(en al' a pril mal' ee ate).
l-Proline, 1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-l-alanyl]-, (S)-, (Z)-2-butenedioate (1:1).
1-[N-[(S)-1-Carboxy-3-phenylpropyl]-l-alanyl]-l-proline 1¢-ethyl ester, maleate (1:1) [76095-16-4].
» Enalapril Maleate contains not less than 98.0 percent and not more than 102.0 percent of C20H28N2O5·C4H4O4, calculated on the dried basis.
Packaging and storage Preserve in well-closed containers, and store at controlled room temperature.
USP Reference standards 11
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.
Specific rotation 781S: between 41.0 and 43.5.
Test solution: 10 mg per mL, in methanol.
Loss on drying 731 Dry it in vacuum at a pressure not exceeding 5 mm of mercury at 60 for 2 hours: it loses not more than 1.0% of its weight.
Residue on ignition 281: not more than 0.2%.
Heavy metals, Method II 231: 0.001%.
pH 6.8 Phosphate buffer, pH 2.5 Phosphate buffer, Solution A, Solution B, Mobile phase, Diluent, Enalapril diketopiperazine solution, System suitability solution, and Chromatographic system Proceed as directed in the Assay.
Standard solution Dissolve an accurately weighed quantity of USP Enalapril Maleate RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 3 µg per mL.
Test solution Use the Assay preparation.
Procedure Separately inject equal volumes (about 50 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak area responses. Calculate the percentage of each impurity in the portion of Enalapril Maleate taken by the formula:
100(CS / CT)(ri / rS)in which CS is the concentration, in mg per mL, of USP Enalapril Maleate RS in the Standard solution; CT is the concentration, in mg per mL, of Enalapril Maleate in the Test solution; ri is the peak area of each impurity obtained from the Test solution; and rS is the peak area of enalapril obtained from the Standard solution: not more than 1.0% of any impurity having a relative retention time of about 1.10 is found; not more than 0.3% of any other individual impurity is found; and not more than 2% of total impurities is found.
pH 6.8 Phosphate buffer Dissolve 2.8 g of monobasic sodium phosphate in about 900 mL of water in a 1000-mL volumetric flask. Adjust with a 9 M sodium hydroxide solution to a pH of about 6.8, dilute with water to volume, and mix.
pH 2.5 Phosphate buffer Dissolve 2.8 g of monobasic sodium phosphate in about 900 mL of water in a 1000-mL volumetric flask. Adjust with phosphoric acid to a pH of about 2.5, dilute with water to volume, and mix.
Solution A Prepare a filtered and degassed mixture of pH 6.8 Phosphate buffer and acetonitrile (19:1).
Solution B Prepare a filtered and degassed mixture of acetonitrile and pH 6.8 Phosphate buffer (33:17).
Mobile phase Use variable mixtures of Solution A and Solution B as directed for Chromatographic system. Make adjustments if necessary (see System Suitability under Chromatography 621).
Diluent Prepare a mixture of pH 2.5 Phosphate buffer and acetonitrile (95:5).
Enalapril diketopiperazine solution Carefully place about 20 mg of USP Enalapril Maleate RS in a 100-mL beaker to form a mound on the bottom of the beaker. Place the beaker on a hot plate at about one-half the maximum hot plate temperature setting. Heat for about 5 to 10 minutes until the solid is melted. Immediately remove the beaker from the hot plate, and allow to cool. [noteAvoid overheating to prevent heat-induced degradation, which would give rise to a brown color. ] To the cooled residue in the beaker add 50 mL of acetonitrile, and sonicate for a few minutes to dissolve. The solution typically contains, in each mL, between 0.2 mg and 0.4 mg of enalapril diketopiperazine.
Standard preparation Dissolve an accurately weighed quantity of USP Enalapril Maleate RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.3 mg per mL.
System suitability solution Add 1 mL of Enalapril diketopiperazine solution to a 50-mL portion of the Standard preparation, and mix.
Assay preparation Transfer about 30 mg of Enalapril Maleate, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix.
Chromatographic system (see Chromatography 621) The liquid chromatograph is equipped with a 215-nm detector and a 4.1-mm × 15-cm column that contains packing L21. The flow rate is about 1.5 mL per minute. The column temperature is maintained at 70. The chromatograph is programmed as follows.
Procedure Separately inject equal volumes (about 50 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 C20H28N2O5·C4H4O4 in the portion of Enalapril Maleate taken by the formula:
100C(rU / rS)in which C is the concentration, in mg per mL, of USP Enalapril Maleate RS 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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USP35NF30 Page 3032Pharmacopeial Forum: Volume No. 29(5) Page 1475