Isosorbide Dinitrate Extended-Release Tablets

» Isosorbide Dinitrate Extended-Release Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of C6H8N2O8.

Packaging and storage— Preserve in well-closed containers.

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

USP Reference standards

—

USP Diluted Isosorbide Dinitrate RS

Identification— Tablets respond to the Identification test under Isosorbide Dinitrate Tablets. Where separation of interferences is required, use the technique given under the Identification test for Isosorbide Dinitrate Extended-Release Capsules.

Dissolution

711

—

test 1—

Medium: water; 500 mL.

Apparatus 2: 50 rpm.

Times: 1, 2, 4, and 6 hours.

Determine the amount of C6H8N2O8 dissolved, using the following method.

pH 3.0 Buffer solution— Add 6.6 g of ammonium sulfate, accurately weighed, to 500 mL of water. Adjust with 1 N sulfuric acid to a pH of 3.0.

Mobile phase— Prepare a filtered and degassed mixture of methanol and pH 3.0 Buffer solution (50:50). Make adjustments if necessary (see System Suitability under Chromatography

621

Chromatographic system (see Chromatography

621

)—The liquid chromatograph is equipped with a UV wavelength detector and a 5-mm × 25-cm column that contains packing L1. The flow rate is about 1 mL per minute. Chromatograph a Standard solution of USP Diluted Isosorbide Dinitrate RS in the same Medium, and record the chromatograms as directed for Procedure: the tailing factor is not more than 2.5; and the relative standard deviation is not more than 2.0%.

Procedure— Separately inject equal volumes (about 20 µL) of a filtered portion of the solution under test, and record the chromatograms. Determine the amount of C6H8N2O8 dissolved in comparison with a Standard solution of USP Diluted Isosorbide Dinitrate RS in the same Medium, similarly chromatographed.

Tolerances— The percentages of the labeled amount of C6H8N2O8 dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	Amount dissolved
1	between 15% and 30%
2	between 50% and 70%
4	between 65% and 85%
6	not less than 75%

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

Medium: pH 1.2 simulated gastric fluid (without pepsin) for the first hour, 900 mL; pH 7.5 simulated intestinal fluid (without enzymes) for the subsequent hours, 900 mL.

Apparatus 2: 50 rpm, with helix sinkers.

Times: 1, 3, 6, and 12 hours.

Determine the amount of isosorbide dinitrate (C6H9NO6) dissolved by employing the following method.

Buffer solution and Mobile phase— Prepare as directed in the Assay under Diluted Isosorbide Dinitrate.

Standard solution— Prepare two solutions, one in each Medium. Dissolve an accurately weighed quantity of USP Diluted Isosorbide Dinitrate RS in Medium, and dilute quantitatively, and stepwise if necessary, with Medium to obtain a solution having a known concentration of about 40 µg per mL.

Test solution— Pass 5 mL of the solution under test through a suitable 10-µm filter. Replace the Medium withdrawn at the 3- and 6-hour timepoints.

Chromatographic system (see Chromatography

621

)— Proceed as directed in the Assay under Diluted Isosorbide Dinitrate. Chromatograph the 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 Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. Calculate the cumulative percentage of isosorbide dinitrate dissolved at each collection point, corrected for the quantities removed at previous collection points (not applicable for the first hour), as follows:

Percentage released at first hour (see Formula 1).

Formula 1

Percentage released at third hour (see Formula 2).

Formula 2

Percentage released at sixth hour (see Formula 3).

Formula 3

Percentage released at twelfth hour (see Formula 4).

Formula 4

in which rU and rS are the peak responses for the Test solution and the Standard solution, respectively; CU is the sample concentration, in µg per mL, at the indicated collection time point; CS is the concentration, in µg per mL, of the Standard solution; 900 is the volume, in mL, of Medium; 1000 is the conversion factor from µg to mg; 100 is the conversion factor to percentage; LC is the Tablet label claim, in mg; and 5 is the volume, in mL, of sample withdrawn and of the Medium replaced.

Tolerances— The percentages of the labeled amount of C6H8N2O8 dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	Amount dissolved
1	between 5% and 25%
3	between 30% and 50%
6	between 50% and 80%
12	not less than 75%

Uniformity of dosage units

905

: meet the requirements.

Assay—

Buffer solution, Mobile phase, Internal standard solution, Standard preparation, and Chromatographic system— Prepare as directed in the Assay under Diluted Isosorbide Dinitrate.

Assay preparation— Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 12.5 mg of isosorbide dinitrate, to a dry, 50-mL volumetric flask, add about 30 mL of Mobile phase, and shake the mixture by hand immediately to prevent clumping. If clumping persists, disperse with the aid of sonication, or break the aggregates with a stirring rod, or warm on a steam bath while keeping the flask stoppered, or allow the flask to stand until the clumps dissipate. [note—If clumping still continues, discard the mixture, and instead disperse an accurately weighed test portion in 15 mL of a 1 in 10 dilution of Buffer solution in water by heating on a steam bath for 1 hour with frequent shaking, then add 15 mL of methanol. ] Shake for 30 minutes. Add 8.0 mL of Internal standard solution, cool to room temperature, add 8 mL of a 1 in 10 dilution of Buffer solution in water, dilute with Mobile phase to volume, and mix. Pass a portion through a microporous membrane filter.

Procedure— Proceed as directed for Procedure in the Assay under Diluted Isosorbide Dinitrate. Calculate the quantity, in mg, of C6H8N2O8 in the portion of Tablets taken by the formula:

50C(RU / RS)

in which C is the concentration, in mg per mL, of isosorbide dinitrate from the USP Diluted Isosorbide Dinitrate RS taken for the Standard preparation; and RU and RS are the ratios of the peak responses obtained from the Assay preparation and the Standard preparation, respectively.

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question	Contact	Expert Committee
Monograph	Sujatha Ramakrishna, Ph.D. Senior Scientific Liaison 1-301-816-8349	(SM22010) Monographs - Small Molecules 2
Reference Standards	RS Technical Services 1-301-816-8129 rstech@usp.org
711	Margareth R.C. Marques, Ph.D. Senior Scientific Liaison 1-301-816-8106	(GCDF2010) General Chapters - Dosage Forms

USP35–NF30 Page 3589

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