Triamterene and Hydrochlorothiazide Capsules
»Triamterene and Hydrochlorothiazide Capsules contain not less than 90.0percent and not more than 110.0percent of the labeled amounts of triamterene (C12H11N7)and hydrochlorothiazide (C7H8ClN3O4S2).
NOTE—The Capsules and Tablets dosage forms should not be considered bioequivalent.If patients are to be transferred from one dosage form to the other,retitration and appropriate changes in dosage may be necessary.
Packaging and storage— Preserve in tight,light-resistant containers.
Labeling— Label the Capsules to indicate the Dissolutiontest with which the product complies.
Identification—
A: Thin-Layer Identification Test á201ñ—
Test solution— Dissolve a portion of the Capsule contents,equivalent to about 50mg of triamterene,in 25mLof methoxyethanol,mix,and filter.Use the filtrate as the Test solution.
Standard solution 1— Prepare a solution of USP Triamterene RSin methoxyethanol containing about 2mg per mL.
Standard solution 2: a sufficient quantity of USP Hydrochlorothiazide RSin methoxyethanol to obtain a solution having a concentration similar to that of the Test solution.
Application volume: 2µL.
Developing solvent system: a mixture of ethyl acetate,glacial acetic acid,and water (8:1:1).
Procedure— Locate the spots under short-wavelength and long-wavelength UVlight:the intensity and RFvalue correspond to that obtained from Standard solution 1and Standard solution 2.
B: The retention times of the major peaks in the chromatogram of the Assay preparationcorrespond to those in the chromatogram of the Standard preparation,as obtained in the Assay.
Dissolution á711ñ—
TEST1: If the product complies with this test,the labeling indicates that it meets USPDissolution Test 1.
Medium: 0.1Macetic acid containing 1%polysorbate 20;900mL.
Apparatus 2: 100rpm.
Time: 120minutes.
Procedure— Determine the amounts of triamterene (C12H11N7)and hydrochlorothiazide (C7H8ClN3O4S2)dissolved from UVabsorption at the wavelength of maximum absorbance at about 357nm for triamterene and 271nm for hydrochlorothiazide (corrected for interference from triamterene on the basis of the absorbances of triamterene at 271nm and 357nm)on a filtered portion of the solution under test,suitably diluted with water,in comparison with a Standard solution having known concentrations of USP Triamterene RSand USP Hydrochlorothiazide RSin the same Medium.
Tolerances— Not less than 80%(Q)of the labeled amounts of C12H11N7and C7H8ClN3O4S2is dissolved in 120minutes.
TEST2: If the product complies with this test,the labeling indicates that it meets USPDissolution Test 2.
Medium: 4.0%tetrasodium ethylenediaminetetraacetate,2.0%polysorbate 40,0.05%pancreatin;900mL.Prepare a solution using the following procedure.Add the polysorbate 40and the tetrasodium ethylenediaminetetraacetate to water,and mix thoroughly.Adjust with phosphoric acid to a pHof 8.0±0.05.Heat to 37,and add the pancreatin powder.Mix thoroughly,and transfer immediately to the dissolution vessel.
Apparatus 1 (use 10-mesh baskets):100rpm.
Time: 8hours.
Mobile phase— Prepare a filtered and degassed solution of 0.08Mmonobasic sodium phosphate buffer and methanol (3:1).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Standard preparation— Transfer about 110mg of USP Triamterene RSand about 55mg of USP Hydrochlorothiazide RS,each accurately weighed,to a 500-mLvolumetric flask.Add 100mLof methanol,sonicate for 10minutes,and heat in a steam bath until completely dissolved.Dilute with Mediumto volume,and mix.Transfer 25mLof this solution into a 100-mLvolumetric flask,dilute with Mediumto volume,and mix gently to minimize foaming.
Test preparation— Filter a portion of the solution under test.[NOTE—Do not use nylon filters.]
Chromatographic system(see Chromatography á621ñ)— The liquid chromatograph is equipped with a 254-nm detector,a guard column that contains packing L7,and an analytical 3.9-mm ×30-cm column that contains packing L11.The flow rate is about 2mLper minute.Chromatograph the Standard preparation,and record the responses as directed for Procedure:the resolution,R,between the triamterene and hydrochlorothiazide peaks is not less than 2.0;and the relative standard deviation for replicate injections of each analyte is not more than 2.0%.
Procedure— Separately inject equal volumes (about 50µL)of the Standard preparationand the Test preparationin the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantities,in mg,of triamterene (C12H11N7)and hydrochlorothiazide (C7H8ClN3O4S2)dissolved by the formula:
900C(rU/rS),
in which Cis the concentration,in mg per mL,of the appropriate USP Reference Standard in the Standard preparation;and rUand rSare the peak responses of the relevant analyte obtained from the Test preparationand the Standard preparation,respectively.
Tolerances— Not less than 70%(Q)of the labeled amount of C12H11N7and not less than 80%(Q)of the labeled amount of C7H8ClN3O4S2are dissolved in 8hours.
TEST3: If the product complies with this test,the labeling indicates that it meets USPDissolution Test 3.
Medium: 0.1Nhydrochloric acid;900mL.
Apparatus 1: 100rpm.
Time: 45minutes.
Procedure— Proceed as directed for Test 1.
Tolerances— Not less than 75%(Q)of the labeled amounts of C12H11N7and C7H8ClN3O4S2is dissolved in 45minutes.
Uniformity of dosage units á905ñ: meet the requirements for Content Uniformitywith respect to triamterene and to hydrochlorothiazide.
Related compounds—
Solution A,Solution B,Mobile phase,Standard solution,and Chromatographic system— Proceed as directed for theRelated compounds test underTriamterene and Hydrochlorothiazide Tablets.
Test solution— Remove,as completely as possible,the contents of not fewer than 20Capsules,and weigh accurately.Mix the combined contents,and transfer an accurately weighed portion of the powder,equivalent to about 150mg of hydrochlorothiazide,to a 100-mLvolumetric flask.Add 60mLof acetonitrile and 6mLof glacial acetic acid,and sonicate for 10minutes.Cool,dilute with water to volume,mix,and filter.
Procedure— Proceed as directed forProcedure in theRelated compounds test underTriamterene and Hydrochlorothiazide Tablets.Calculate the quantity,in mg,of benzothiadiazine related compound Ain the hydrochlorothiazide contained in the portion of Capsules taken by the formula:
100C(rU/rS),
in whichCis the concentration,in mg per mL,of USP Benzothiadiazine Related Compound A RSin theStandard solution;andrUandrSare the peak areas of benzothiadiazine related compound Aobtained from theTest solutionand theStandard solution,respectively:not more than 1.0%is present.
Assay—
Buffer solution,Mobile phase,and Standard preparation— Proceed as directed in the Assayunder Triamterene and Hydrochlorothiazide Tablets.
Assay preparation— Remove,as completely as possible,the contents of not fewer than 20Capsules,combine the contents,and transfer an accurately weighed portion of powder,equivalent to about 50mg of hydrochlorothiazide,to a 200-mLvolumetric flask.Add 20mLof acetonitrile,and sonicate for 10minutes.Add 20mLof boiling water,sonicate for 5minutes,and mix.Add 10mLof acetic acid,sonicate for 10minutes,and mix.Add 140mLof water,mix,and allow to cool to room temperature.Dilute with water to volume,mix,and filter,discarding the first 3mLof the filtrate.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 280-nm detector and a 3.9-mm ×30-cm column that contains packing L1.The flow rate is about 1mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the relative retention times are 0.65for hydrochlorothiazide and 1.0for triamterene;the resolution,R,between hydrochlorothiazide and triamterene is not less than 3.0;and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses of the major peaks.Calculate the quantity,in mg,of triamterene (C12H11N7)in the portion of Capsules taken by the formula:
200C(rU/rS),
in which Cis the concentration,in mg per mL,of USP Triamterene RSin the Standard preparation;and rUand rSare the peak responses obtained from the Assay preparationand the Standard preparation,respectively.Calculate the quantity,in mg,of hydrochlorothiazide (C7H8ClN3O4S2)in the portion of Capsules taken by the same formula,changing the terms to refer to hydrochlorothiazide.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(PA5)Pharmaceutical Analysis 5
USP28–NF23Page 1966
Pharmacopeial Forum:Volume No.29(3)Page 672
Phone Number:1-301-816-8305