Isosorbide Mononitrate 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 Mononitrate Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of isosorbide mononitrate (C₆H₉NO₆).

2 IDENTIFICATION

Change to read:

A. Thin-Layer Chromatographic Identification Test 〈201〉

Standard solution: 0.5 mg/mL of isosorbide mononitrate in absolute alcohol (USP 1-Dec-2024) from USP Diluted Isosorbide Mononitrate RS (USP 1-Dec-2024)

Sample stock solution: Nominally 2.4 mg/mL of isosorbide mononitrate prepared as follows. Finely powder NLT 20 Tablets and transfer asuitable portion of the powder to a suitable container. Add a suitable volume of absolute alcohol, sonicate for 10 min, and centrifuge. Use the supernatant. (USP 1-Dec-2024)

Sample solution: Nominally 0.48 mg/mL of isosorbide mononitrate in absolute alcohol, from Sample stock solution (USP 1-Dec-2024)

Chromatographic system

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture (USP 1-Dec-2024)

Application volume: 20 μL

Developing solvent system: Chloroform and methanol (95:5)

Spray reagent: Dissolve 1 g of soluble starch in 100 mL of boiling water. Cool, and add 0.5 g of potassium iodide.

Analysis

Samples: Standard solution and Sample solution

Examine the plate under short-wave UV light, marking any observed spots. Visualize nitrates on the plate by spraying with Spray reagent and illuminating with short-wave UV light for 10 min.

Acceptance criteria: Isosorbide mononitrate and other nitrates appear as a violet spot on a white-to-light-violet background.

Change to read:

B. The retention time of the major peak of the Sample solution corresponds to that of Standard solution B, (USP 1-Dec-2024) as obtained in the Assay.

3 ASSAY

Change to read:

Procedure

Mobile phase: Methanol and water(20:80) (USP 1-Dec-2024)

Standard solution A: 0.15 mg/mL of isosorbide mononitrate related compound A in water, (USP 1-Dec-2024) from USP Diluted Isosorbide

Mononitrate Related Compound A RS (USP 1-Dec-2024)

Standard solution B: 0.12 mg/mL of isosorbide mononitrate prepared as follows. Transfer a suitable amount of USP Diluted Isosorbide

Mononitrate RS to a suitable volumetric ask, dissolve in a suitable volume of water, add methanol to 20% of the final volume, and dilute with water to volume. (USP 1-Dec-2024)

System suitability solution: (USP 1-Dec-2024) 0.12 mg/mL of isosorbide mononitrate and 6 μg/mL of isosorbide mononitrate related compound A prepared as follows. Transfer a suitable amount of USP Diluted Isosorbide Mononitrate RS to a suitable volumetric flask, dissolve in a suitable volume of water. Add a suitable amount of Standard solution A, add methanol to 20% of the final volume, (USP 1-Dec- 2024) and dilute with water to volume.

Sample stock solution: Nominally 0.6 mg/mL of isosorbide mononitrate prepared as follows. Finely powder NLT 20 Tablets and transfer a suitable portion of the powder to a suitable volumetric flask. Add methanol to 50% of the final volume, and sonicate for about 30 min with cooling. Warm to ambient temperature, and dilute with methanol to volume. Centrifuge a portion of the solution and use the clear supernatant. (USP 1-Dec-2024)

Sample solution: Nominally 0.12 mg/mL of isosorbide mononitrate prepared as follows. Dilute the Sample stock solution with water and pass a portion of the solution through a suitable filter of 0.45-μm pore size. (USP 1-Dec-2024)

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4-mm × 12.5-cm; 5-μm (USP 1-Dec-2024) packing L1

Flow rate: 1.5 mL/min

Injection volume: 20 μL

Run time: NLT 2 times the retention time of isosorbide mononitrate (USP 1-Dec-2024)

System suitability

Samples: Standard solution B and System suitability solution

[Note—The relative retention times for isosorbide mononitrate related compound A and isosorbide mononitrate are 0.8 and 1.0,

respectively.] (USP 1-Dec-2024)

Suitability requirements

Resolution: NLT 1.5 between isosorbide mononitrate related compound A and isosorbide mononitrate, System suitability solution

Tailing factor: NMT 1.5, Standard solution B

Relative standard deviation: NMT 1.0%, (USP 1-Dec-2024) Standard solution B

Analysis

Samples: Standard solution B and Sample solution

Calculate the percentage of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) in the portion of Tablets taken:

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

r_U = peak response of isosorbide mononitrate from the Sample solution

r_S = peak response of isosorbide mononitrate from Standard solution B

C_S = concentration of isosorbide mononitrate in Standard solution B (mg/mL)

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

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

Medium: Water; 900 mL

Apparatus 2: 50 rpm; Tablets are placed in a metal helix prepared by winding 10 in of a 0.8-mm stainless steel wire around a 9/32-in shaft and pulling the coils to form a helix 1 in long.

Times: 1, 2, 4, 8, and 12 h

Mobile phase: Methanol and water(30:70) (USP 1-Dec-2024)

Standard solution: (L/1000) mg/mL of isosorbide mononitrate from (USP 1-Dec-2024) USP Diluted Isosorbide Mononitrate RS in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test (USP 1-Dec-2024) through a suitable nylon filter of 0.45-μm pore size, discarding the first 4–6 mL of the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 5-μm (USP 1-Dec-2024) packing L1

Flow rate: 1 mL/min

Injection volume: 25 μL

Run time: NLT 1.8 times the retention time of isosorbide mononitrate (USP 1-Dec-2024)

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 1.5%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of isosorbide mononitrate (C₆H₉NO₆) 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 mononitrate from the Sample solution

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amounts of isosorbide mononitrate (C₆H₉NO₆) 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

Result₅ = ({C₅ × [V − (4 × V_S)]} + [(C₄ + C₃ + C₂ + C₁ ) × V_S]) × (1/L) × 100

C_i = concentration of isosorbide mononitrate in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of Sample solution withdrawn at each time point (mL) (USP 1-Dec-2024)

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) 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.

Medium: Simulated gastric fluid (without enzymes); 500 mL

Apparatus 2: 50 rpm

Times: 1, 2, 6, and 12 h

Mobile phase: Methanol and water(40:60) (USP 1-Dec-2024)

Standard stock solution: 1.2 mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS (USP 1-Dec-2024) in Medium

Standard solution

For Tablets labeled to contain 30 mg: 60 μg/mL of isosorbide mononitrate in Medium, from the Standard stock solution

For Tablets labeled to contain 60 mg: 120 μg/mL of isosorbide mononitrate in Medium, from the Standard stock solution

Sample solution: Pass a portion (USP 1-Dec-2024) of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 10-μm packing L1

Flow rate: 1 mL/min

Injection volume: 20 μL

Run time: NLT 1.6 times the retention time of isosorbide mononitrate (USP 1-Dec-2024)

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C )

(USP 1-Dec-2024) of isosorbide mononitrate (C₆H₉NO₆ ) in the sample withdrawn from the vessel

(USP 1-Dec-2024) at each time point (i):

Result_i = (r_U/r_S)xC_S

r_U = (USP 1-Dec-2024) = peak response of isosorbide mononitrate from the Sample solution (USP 1-Dec-2024)

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) 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 mononitrate 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 Sample solution withdrawn at each time point (mL) (USP 1-Dec-2024)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) dissolved at the times specified conform to Dissolution

〈711〉, Acceptance Table 2.

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

Medium: Simulated gastric fluid (without enzymes); 500 mL

Apparatus 2: 50 rpm

Times: 1, 2, 6, and 12 h

Buffer: Transfer 15.4 g of ammonium acetate and 11.5 mL of glacial acetic acid (USP 1-Dec-2024) to a 1-L volumetric flask containing 500 mL of water. Adjust with glacial acetic acid (USP 1-Dec-2024) to a pH of 4.7, and dilute with water to volume.

Mobile phase: Methanol, Buffer, and water(30:10:60) (USP 1-Dec-2024)

Standard stock solution: 0.12 mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS in Medium

Standard solution

For Tablets labeled to contain 30 mg: 0.06 mg/mL of isosorbide mononitrate in Medium, from the Standard stock solution

For Tablets labeled to contain 60 mg: Use the Standard stock solution with no further dilution.

Sample solution: Pass a portion (USP 1-Dec-2024) of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1 mL/min

Injection volume: 100 μL

Run time: NLT 1.8 times the retention time of isosorbide mononitrate (USP 1-Dec-2024)

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C )

(USP 1-Dec-2024) of isosorbide mononitrate (C₆H₉NO₆) in the sample withdrawn from the vessel

(USP 1-Dec-2024) at each time point (i):

Result_i = (r_U/r_S)xC_S

r_U = (USP 1-Dec-2024) = peak response of isosorbide mononitrate from the Sample solution (USP 1-Dec-2024)

r_S = peak response of isosorbide mononitrate from the Standard solution

C_U = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) 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 mononitrate 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 Sample solution withdrawn at each time point (mL) (USP 1-Dec-2024)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of isosorbide mononitrate dissolved at the times specfiIed 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: 0.2% sodium chloride in 0.1 N hydrochloric acid; 500 mL

Apparatus 2: 50 rpm; sinker baskets (see Dissolution 〈711〉, Figure 2a)

Times: 1, 2, 6, and 12 h

Mobile phase: Methanol and water(18:82) (USP 1-Dec-2024)

Standard solution: (L/500) mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion (USP 1-Dec-2024) 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 × 15-cm; 5-μm packing L1

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 20 μL

Run time: NLT 2 times the retention time of isosorbide mononitrate (USP 1-Dec-2024)

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of isosorbide mononitrate (C₆H₉NO₆) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_i/r_S)xC_S

r_i = peak response of isosorbide mononitrate from the Sample solution at the specified time point

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) 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 mononitrate 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 Sample solution withdrawn from the Medium (mL)

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of isosorbide mononitrate 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: 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm; helix sinkers

Times

For 60 mg and 60 mg half-Tablets: 1, 2, 4, 6, and 10 h

For 30 mg Tablets: 1, 2, 4, and 10 h

Mobile phase: Methanol and water (15:85)

System suitability solution

For 60 mg Tablets: 0.033 mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS in Medium prepared as follows.

Transfer a quantity of USP Diluted Isosorbide Mononitrate RS to an appropriate volumetric flask and add 60% of the flask volume of Medium. Shake for 30 min, sonicate for 5 min, and dilute with Medium to volume.

For 30 mg and 60 mg half-Tablets: 0.017 mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS in Medium

prepared as follows. Transfer a quantity of USP Diluted Isosorbide Mononitrate RS to an appropriate volumetric flask and add 60% of the flask volume of Medium. Shake for 30 min, sonicate for 5 min, and dilute with Medium to volume.

Standard solution:

For 60 mg Tablets: 0.067 mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS in Medium prepared as follows.

Transfer a quantity of USP Diluted Isosorbide Mononitrate RS to an appropriate volumetric flask and add 60% of the flask volume of Medium. Shake for 30 min, sonicate for 5 min, and dilute with Medium to volume.

For 30 mg and 60 mg half-Tablets: 0.033 mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS in Medium prepared as follows. Transfer a quantity of USP Diluted Isosorbide Mononitrate RS to an appropriate volumetric flask and add 60% of the flask volume of Medium. Shake for 30 min, sonicate for 5 min, and dilute with Medium to volume.

Sample solution: At the times specified, pass a portion of the solution under test through a suitable filter. Replace the portion removed with an equal volume of fresh Medium at 37°.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4-mm × 12.5-cm; 5-μm packing L1

Flow rate: 1 mL/min

Injection volume: 50 μL

Run time: NLT 1.5 times the retention time of isosorbide mononitrate (USP 1-Dec-2024)

System suitability

Sample: System suitability solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

For 60 mg Tablets and 60 mg half-Tablets:

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of isosorbide mononitrate (C₆H₉NO₆) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_i/r_S)xC_S

r_i  = peak response of isosorbide mononitrate from the Sample solution at the specified time point

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amounts of isosorbide mononitrate (C₆H₉NO₆) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

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

Result₅ = ({C₅ × V) + [(C₄ + C₃ + C₂ + C₁) × V_S]} × (1/L) × 100

C_i = concentration of isosorbide mononitrate in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet) or label claim (mg/half-Tablet)

V_S = volume of the Sample solution withdrawn at each time point and replaced withMedium (mL)

For 30 mg Tablets:

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of isosorbide mononitrate (C₆H₉NO₆) in the sample withdrawn from the vessel at time point i:

Result_i = (r_i/r_S)xC_S

r_i = peak response of isosorbide mononitrate from the Sample solution at time point i

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amounts of isosorbide mononitrate (C₆H₉NO₆) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

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

C_i = concentration of isosorbide mononitrate 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 each time point and replaced with Medium (mL)

Tolerances: See Table 5 and Table 6.

Table 5

Table 6

The percentages of the labeled amount of isosorbide mononitrate 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, Apparatus 2, Times, Mobile phase, Standard solution,

(USP 1-Dec-2024) and System suitability: Proceed as directed in Test 1.

Sample solution: Pass a portion of the solution under test through a suitable filter. Replace the amount of solution withdrawn at each time point with the same volume of Medium. (USP 1-Dec-2024)

Chromatographic system: Proceed as directed in Test 1 except for the Injection volume.

Injection volume: 50 μL

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of isosorbide mononitrate (C₆H₉NO₆) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_i/r_S)xC_S

r_i = peak response of isosorbide mononitrate from the Sample solution at the specified time point

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amounts of isosorbide mononitrate (C₆H₉NO₆) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

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

Result₅ = ({C₅ × V) + [(C₄ + C₃ + C₂ + C₁) × V_S]} × (1/L) × 100

C_i = concentration of isosorbide mononitrate in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point and replaced with (USP 1-Dec-2024) Medium (mL)

Tolerances: See Table 7.

Table 7

The percentages of the labeled amount of isosorbide mononitrate dissolved at the times specified conform to Dissolution 〈711〉 ,

Acceptance Table 2.

Test 7: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.

Medium, Apparatus 2, Mobile phase, and Chromatographic system: Proceed as directed in Test 5.

Times: 1, 4, 8, and 12 h

Standard solution 1: 0.133 mg/mL of isosorbide mononitrate

(USP 1-Dec-2024) in Medium

prepared as follows. Transfer an appropriate amount of USP Diluted Isosorbide Mononitrate RS to a suitable volumetric flask, (USP 1-

Dec-2024) add Medium to 60% of the total volume, shake for 30 min, sonicate for 5 min, and then dilute with Medium to volume.

Standard solution 2: 0.067 mg/mL of isosorbide mononitrate

(USP 1-Dec-2024) in Medium prepared as follows. Transfer an appropriate amount of USP Diluted Isosorbide Mononitrate RS to a suitable volumetric flask, (USP 1- Dec-2024) add Medium to 60% of the total volume, shake for 30 min, sonicate for 5 min, and then dilute with Medium to volume.

Sample solution: Pass a portion (USP 1-Dec-2024) of the solution under test through a suitable filter.

System suitability

Sample: Standard solution 1

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution 1, Standard solution 2, and Sample solution

Calculate the response factor for Standard solution 1 and Standard solution 2:

Result = C_S/r_S

C_S = concentration of isosorbide mononitrate in Standard solution 1 or Standard solution 2 (mg/mL)

r_S = peak response of isosorbide mononitrate from Standard solution 1 or Standard solution 2

Calculate the concentration (C_i) of isosorbide mononitrate (C₆H₉NO₆) in the sample withdrawn from the vessel at each time point (i):

Result_i = r_i × F_R

r_i = peak response of isosorbide mononitrate from the Sample solution at the specified time point

F_R = average response factor from Standard solution 1 and Standard solution 2

Calculate the percentage of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) 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 mononitrate in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn from Medium (mL)

Tolerances: See Table 8.

Table 8

The percentages of the labeled amount of isosorbide mononitrate dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 8: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8.

Medium: Water, deaerated; 900 mL

Apparatus 2: 50 rpm with suitable sinkers

Times

For Tablets labeled to contain 30 and 60 mg: 1, 2, 4, 8, and 10 h

For Tablets labeled to contain 120 mg: 1, 2, 4, 8, and 12 h

Mobile phase: Prepare as directed in Test 1.

Standard stock solution: 0.67 mg/mL of isosorbide mononitrate from USP Diluted Isosorbide Mononitrate RS in Medium prepared as follows. Transfer an appropriate portion of USP Diluted Isosorbide Mononitrate RS to a suitable volumetric flask. Add Medium to about 70% of the final volume, and sonicate to dissolve. Dilute with Medium to volume.

Standard solution: (L/900) mg/mL of isosorbide mononitrate in Medium, from the Standard stock solution, where L is the label claim in mg/Tablet

Sample solution: At the times specified, withdraw 10 mL of the solution under test. Replace the aliquots withdrawn for analysis with equal volumes of Medium maintained at 37°. Pass the solution through a suitable PVDF filter of 0.45-μm pore size. Discard the first 3 mL of the ltrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 5-μm packing L1

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 25 μL

Run time: NLT 2 times the retention time of isosorbide mononitrate

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.5%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of isosorbide mononitrate (C₆H₉NO₆) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_i/r_S)xC_S

r_i = peak response of isosorbide mononitrate from the Sample solution at the specified time point

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of isosorbide mononitrate (C₆H₉NO₆) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

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

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

Result₅ = ({C₅ × V) + [(C₄ + C₃ + C₂ + C₁) × V_S]} × (1/L) × 100

C_i = concentration of isosorbide mononitrate in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

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

Tolerances: See Table 9 and Table 10.

Table 9

Table 10

The percentages of the labeled amount of isosorbide mononitrate dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Change to read:

Uniformity of Dosage Units 〈905〉: Meet the requirements (USP 1-Dec-2024)

5 IMPURITIES

Add the following:

Limit of Nitrate

[Note—Use water with a resistivity of NLT 18 megohm-cm to prepare the solutions.]

Mobile phase: 20 mM potassium hydroxide in water. [Note—The Mobile phase can be generated electrolytically by using an automatic eluant generator.]

Sensitivity solution: 0.5 μg/mL of USP Potassium Nitrate RS in water

Standard solution: 1.0 μg/mL of USP Potassium Nitrate RS in water

Sample solution: Nominally 200 μg/mL of isosorbide mononitrate prepared as follows. Transfer a suitable portion of finely powdered Tablets (NLT 20) to a suitable flask. Add water to about 40% of the final volume and sonicate for about 10 min with intermittent shaking. Cool to ambient temperature, and add additional water to 10% of the final volume. Agitate vigorously using a mechanical shaker for about 30 min.

Centrifuge a portion of the solution and use the clear supernatant.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: Conductivity with suppression

Columns

Guard: 4.0-mm × 0.5-cm; 5.0-μm packing L91

Analytical: 4.0-mm × 15-cm; 5.0-μm packing L91

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 100 μL

Run time: NLT 2 times the retention time of nitrate

System suitability

Sample: Sensitivity solution

Suitability requirements

Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of nitrate as potassium nitrate in the portion of Tablets taken:

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

r_U = peak response of the nitrate ion from the Sample solution

r_S = peak response of the nitrate ion from the Standard solution

C_S = concentration of USP Potassium Nitrate RS in the Standard solution (μg/mL)

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

Acceptance criteria: NMT 0.5% (USP 1-Dec-2024)

Delete the following:

Organic Impurities, Procedure 1 (USP 1-Dec-2024)

Delete the following:

Organic Impurities, Procedure 2 (USP 1-Dec-2024)

Add the following:

Organic Impurities

[Note—It is recommended to use GC-grade methanol to prepare the solutions.]

Sensitivity solution: 3 μg/mL of isosorbide mononitrate prepared as follows. Transfer a suitable amount of USP Diluted Isosorbide

Mononitrate RS to a suitable volumetric flask. Add methanol to about 80% of the final volume and sonicate for 30 min with intermittent shaking. Dilute with methanol to volume. Centrifuge a portion of the solution and use the clear supernatant.

Standard solution: 30 μg/mL of isosorbide and 7.5 μg/mL each of isosorbide mononitrate, isosorbide related compound A, and isosorbide dinitrate in methanol, prepared as follows. Transfer a suitable amount of USP Diluted Isosorbide Mononitrate RS, USP Diluted Isosorbide

Mononitrate Related Compound A RS, and USP Diluted Isosorbide Dinitrate RS to a suitable volumetric flask. Add methanol to about 80% of the final volume and sonicate for 30 min with intermittent shaking. Add an appropriate amount of USP Isosorbide RS to the volumetric flask, and dilute with methanol to volume. Centrifuge a portion of the solution and use the clear supernatant.

Sample solution: Nominally 3 mg/mL of isosorbide mononitrate prepared as follows. Transfer a suitable portion of finely powdered Tablets (NLT 20) to a suitable volumetric flask. Add methanol to about 80% of the final volume and sonicate for 30 min with intermittent shaking, cool to ambient temperature, and dilute with methanol to volume. Centrifuge a portion of the solution and use the clear supernatant.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC

Detector: Flame ionization

Column: 0.53-mm × 30-m fused silica capillary; coated with a 1.5-μm

lm of phase G2

Temperatures

Injection port: 150°

Column: 125°, isothermal

Detector: 275°

Carrier gas: Hydrogen

Flow rate: 180 cm/s (linear velocity)

Injection volume: 1 μL

Injection type: Split, split ratio 1:6

Run time: NLT 3 times the retention time of isosorbide mononitrate

System suitability

Samples: Sensitivity solution and Standard solution

[Note—See Table 11 for the relative retention times.]

Suitability requirements

Relative standard deviation: NMT 5.0% each for isosorbide mononitrate, isosorbide, isosorbide related compound A, and isosorbide dinitrate, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of isosorbide, isosorbide related compound A, and isosorbide dinitrate in the portion of Tablets taken:

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

r_U =  peak response of isosorbide, isosorbide related compound A, or isosorbide dinitrate from the Sample solution

r_S = peak response of isosorbide, isosorbide related compound A, or isosorbide dinitrate from the Standard solution

C_S = concentration of isosorbide, isosorbide related compound A, or isosorbide dinitrate in the Standard solution (mg/mL)

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

Calculate the percentage of any unspecified degradation product in the portion of Tablets taken:

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

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

r_S = peak response of isosorbide mononitrate from the Standard solution

C_S = concentration of isosorbide mononitrate in the Standard solution (mg/mL)

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

Acceptance criteria: See Table 11. The reporting threshold is 0.1%.

Table 11

^a Total degradation products excluding isosorbide.

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in tight containers. Store at a temperature of 20°–30°, with excursions permitted between 15° and 30°. (USP 1-Dec-2024)

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 Isosorbide RS

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

Compound A RS (USP 1-Dec-2024) 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 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 in lactose. (USP 1-Dec-2024)

C₆H₉NO_6.    191.14

USP Potassium Nitrate RS (USP 1-Dec-2024)