Isosorbide Dinitrate 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-isosorbide-dinitrate-tabs-20230526.

1 DEFINITION

Isosorbide Dinitrate Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈).

2 IDENTIFICATION

A.

Sample: Transfer a suitable quantity of finely powdered Tablets to a glass-stoppered centrifuge tube. Add 10 mL of sodium hydroxide solution (1 in 250), shake to wet the powder, add 15 ml of hexane, and again shake. Centrifuge the mixture, and transfer the upper phase to a beaker. Evaporate the solvent, and dry the residue under vacuum over calcium chloride at room temperature for 16 h.

Acceptance criteria: The IR absorption spectrum of a suitable solution in chloroform of the Sample exhibits maxima only at the same wavelengths as that of a similar preparation from the residue obtained from USP Diluted Isosorbide Dinitrate RS.

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

PROCEDURE

Solution A: Methanol and water (6:94)

Solution B: Methanol and water (50:50)

Mobile phase: See Table 1.

Diluent: Methanol and water (15:85)

Standard solution: 0.25 mg/mL of isosorbide dinitrate prepared as follows. Transfer a suitable portion of USP Diluted Isosorbide Dinitrate RS, equivalent to an appropriate amount of isosorbide dinitrate, to a suitable volumetric flask. Add methanol to 10% of the flask volume and sonicate. Dilute with Diluent to 60% of the flask volume, and sonicate with occasional shaking until the solids are dissolved. Cool to room temperature and dilute with Diluent to volume.

Sample solution: Nominally 0.25 mg/mL of isosorbide dinitrate prepared as follows. Transfer a suitable portion of finely powdered Tablets (NLT 10), equivalent to 50 mg of isosorbide dinitrate, to a 200-mL volumetric flask. Add 10 mL of methanol and sonicate. Dilute with Diluent to 60% of the flask volume and sonicate with occasional shaking until solids are dissolved. Cool to room temperature and dilute with Diluent to volume. Pass the solution through a suitable filter of 0.45-µm pore size and use the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 214 nm

Column: 4.6-mm x 5-cm, 5-um packing 11

Column temperature: 30"

Flow rate: 3 mL/min

Injection volume: 75 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) in the portion of Tablets taken:

Result = (r_U/r_S)x(C_S/C_U)×100

r_U = peak response of isosorbide dinitrate from the Sample solution

r_S = peak response of isosorbide dinitrate from the Standard solution

C_S = concentration of isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS in the Standard solution (mg/mL)

C_U = nominal concentration of isosorbide dinitrate in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION (711)

Test 14 (RB 1-Jun-2023)

Medium: Water: 1000 mL

Apparatus 2: 75 rpm

Time: 45 min

Mobile phase: Methanol and pH 3.0, 0.1 M ammonium sulfate (1:1). (NOTE-Make adjustments, if necessary (see Chromatogranby.(621)

System Suitability), using sulfuric acid for any necessary pH adjustment.]

Standard solution: A known concentration of USP Diluted Isosorbide Dinitrate RS in Medium

Sample solutions: Pass a portion of the solution under test through a suitable filter.

Chromatographic system

(See Chromatography (621) System Suitability)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 5-cm; packing 11

Flow rate: 1.0 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) dissolved.

Tolerances: NLT 70% (Q) of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) is dissolved.

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

Medium: 0.1 N bydrochloric acid: 1000 mL

Apparatus 2: 75 rpm

Time: 20 min

Buffer: 13.2 g/L ammonium sulfate in water prepared as follows. Dissolve 13.2 g of ammonium sulfate in 900 ml of water, adjust with sulfuric acid to a pH of 3.0, and dilute with water to 1000 mL..

Mobile phase: Methanol and Buffer (40:60)

Standard stock solution: 0.1 mg/ml, of isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS prepared as follows. Transfer an appropriate quantity of USP Diluted Isosorbide Dinitrate RS, equivalent to an appropriate amount of isosorbide dinitrate, to a suitable volumetric flask. Add separately methanol and Medium, each to 10% of the final flask volume. Sonicate to dissolve. Dilute with Medium to volume.

Standard solution: (L/1000) mg/mL of isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS from the Standard stock solution in Mediurn, where L is the label claim in mg/Tablet

Sample solutions: Pass a portion of the solution under test through a suitable filter of 0.45-um pore size, discarding the first 4 mL of filtrate.

Chromatographic system

(See Chromatography (621), Svstern Suitability,)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 5-cm; 5-um packing 11

Column temperature: 30"

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 2.3 times the retention time of isosorbide dinitrate

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) dissolved

Result = (r_U/r_S)xC_S x V x (1/L) x 100

r_u = peak response of isosorbide dinitrate from the Sample solution

r_S = peak response of isosorbide dinitrate from the Standard solution

C_S = concentration of isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS in the Standard solution (mg/mL)

V = volume of Medium, 1000 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) is dissolved.

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

Medium: 0.1 N hydrochloric acid: 500 mL

Apparatus 2: 75 rpm

Time: 15 min

Mobile phase: Methanol and water (20:80)

Standard stock solution: 0.2 mg/mL isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS in Medium prepared as follows. Transfer an appropriate quantity of USP Diluted Isosorbide Dinitrate RS, equivalent to an appropriate amount of isosorbide dinitrate, to a suitable volumetric flask. Add Medium to 70% of the final flask volume. Sonicate with intermittent shaking to dissolve. Cool to room temperature. Dilute with Medium to volume.

Standard solution: (L/500) mg/mL of isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS from the Standard stock solution in

Medium, where L is the label claim in mg/Tablet.

Sample solutions: Pass a portion of the solution under test through a suitable filter of 0.45-um pore size, discarding the first 3 ml. of filtrate.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1.2 mL/min

Injection volume: 20 µL

Run time: NLT 1.8 times the retention time of isosorbide dinitrate

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈ ) dissolved:

Result = (r_U/r_S) x C_S x V x (1/L) x 100

r_U = peak response of isosorbide dinitrate from the Sample solution

r_S = peak response of isosorbide dinitrate from the Standard solution

C_S = concentration of isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS in the Standard solution (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) is dissolved. (RB 1-Jun-2023)

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Organic Impurities

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

Standard stock solution: 0.3 mg/mL of isosorbide dinitrate prepared as follows. Transfer a suitable portion of USP Diluted Isosorbide

Dinitrate RS, equivalent to an appropriate amount of isosorbide dinitrate, to a suitable volumetric flask. Add methanol to 10% of the flask volume and sonicate. Dilute with Diluent to 60% of the flask volume and sonicate with occasional shaking until the solids are dissolved.

Cool to room temperature and dilute with Diluent to volume.

Standard solution: 7.5 μg/mL of isosorbide dinitrate in Diluent from Standard stock solution

Sensitivity solution: 0.375 μg/mL of isosorbide dinitrate in Diluent from Standard solution

Sample solution: Nominally 750 μg/mL of isosorbide dinitrate prepared as follows. Transfer a suitable portion of finely powdered Tablets (NLT 20) equivalent to 75 mg of isosorbide dinitrate, to a 100-mL volumetric flask. Add 10 mL of methanol and sonicate. Dilute with Diluent to 60% of the flask volume and sonicate with occasional shaking. Cool to room temperature and dilute with Diluent to volume. Pass the solution through a suitable fillter of 0.45-μm pore size and use the fitrate.

System suitability

Samples: Standard solution and Sensitivity solution

[Note—See Table 2 for relative retention times.]

Suitability requirements

Relative standard deviation: NMT 2.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each degradation product in the portion of Tablets taken:

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

r_U = peak response of each degradation product from the Sample solution

r_S = peak response of isosorbide dinitrate from the Standard solution

C_S = concentration of isosorbide dinitrate from USP Diluted Isosorbide Dinitrate RS in the Standard solution (μg/mL)

C_U = nominal concentration of isosorbide dinitrate in the Sample solution (μg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.1%.

^a 1,4:3,6-Dianhydro-d-glucitol 2-nitrate.

^b 1,4:3,6-Dianhydro-d-glucitol 5-nitrate.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature.

Add the following:

Labeling: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used (RB 1-Jun-2023)

USP Reference Standards 〈11〉

USP Diluted Isosorbide Dinitrate RS