gluconate, 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)

Analysis

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

Proceed as directed in the chapter. The solvent chamber is used without previous equilibration. When the solvent front has moved 15 cm, remove the plate from the chamber, mark the solvent front, and allow the solvent to evaporate. Spray with glacial acetic acid. Locate the spots on the plate by examination 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 C is not greater in size or intensity than that corresponding spot. Apart from these spots and from the spots appearing at the Rf value of quinidine gluconate and dihydroquinidine gluconate (the two spots most evident from Standard solution A), any additional fluorescent spot is not greater in size or intensity than the principal spot of Standard solution B.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed, light-resistant containers.

Labeling: The labeling indicates the Dissolution Test with which the product complies.

USP Reference Standards 〈11〉

USP Quinidine Gluconate RS

USP Quininone RS

Cinchonan-9-one, 6′-methoxy-, (8α)-.

C₂₀H₂₂N₂O₂ 322.40

¹ A suitable sinker is available from www.agilent.com, catalog number 12-3062.