Isosorbide Dinitrate 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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1 DEFINITION

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

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy (USP 1-AUG-2023)

Sample solution: 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 shake again. 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. Where separation of interferences is required, proceed as follows. Transfer a quantity of finely powdered Tablets, equivalent to 20 mg of isosorbide dinitrate, 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 solvent hexane, and shake again. Centrifuge the mixture, and transfer the upper phase to a beaker. Place in a freezer, at a temperature of -14°, the beaker and a short-stem funnel fitted with a cotton plug that previously has been chloroform washed and dried. After 30 min, filter the solution while still in the freezer. Evaporate the solvent, and dry the residue in vacuum over calcium chloride for 16 h, dissolved in 0.4 mL of chloroform.

Standard solution: Prepare a solution with USP Diluted Isosorbide Dinitrate RS following a similar preparation as the Sample solution.

Acceptance criteria: The IR absorption spectrum of the Sample solution exhibits maxima only at the same wavelengths as that of the Standard solution. If separation of interference is required, the IR absorption spectrum of the Sample solution determined in a 0.1-mm cell shows all of the significant absorption bands present in the spectrum obtained for a similar preparation from the Standard solution. The major peaks are at 1650 cm^-1, 1284 cm^-1 and 1275 cm-¹ (a doublet), 1106 cm^-1, and 844 cm^-1.

Add the following:

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. (USP 1-Aug-2023)

3 ASSAY

Change to read:

3.1 PROCEDURE

Solution A: Methanol and water (6:94)

Solution B: Methanol and water (50:50)

Mobile phase: See Table 1.

Table 1

Diluent: Methanol and water (15:85)

Standard solution: 0.25 mg/mL of isosorbide dinitrate prepared as follows. Transfer a portion of USP Diluted Isosorbide Dinitrate RS equivalent to 25 mg of isosorbide dinitrate to a 100-mL volumetric flask. Add 10 ml of methanol and sonicate for NLT 5 min. Add Diluent to 60% of the flask volume and sonicate for NLT 15 min with occasional shaking until the solids are dissolved. Dilute with Diluent to volume.

Sample solution: Nominally 0.25 mg/ml of isosorbide dinitrate prepared as follows. Transfer a portion of finely powdered Tablets (NLT 20) equivalent to 50 mg of isosorbide dinitrate, to a 200-ml volumetric flask. Add 20 mL of methanol, shake immediately, and sonicate for about 5 min to avoid clumping. Add Diluent to 60% of the flask volume and sonicate for about 15 min with occasional shaking. Shake for another 30 min on a shaker and allow the solution to come to room temperature. Dilute with Diluent to volume. Centrifuge a portion of the solution and use the clear supernatant.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 214 nm

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

Column temperature: 30"

Flow rate: 2 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 esolution (mg/mL) (USP 1-Aug-2023)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

DISSOLUTION (711)

Test 1

Medium: Water, 500 mL

Apparatus 2: 50 rpm

Time: 1, 2, 4, and 6 h

Solution A: 13.2 g/L of ammonium sulfate in water. Adjust with 1 N sulfuric acid to a pH of 3.0.

Mobile phase: Methanol and Solution A (50:50)

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

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

Chromatographic system

(See Chromatography (621), Systern Suitability.)

Mode: LC

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

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C) of isosorbide dinitrate (C₆H₈N₂O₈) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) xC_S

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)

Calculate the percentage of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) dissolved at each time point (i):

Result₁ = C₁ × V_S × (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 isosorbide dinitrate in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

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

(USP 1-Aug-2023)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

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

Acid stage medium: pH 1.2 simulated gastric fluid (without pepsin); 900 mL

Buffer stage medium: pH 7.5 simulated intestinal fluid (without enzymes); 900 mL

Apparatus 2: 50 rpm, with helix sinkers

Times

Acid stage: 1 h

Buffer stage: 3, 6, and 12 h. The times in the Buffer stage medium include the time in the Acid stage medium.

Solution A: Dissolve 15.4 g of ammonium acetate in water, add 11.5 mL of glacial acetic acid, dilute with water to 1000 mL, and mix to obtain a solution having a pH of about 4.7.

Mobile phase: Mix 350 mL of water, 100 mL of Solution A, and 550 mL of methanol. Dilute with water to 1000 mL.

Standard solution: 40 μg/mL of isosorbide dinitrate in respective medium from USP Diluted Isosorbide Dinitrate RS

Sample solution: Run the test with Acid stage medium for 1 h followed by collecting the Acid stage medium sample. Continue the test in

Buffer stage medium by withdrawing samples at the time points specified in Table 3. (USP 1-Aug-2023) Withdraw a 5-mL aliquot and pass a portion of the solution under test through a suitable filter of 10-μm pore size. Replace the aliquots withdrawn at the 3 and 6 h timepoints with equal volumes of Buffer stage medium.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4-mm × 25-cm; packing L1

Flow rate: 1 mL/min

Injection volume: 20 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 the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) dissolved in Acid stage medium at time point 1 h (Q):

Result = (r_U/r_S) × C_S × V_A × (1/L) × 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_A = volume of the Acid stage medium, 900 mL

L = label claim (mg/Tablet)

Calculate the concentration (C ) of isosorbide dinitrate (C₆H₈N₂O₈) in the sample withdrawn at each Buffer stage time point (i):

Result = (r_U/r_S) × C_S

r_U = peak response of isosorbide dinitrate from the Sample solution at each time point i

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)

Calculate the percentage of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈) dissolved at each Buffer stage time point (i):

Result₁ = [C₁ × V_B × (1/L) × 100] + Q_A

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

Result₃ = ({(C₃ × V_B) + [(C₂ + C₁) × V_S]} × (1/L) × 100) + Q_A

C_i = concentration of isosorbide dinitrate in the Sample solution withdrawn at the specified time point (i) (mg/mL)

V_B = volume of the Buffer stage medium, 900 mL

L = label claim (mg/Tablet)

Q_A = percentage of the labeled amount of isosorbide dinitrate dissolved in the Acid stage medium

V_S = volume of the Sample solution withdrawn at each time point (i), 5 mL

(USP 1-Aug-2023)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of isosorbide dinitrate (C₆H₈N₂O₈ ) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Uniformity of Dosage Units 〈905〉: Meet the requirements

Add the following:

5 IMPURITIES

Organic Impurities

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

System suitability stock solution: 300 μg/mL of USP Diluted Isosorbide Mononitrate Related Compound A RS and USP Diluted Isosorbide

Mononitrate RS prepared as follows. Transfer a portion of USP Diluted Isosorbide Mononitrate Related Compound A RS, equivalent to 30mg of isosorbide mononitrate related compound A and USP Diluted Isosorbide Mononitrate RS, equivalent to 30 mg of isosorbide mononitrate to a 100-mL volumetric flask. Add 10 mL of methanol and sonicate for NLT 5 min. Add Diluent to 60% of the flask volume and sonicate for NLT 15 min with occasional shaking until the solids are dissolved. Dilute with Diluent to volume.

System suitability solution: 1.5 μg/mL of isosorbide mononitrate related compound A and isosorbide mononitrate in Diluent from System suitability stock solution

Standard stock solution: 300 μg/mL of isosorbide dinitrate prepared as follows. Transfer a portion of USP Diluted Isosorbide Dinitrate RS, equivalent to 30 mg of isosorbide dinitrate, to a 100-mL volumetric flask. Add 10 mL of methanol and sonicate for NLT 5 min. Add Diluent to 60% of the flask volume and sonicate for NLT 15 min with occasional shaking until the solids are dissolved. Dilute with Diluent to volume.

Standard solution: 1.5 μg/mL of isosorbide dinitrate in Diluent from Standard stock solution

Sensitivity solution: 0.75 μg/mL of isosorbide dinitrate in Diluent from Standard stock solution

Sample solution: Nominally 750 μg/mL of isosorbide dinitrate prepared as follows. Transfer a 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 for 5 min to avoid clumping.

Add Diluent to 60% of the flask volume and sonicate for 20 min with occasional shaking. Shake for another 30 min on a shaker and allow the solution to come to room temperature. Dilute with Diluent to volume. Centrifuge a portion of the solution and use the clear supernatant.

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[Note—The relative retention times for isosorbide mononitrate related compound A and isosorbide mononitrate are about 0.7 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2 between isosorbide mononitrate related compound A and isosorbide mononitrate, System suitability solution

Relative standard deviation: NMT 5.0%, 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 4)

Acceptance criteria: See Table 4. The reporting threshold is 0.1%.

Table 4

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature. (USP 1-Aug-2023)

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

Change to read:

USP Reference Standards 〈11〉

[Note—USP Diluted Isosorbide Dinitrate RS, USP Diluted Isosorbide Mononitrate RS, and USP Diluted Isosorbide Mononitrate Related

Compound A RS are dry mixtures of an active component and suitable excipients to permit safe handling. For quantitative applications, calculate the concentration of the active component based on the content stated on the label.] (USP 1-Aug-2023)

USP Diluted Isosorbide Dinitrate RS

USP Diluted Isosorbide Mononitrate RS

USP Diluted Isosorbide Mononitrate Related Compound A RS

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

C₆H₉NO₉ 191.14 (USP 1-Aug-2023)