Isosorbide Dinitrate Extended-Release Capsules

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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Isosorbide Dinitrate Extended-Release Capsules 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. 

USP Reference standards 〈11〉— 

USP Diluted Isosorbide Dinitrate RS 

Identication—The finely powdered contents of the Capsules respond to the Identification test under Isosorbide Dinitrate Tablets. If separation of interferences is required, transfer a quantity of the finely powdered contents of the Capsules, equivalent to about 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 about −14°, the beaker and a short-stem funnel fitted with a cotton plug that previously has been chloroform-washed and dried. After 30 minutes, filter the solution while still in the freezer. Evaporate the solvent, and dry the residue in vacuum over calcium chloride for 16 hours: the IR absorption spectrum of the residue so obtained, dissolved in 0.4 mL of chloroform and determined with the use of matched 0.1-mm cells, shows all of the significant absorption bands present in the spectrum obtained for a similar preparation from the residue obtained from USP Diluted Isosorbide Dinitrate RS. The major peaks are at about 1650 cm−1, 1284 cm−1 and 1275 cm−1 (a doublet), 1106 cm−1, and 844 cm−1. Dissolution 〈711〉—Proceed as directed for Method B in Delayed-Release Dosage Forms in Procedure, Apparatus 1 and Apparatus 2, except to operate the apparatus in the acid medium for 1 hour instead of 2 hours and to use Acceptance Table 2 in Extended-Release Dosage Forms in Interpretation. 

Apparatus 2: 50 rpm. 

Times: 2, 4, and 8 hours. 

Determine the amount of C₆H₈N₂O₈ dissolved employing the following method. 

Mobile phase—Prepare a filtered and degassed mixture of 0.05 M monobasic potassium phosphate and acetonitrile (52:48). Make adjustments, if necessary (see System Suitability under Chromatography 〈621〉). 

Chromatographic system (see Chromatography 〈621〉)—The liquid chromatograph is equipped with a 224-nm detector and a 4-mm × 30-cm column that contains packing L1. The flow rate is about 2 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 and similarly chromatographed. 

Tolerances—The percentages of the labeled amount of C₆H₈N₂O₈ dissolved at the times specified conform to Acceptance Table 2. [Note—The test times given are cumulative, beginning with the 1 hour in the acid medium.] 

Uniformity of dosage units 〈905〉: meet the requirements. 

Assay— 

Buffer solution—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 Buffer solution, and 550 mL of methanol. Cool to room temperature, dilute with water to 1000 mL, mix, degas, and filter. Make adjustments if necessary (see System Suitability under Chromatography 〈621〉). 

Internal standard solution—Transfer a quantity of diluted Nitroglycerin to a suitable volumetric flask, add about 60% of the flask volume of methanol, sonicate for 5 minutes, and shake for 30 minutes. Dilute with methanol to volume to obtain a solution having a concentration of about 3 mg of nitroglycerin per mL, and mix. Allow any undissolved material to settle, filter, and store the filtrate in an airtight container. 

Standard preparation—Transfer about 125 mg of recently mixed USP Diluted Isosorbide Dinitrate RS, accurately weighed, to a 50-mL volumetric flask, add about 30 mL of Mobile phase, shake for 30 minutes, dilute with Mobile phase to volume, and mix. Pipet 10 mL of the resulting solution into a 25-mL volumetric flask, and add 4.0 mL of Internal standard solution and 4 mL of dilute Buffer solution (1 in 10). Cool to room temperature, dilute with Mobile phase to volume, and mix to obtain a solution having a known concentration of about 0.25 mg of isosorbide dinitrate per mL, based on the quantity of USP Diluted Isosorbide Dinitrate RS weighed and the labeled content of isosorbide dinitrate. Pass a portion of this solution through a 0.45-μm filter. 

Assay preparation—Weigh and finely powder the contents of not fewer than 20 Capsules. 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. 

Chromatographic system (see Chromatography 〈621〉)—The liquid chromatograph is equipped with a 220-nm detector and a 4-mm × 25-cm column that contains packing L1. The flow rate is about 1 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the resolution, R, between isosorbide dinitrate and nitroglycerin is not less than 2.0; and the relative standard deviation for replicate injections determined from the peak response ratios is not more than 2%. [Note—The relative retention times are about 0.75 for isosorbide dinitrate and 1.0 for nitroglycerin. The relative retention times for isosorbide mononitrates, if present, are about 0.38.] 

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 C₆H₈N₂O₈ in the portion of Capsules taken by the formula: 

50C(R_U/R_S) 

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 R_U and R_S are the ratios of the peak responses obtained from the Assay preparation and the Standard preparation. respectively.