Isosorbide Mononitrate Extended-Release Tablets
» Isosorbide Mononitrate Extended-Release Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of isosorbide mononitrate (C6H9NO6).
Packaging and storage— Preserve in tight containers. Store at a temperature between 20 and 30.
Labeling— When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used.
USP Reference standards 11
USP Isosorbide RS Click to View Structure
[Note—The following Reference Standards 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 Click to View Structure
USP Diluted Isosorbide Mononitrate RS Click to View Structure
USP Diluted Isosorbide Mononitrate Related Compound A RS Click to View Structure
1,4:3,5-Dianhydro-d-glucitol 2-nitrate.
    C6H9NO6     191.14
Identification—
A: Thin-Layer Chromatographic Identification Test 201 Proceed as directed for Identification test A under Isosorbide Mononitrate Tablets.
B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
Dissolution 711
test 1—
Medium: water; 900 mL.
Apparatus 2: 50 rpm. The Tablets are placed in a metal helix, prepared by winding 10 inches of a 0.8-mm stainless steel wire around a 9/32-inch shaft and pulling the coils to form a helix 1 inch long.
Times: 1, 2, 4, 8, and 12 hours.
Determine the amount of C6H9NO6 dissolved by employing the following method.
Mobile phase— Prepare a filtered and degassed mixture of water and methanol (7:3). Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard solution— Dissolve an accurately weighed quantity of USP Diluted Isosorbide Mononitrate RS in Medium, and dilute quantitatively, and stepwise if necessary, with Medium to obtain a solution having a known concentration of about LC/1000 where LC is the Tablet label claim in mg.
Test solution— Use portions of the solution under test passed through a 0.45-µm nylon filter, discarding the first 4 to 6 mL of the filtrate.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 220-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 1.0 mL per minute. Chromatograph the Standard solution, and record the chromatogram as directed for Procedure: the relative standard deviation for replicate injections is not more than 1.5%.
Procedure— Separately inject equal volumes (about 25 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. Determine the amount, in mg, of isosorbide mononitrate dissolved at each interval by the formula:
Click to View Image
in which rU and rS are the peak responses for the Test solution and the Standard solution, respectively; CS is the concentration, in mg per mL, of the Standard solution; and V is the volume, in mL, of Medium in the vessel at each time point.
Calculate the amount, in mg, of isosorbide mononitrate removed by sampling at the previous time points by the formula:
Click to View Image
in which AD is the amount, in mg, of isosorbide mononitrate dissolved at each time point; VS is the volume, in mL, of the sample taken; and V is the volume, in mL, of Medium in the vessel at each time point.
Calculate the percentage of isosorbide mononitrate dissolved at each time point by the formula:
Click to View Image
in which AD is the amount, in mg, of isosorbide mononitrate dissolved at a given time point; AR is the amount, in mg, of isosorbide mononitrate removed at the previous time point; 100 is the conversion factor to percentage; and LC is the Tablet label claim, in mg.
Tolerances— The percentages of the labeled amount of C6H9NO6 dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 15% and 35%
2 between 28% and 48%
4 between 43% and 68%
8 between 65% and 90%
12 not less than 80%
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 hours.
Determine the amount of C6H9NO6 dissolved by employing the following method.
Mobile phase— Prepare a filtered and degassed mixture of water and methanol (3:2). Make adjustments if necessary (see System suitability under Chromatography 621).
Standard stock solution— Dissolve an accurately weighed quantity of USP Diluted Isosorbide Mononitrate RS in Medium, and dilute quantitatively, and stepwise if necessary, with Medium to obtain a solution having a known concentration of about 1.2 mg of isosorbide mononitrate per mL.
Working standard solution— Dilute the Standard stock solution with Medium to obtain a final concentration of 60 µg per mL for Tablets labeled to contain 30 mg and a final concentration of 120 µg per mL for Tablets labeled to contain 60 mg.
Test solution— Use portions of the solution under test passed through a suitable 0.45-µm filter.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 220-nm detector and a 4.6-mm × 25-cm column that contains 10-µm packing L1. The flow rate is about 1.0 mL per minute. Chromatograph the Working standard solution, and record the chromatogram as directed for Procedure: the tailing factor is not more than 2.0, and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 20 µL) of the appropriate Working standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. Calculate the concentration (Ci), in mg per mL, of isosorbide mononitrate removed at each time point by the formula:
Click to View Image
in which rU(i) is the peak response for the Test solution at time point i; rS is the peak response for the Working standard solution; and CS is the concentration, in mg per mL, of the Working standard solution. Calculate the total amount, in percentage, of drug release at each time point i by the formula:
Click to View Image
in which Ci is the concentration, in mg per mL, of drug removed at time point i; V0 is the initial volume, in mL, of Medium; Vt is the volume, in mL, of sample removed at each sampling time; Cj is the concentration, in mg per mL, of drug released at time j; 100 is the conversion factor to percentage; and LC is the Tablet label claim, in mg.
Tolerances— The percentages of the labeled amount of C6H9NO6 dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 25% and 45%
2 between 35% and 60%
6 between 72% and 90%
12 not less than 80%
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 hours.
Determine the amount of C6H9NO6 dissolved by employing the following method.
Buffer solution— Transfer 15.4 g of ammonium acetate and 11.5 mL of acetic acid to a 1-L volumetric flask containing about 500 mL of water. Adjust with acetic acid to a pH of 4.7. Dilute with water to volume.
Standard stock solution— Dissolve an accurately weighed quantity of USP Diluted Isosorbide Mononitrate RS in Medium, and dilute quantitatively, and stepwise if necessary, with Medium to obtain a solution having a known concentration of about 0.12 mg of isosorbide mononitrate per mL.
Working standard solution— For Tablets labeled to contain 60 mg, use the Standard stock solution with no further dilution. For Tablets labeled to contain 30 mg, transfer 25.0 mL of the Standard stock solution to a 50-mL volumetric flask. Dilute with Medium to volume.
Test solution— Use portions of the solution under test passed through a suitable 0.45-µm filter.
Mobile phase— Prepare a filtered and degassed mixture of water, methanol, and Buffer solution (6:3:1). Make adjustments if necessary (see System Suitability under Chromatography 621).
Chromatographic system (see Chromatography 621) The liquid chromatograph is equipped with a 220-nm detector and a 4.6-mm × 15-cm column that contains 5-µm packing L1. The flow rate is about 1.0 mL per minute. Chromatograph the Working standard solution, and record the chromatogram as directed for Procedure: the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 100 µL) of the appropriate Working standard solution and Test solution into the chromatograph, record the chromatograms, and measure the peak responses. Calculate the concentration (Ci), in mg per mL, of isosorbide mononitrate removed at each time point by the formula:
Click to View Image
in which rU(i) is the peak response for the Test solution at time point i; rS is the peak response for the Working standard solution; and CS is the concentration, in mg per mL, of the Working standard solution. Calculate the total amount, in percentage, of drug release at each time point i by the formula:
Click to View Image
in which Ci is the concentration, in mg per mL, of drug removed at time point i; V0 is the initial volume, in mL, of Medium; Vt is the volume, in mL, of sample removed at each sampling time; Cj is the concentration, in mg per mL, of drug released at time j; 100 is the conversion factor to percentage; and LC is the Tablet label claim, in mg.
Tolerances— The percentages of the labeled amount of isosorbide mononitrate dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 20% and 40%
2 between 30% and 50%
6 between 70% and 90%
12 not less than 85%
Uniformity of dosage units 905: meet the requirements for Content Uniformity. Proceed as directed in the Assay, except to use 1 Tablet instead of the portion of powdered Tablets used in the Assay preparation.
Related compounds—
test 1—
Adsorbent: 0.25-mm layer of chromatographic silica gel mixture.
Standard solution 1— Weigh accurately a quantity of USP Isosorbide RS, and dilute quantitatively, and stepwise if necessary, with acetonitrile to obtain a solution having a known concentration of about 0.0125 mg of isosorbide per mL.
Standard solution 2— Weigh accurately a quantity of USP Isosorbide RS, and dilute quantitatively, and stepwise if necessary, with acetonitrile to obtain a solution having a known concentration of about 0.025 mg of isosorbide per mL.
Standard solution 3— Weigh accurately a quantity of USP Isosorbide RS, and dilute quantitatively, and stepwise if necessary, with acetonitrile to obtain a solution having a known concentration of about 0.05 mg of isosorbide per mL.
Test solution— Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 100 mg of isosorbide mononitrate, to a suitable flask containing 20.0 mL of acetonitrile. Sonicate for 10 minutes and then centrifuge. Use the supernatant.
Application volume: 20 µL.
Developing solvent system: a mixture of toluene, ethyl acetate, and isopropyl alcohol (53:32:15).
Procedure— Proceed as directed for Thin-Layer Chromatography under Chromatography 621. After developing, dry the plate with warm air for about 10 minutes, dip the plate in a solution prepared by dissolving 1.25 g of potassium permanganate and 10.0 g of sodium hydroxide in 500 mL of water (prepared fresh for each plate), and heat at 105 for 5 minutes. Any spot in the chromatogram obtained from the Test solution and corresponding to the RF value of the spots obtained from the Standard solutions is not more intense than the spot in the chromatogram obtained from Standard solution 3: not more than 1% of any individual impurity is found. [note—The RF values of isosorbide and isosorbide mononitrate are about 0.2 and 0.6, respectively. ] If the spot in the chromatogram obtained from the Test solution is nearly as intense as the spot obtained from Standard solution 3, further dilute the Test solution with acetonitrile (1:1), repeat the test, and compare the intensity of the isosorbide spot in the diluted Test solution with the intensity of the spots obtained from the Standard solutions, correcting the percentage level for the additional dilution of the Test solution.
test 2—
Mobile phase— Prepare a filtered and degassed mixture of water and methanol (75:25). Make adjustments if necessary (see System Suitability under Chromatography 621).
Isosorbide mononitrate related compound A standard stock solution— Dissolve an accurately weighed quantity of USP Diluted Isosorbide Mononitrate Related Compound A RS in water, and dilute quantitatively, and stepwise if necessary, with water to obtain a solution having a known concentration of about 0.3 mg of isosorbide mononitrate related compound A per mL.
Isosorbide dinitrate standard stock solution— Dissolve an accurately weighed quantity of USP Diluted Isosorbide Dinitrate RS in methanol, and dilute quantitatively, and stepwise if necessary, with methanol to obtain a solution having a known concentration of about 0.15 mg of isosorbide dinitrate per mL.
Standard stock solution— Transfer 2.0 mL of Isosorbide mononitrate related compound A standard stock solution and 4.0 mL of Isosorbide dinitrate standard stock solution to a 100-mL volumetric flask. Dilute with water to volume, and mix.
Resolution solution— Transfer a quantity of USP Diluted Isosorbide Mononitrate RS, equivalent to about 24 mg of isosorbide mononitrate, to a 100-mL volumetric flask, add 10.0 mL of Standard stock solution, add 20 mL of methanol, and dilute with water to volume.
Standard solution— Transfer 10.0 mL of Standard stock solution and 20 mL of methanol to a 100-mL volumetric flask. Dilute with water to volume, and mix.
Test solution— Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 60 mg of isosorbide mononitrate, to a 50-mL volumetric flask, add 40 mL of methanol, and sonicate for about 30 minutes with cooling. Warm to ambient temperature, dilute with methanol to volume, and mix. Centrifuge at about 3000 rpm for 10 minutes. Quantitatively dilute the supernatant with water (10 in 50). Pass a portion of this solution through a filter having a 0.45-µm or finer porosity, and use the filtrate.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 220-nm detector and a 4.6-mm × 25-cm column that contains packing L1. The flow rate is about 1.0 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between isosorbide mononitrate related compound A and isosorbide mononitrate is not less than 1.0. [note—The relative retention times are about 0.9 for isosorbide mononitrate related compound A, 1.0 for isosorbide mononitrate, and 5.6 for isosorbide dinitrate. ] Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 10% for the isosorbide mononitrate related compound A and isosorbide dinitrate peaks.
Procedure— Separately inject equal volumes (about 100 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the areas for the major peaks. Calculate the percentage of isosorbide mononitrate related compound A and isosorbide dinitrate in the portion of Tablets taken by the formula:
25(C/W)(rU / rS)
in which C is the concentration, in µg per mL, of the appropriate Standard, USP Diluted Isosorbide Mononitrate Related Compound A RS or USP Diluted Isosorbide Dinitrate RS, in the Standard solution; W is the weight, in mg, of isosorbide mononitrate in the sample used to prepare the Test solution; and rU and rS are the peak areas of the corresponding component obtained from the Test solution and the Standard solution, respectively: not more than 0.25% of isosorbide mononitrate related compound A is found, and not more than 0.25% of isosorbide dinitrate is found. Calculate the percentage of each other impurity (other than isosorbide mononitrate related compound A or isosorbide dinitrate) in the portion of Tablets taken by the formula:
100(ri / rs)
in which ri is the peak area for each other impurity obtained from the Test solution; and rs is the sum of the areas of all the peaks: not more than 0.25% of total other impurities is found, and not more than 0.5% of total impurities is found, including isosorbide mononitrate related compound A and isosorbide dinitrate.
Assay—
Mobile phase— Prepare a filtered and degassed mixture of water and methanol (8:2). Make adjustments if necessary (see System Suitability under Chromatography 621).
Isosorbide mononitrate related compound A standard preparation— Dissolve an accurately weighed quantity of USP Diluted Isosorbide Mononitrate Related Compound A RS in water, and dilute quantitatively, and stepwise if necessary, with water to obtain a solution having a known concentration of about 0.15 mg of isosorbide mononitrate related compound A per mL.
Resolution solution— Transfer a quantity of USP Diluted Isosorbide Mononitrate RS, accurately weighed and equivalent to about 30 mg of isosorbide mononitrate, to a 250-mL volumetric flask. Dissolve in water, add 10.0 mL of Isosorbide mononitrate related compound A standard preparation, add 50 mL of methanol, and dilute quantitatively, and stepwise if necessary, with water to obtain a solution having a concentration of about 0.12 mg of isosorbide mononitrate per mL and about 0.006 mg of isosorbide mononitrate related compound A per mL.
Standard preparation— Transfer a quantity of USP Diluted Isosorbide Mononitrate RS, accurately weighed, to a suitable volumetric flask. Dissolve in water, add a portion of methanol equivalent to about 20% of the flask volume, and dilute with water to volume to obtain a solution having a known concentration of about 0.12 mg of isosorbide mononitrate per mL.
Assay preparation— Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 60 mg of isosorbide mononitrate, to a 100-mL volumetric flask, add 50 mL of methanol, and sonicate for about 30 minutes with cooling. Warm to ambient temperature, dilute with methanol to volume, and mix. Centrifuge at about 3000 rpm for 10 minutes. Quantitatively dilute the supernatant with water (10 in 50). Pass a portion of this solution through a filter having a 0.45-µm or finer porosity, and use the filtrate.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 220-nm detector and a 4-mm × 12.5-cm column that contains packing L1. The flow rate is about 1.5 mL per minute. Chromatograph the Resolution solution, and record the peak responses as directed for Procedure: the resolution, R, between isosorbide mononitrate related compound A and isosorbide mononitrate is not less than 1.5. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the tailing factor is not more than 1.5, and the relative standard deviation for replicate injections is not more than 1.5%.
Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of isosorbide mononitrate (C6H9NO6) in the portion of Tablets taken by the formula:
500C(rU / rS)
in which C is the concentration, in mg per mL, of isosorbide mononitrate in the Standard preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.
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