Minor editorial changes have been made to update the monograph to the current USP style.

Transcription

1 Amlodipine, Valsartan and Hydrochlorothiazide Tablets Type of Posting Revision Bulletin Posting Date 27 May 2016 Official Date 01 Jun 2016 Expert Committee Chemical Medicines Monographs 2 Reason for Revision Compliance In accordance with the Rules and Procedures of the Council of Experts, the Chemical Medicines Monographs 2 Expert Committee has revised the Amlodipine, Valsartan and Hydrochlorothiazide Tablets monograph. The purpose of this revision is to be consistent with the FDA-approved drug products and is described below. The acceptance criteria under Definition and Assay is widened from NLT 95.0% and NMT 105.0% to NLT 92.5% and NMT 107.5% for amlodipine, valsartan and hydrochlorothiazide. In the test for organic Impurities, the acceptance criteria for Benzothiadiazine related compound A is widened from NMT 0.4% to NMT 1.0%, Chlorothiazide and hydrochlorothiazide dimer from NMT 0.2% to NMT 0.50%, and the total products is widened from NMT 1.5% to NMT 2.0%. A Dis Test 2 is added. The liquid chromatographic procedure is validated using an Inertsil ODS 3V brand of L1 column. The typical retention times for amlodipine, valsartan and hydrochlorothiazide are about 5.0 min and 7.5 min and 2.5 min respectively. A Dis Test 3 is added. The liquid chromatographic procedure is validated using an Oyster ODS 3 brand of L1 column. The typical retention times for hydrochlorothiazide and valsartan are about 2.3 min and 3.6 min respectively. The typical retention time for amlodipine is about 2.8 min. Minor editorial changes have been made to update the monograph to the current USP style. The Amlodipine, Valsartan and Hydrochlorothiazide Tablets Revision Bulletin supersede the currently official Amlodipine, Valsartan and Hydrochlorothiazide Tablets monograph. The Revision Bulletin will be incorporated in the USP 40 NF 35. Should you have any questions, please contact Sujatha Ramakrishna, Ph.D., MBA. Senior Scientific Liaison ( or sxr@usp.org).

2 . Table Revision Bulletin Official June 1, 2016 Amlodipine 1 2 Amlodipine, Valsartan, and Tablet Hydrochlorothiazide Tablets Strength Nominal Amlodipine/ Nominal Concentra- Valsartan/ Concentra- Nominal tion DEFINITION Hydrochlo- tion Concentra- of Hydrorothiazide of tion chlorothia- Change to read: (mg/mg/ Amlodipine of Valsartan zide mg) (mg/ml) (mg/ml) (mg/ml) Amlodipine, Valsartan, and Hydrochlorothiazide Tablets 5/160/ contain.nlt 92.5% and NMT 107.5% (RB 1-Jun-2016) each 10/160/ of the labeled amounts of amlodipine (C 20H 25ClN 2O 5), 5/160/ valsartan (C 24H 29N 5O 3), and hydrochlorothiazide 10/160/ (C 7H 8ClN 3O 4S 2). 10/320/ IDENTIFICATION A. The UV absorption spectra of the amlodipine, valml of amlodipine in Diluent from Sample stock Sample A: Nominally equivalent to 0.1 mg/ sartan, and hydrochlorothiazide peaks of Sample A, Sample B, and Sample C and those of Sample B: Nominally equivalent to mg/ the exhibit maxima and minima at the ml of valsartan in Diluent from Sample stock same wavelengths, as obtained in the Assay. Sample C: Nominally equivalent to B. The retention times of the amlodipine, valsartan, and mg/ml of hydrochlorothiazide in Diluent from hydrochlorothiazide peaks of Sample A, Sample Sample stock B, and Sample C correspond to those of Chromatographic system the, as obtained in the Assay. Mode: LC ASSAY Detector Assay: 225 nm Identification test A: Diode array,.uv Change to read: nm (RB 1-Jun-2016) Column: 4.6-mm 15-cm; 3-µm packing L1 PROCEDURE Column temperature: 40 Use amber glassware for all s containing drug Flow rate: 1.5 ml/min substances. Injection volume: 10 µl Solution A: Acetonitrile, water, and phosphoric acid System suitability (50:950:1) Sample: Solution B: Acetonitrile, water, and phosphoric acid Suitability requirements (950:50:1) Tailing factor: NMT 2.0 for amlodipine, valsartan, Mobile phase: See Table 1. and hydrochlorothiazide Relative standard deviation: NMT 2.0% for Table 1 amlodipine, valsartan, and hydrochlorothiazide Samples:, Sample A, Sample B, and Sample C amlodipine (C 20H 25ClN 2O 5) in the portion of Tablets taken: Result = (r U/r S) (C S/C U) (M r1/m r2) r U = peak response of amlodipine from Sample A Diluent: Acetonitrile and water (500:500) r S = peak response of amlodipine from the 0.1% Phosphoric acid: Water and phosphoric acid (1000:1) C S = concentration of USP Amlodipine Besylate RS : 0.14 mg/ml of USP Amlodipine in the (mg/ml) Besylate RS, mg/ml of USP Valsartan RS, and C U = nominal concentration of amlodipine in mg/ml of USP Hydrochlorothiazide RS in Diluent Sample A (mg/ml) Sample stock : Transfer NLT 10 Tablets into a M r1 = molecular weight of amlodipine, suitable volumetric flask. Add 0.1% Phosphoric acid to 4% of the total volume to disperse the Tablets. Soni- cate for 10 min. Add 4% of the total volume of aceto- nitrile, swirl to mix, and add 60% of the total volume valsartan (C 24H 29N 5O 3) in the portion of Tablets taken: of Diluent. Sonicate for 20 min. Dilute with Diluent to volume to obtain s of nominal concentrations stated in Table 2. Centrifuge, and use the clear supernatant. r U = peak response of valsartan from Sample B r S = peak response of valsartan from the Standard C S = concentration of USP Valsartan RS in the (mg/ml)

3 2 Amlodipine Official June 1, 2016 C U = nominal concentration of valsartan in Sample Mode: LC B (mg/ml) Detector: UV 250 nm Column: 4.6-mm 5-cm; 3-µm packing L1 hydrochlorothiazide (C 7H 8ClN 3O 4S 2) in the portion of Column temperature: 30 Tablets taken: Flow rate: 1.5 ml/min Injection volume: 5 µl for 10/320/25 (mg/mg/mg) of Tablet strengths (amlodipine/valsartan/hydrochlorothiazide); 10 µl for 5/160/12.5, 10/160/12.5, 5/ r U = peak response of hydrochlorothiazide from 160/25, and 10/160/25 (mg/mg/mg) of Tablet Sample C strengths (amlodipine/valsartan/hydrochlorothiazide) r S = peak response of hydrochlorothiazide from the System suitability Sample: C S = concentration of USP Hydrochlorothiazide RS Suitability requirements in the (mg/ml) Re: NLT 3.0 between amlodipine and C U = nominal concentration of hydrochlorothiazide valsartan in Sample C (mg/ml) Tailing factor: NMT 2.0 for amlodipine, valsartan, Acceptance criteria:.92.5% 107.5% (RB 1-Jun-2016) and hydrochlorothiazide Relative standard deviation: NMT 2.0% for PERFORMANCE TESTS amlodipine, valsartan, and hydrochlorothiazide Change to read: Samples: and Sample DISSOLUTION 711 amlodipine (C 20H 25ClN 2O 5) dissolved:.test 1 Buffer: (RB Dissolve 1-Jun-2016) g of monobasic potassium Result = (r U/r S) C S V (M r1/m r2) (1/L 1) 100 phosphate and g of sodium hydroxide in 1000 ml of water. Adjust with 0.2 N sodium hydrox r U = peak response of amlodipine from the Sample ide or 1 M phosphoric acid to a ph of 6.8. Medium: Buffer; 900 ml r S = peak response of amlodipine from the Apparatus 2: 50 rpm for 5/160/12.5, 10/160/12.5, 5/160/25, and 10/160/25 (mg/mg/mg) of Tablet C S = concentration of USP Amlodipine Besylate RS strengths (amlodipine/valsartan/hydrochlorothiazide); in the (mg/ml) 55 rpm for 10/320/25 (mg/mg/mg) of Tablet V = volume of Medium, 900 ml strengths (amlodipine/valsartan/hydrochlorothiazide) M r1 = molecular weight of amlodipine, Time: 30 min Solution A: Acetonitrile, water, and phosphoric acid (50:950:1) L 1 = label claim for amlodipine (mg/tablet) Solution B: Acetonitrile, water, and phosphoric acid (950:50:1) valsartan (C 24H 29N 5O 3) dissolved: Mobile phase: See Table 3. Result = (r U/r S) C S V (1/L 2) 100 Table 3 r U = peak response of valsartan from the Sample r S = peak response of valsartan from the Standard C S = concentration of USP Valsartan RS in the (mg/ml) V = volume of Medium, 900 ml L 2 = label claim for valsartan (mg/tablet) Diluent: 1 mg/ml of polysorbate 80 in Buffer hydrochlorothiazide (C 7H 8ClN 3O 4S 2) dissolved: Standard stock A: 0.07 mg/ml of USP Amlodipine Besylate and mg/ml of USP Hydrochlorothiazide RS. Initially dissolve with 4% of the to- Result = (r U/r S) C S V (1/L 3) 100 tal volume of methanol, and dilute with Diluent to r U = peak response of hydrochlorothiazide from the volume. Sample Standard stock B: 3.2 mg/ml of USP Val- r S = peak response of hydrochlorothiazide from the sartan RS in methanol : mg/ml of USP Amlodipine C S = concentration of USP Hydrochlorothiazide RS Besylate RS, 0.16 mg/ml of USP Valsartan RS, and in the (mg/ml) mg/ml of USP Hydrochlorothiazide RS in Dilu- V = volume of Medium, 900 ml ent from Standard stock A and Standard stock L 3 = label claim for hydrochlorothiazide (mg/ B, respectively Tablet) Sample : Pass a portion of the under Tolerances: NLT 75% (Q) of the labeled amount of test through a suitable filter of 0.45-µm pore size. Disof the labeled amount of valsartan (C 24H 29N 5O 3) is dis- amlodipine (C 20H 25ClN 2O 5) is dissolved, NLT 80% (Q) card at least the first 10 ml of the filtrate. Chromatographic system solved, and NLT 80% (Q) of hydrochlorothiazide (C 7H 8ClN 3O 4S 2) is dissolved..test 2: If the product complies with this test, the labeling indicates that the product meets USP Dis Test 2.

4 Official June 1, 2016 Amlodipine 3 Medium: Proceed as directed under Dis Test 1, r U = peak response of amlodipine from the Sample 900 ml. Apparatus 2 r S = peak response of amlodipine from the For Tablets labeled to contain amlodipine/val- sartan/hydrochlorothiazide, 5/160/12.5, 10/160/ C S = concentration of USP Amlodipine Besylate RS 12.5, 5/160/25, 10/160/25, and 5/80/12.5 (mg/ in the (mg/ml) mg/mg): 50 rpm V = volume of Medium, 900 ml For Tablets labeled to contain amlodipine/val- M r1 = molecular weight of amlodipine, sartan/hydrochlorothiazide, 10/320/25 (mg/mg/ mg): 55 rpm Time: 30 min for valsartan and hydrochlorothiazide, L 1 = label claim for amlodipine (mg/tablet) 45 min for amlodipine Buffer: Mix 7.0 ml of triethylamine with 1000 ml of valsartan (C 24H 29N 5O 3) dissolved: water. Adjust with phosphoric acid to a ph of 3.0. Solution A: Acetonitrile and Buffer (10:90). Result = (r U/r S) C S V (1/L 2) 100 Solution B: Acetonitrile and Buffer (90:10). Mobile phase: See Table 4. r U = peak response of valsartan from the Sample Table 4 r S = peak response of valsartan from the Standard C S = concentration of USP Valsartan RS in the (mg/ml) V = volume of Medium, 900 ml L 2 = label claim for valsartan (mg/tablet) hydrochlorothiazide (C 7H 8ClN 3O 4S 2) dissolved: Standard stock A: 0.35 mg/ml of USP Result = (r U/r S) C S V (1/L 3) 100 Amlodipine Besylate RS prepared as follows. Initially r U = peak response of hydrochlorothiazide from the dissolve in 10% of the final volume of methanol and Sample dilute with Medium to volume. r S = peak response of hydrochlorothiazide from the Standard stock B: 1.6 mg/ml of USP Val- sartan RS in methanol C S = concentration of USP Hydrochlorothiazide RS Standard stock C: 0.7 mg/ml of USP Hydro- in the (mg/ml) chlorothiazide RS prepared as follows. Initially dissolve V = volume of Medium, 900 ml in 25% of the final volume of methanol and dilute L 3 = label claim for hydrochlorothiazide (mg/ with Medium to volume. Tablet) : (L 1/1000) mg/ml of amlodipine, Tolerances: NLT 75% (Q) of the labeled amount of L 2/1000) mg/ml of valsartan, and (L 3/1000) mg/ml amlodipine (C 20H 25ClN 2O 5) is dissolved, NLT 80% (Q) of hydrochlorothiazide in Diluent from Standard stock of the labeled amount of valsartan (C 24H 29N 5O 3) is dis A, Standard stock B, and Standard solved, and NLT 80% (Q) of the labeled amount of stock C, where L 1 is the label claim of hydrochlorothiazide (C 7H 8ClN 3O 4S 2) is dissolved. amlodipine in mg/tablet, L 2 is the label claim of val- Test 3: If the product complies with this test, the labelsartan in mg/tablet, and L 3 is the label claim of hy- ing indicates that the product meets USP Dis drochlorothiazide in mg/tablet Test 3. Sample : Pass a portion of the under Medium: Dissolve 6.80 g of monobasic potassium test through a suitable filter of 1-µm pore size. phosphate in 1000 ml of water. Adjust with 10% so- Chromatographic system dium hydroxide to a ph of 6.8.; 1000 ml for valsartan and hydrochlorothiazide; 900 ml for Mode: LC amlodipine Detector: UV 237 nm Apparatus 2: 50 rpm for valsartan and hydrochloro- Column: 4.6-mm 15-cm; 5-µm packing L1 thiazide; 55 rpm for amlodipine in Tablets labeled to Temperatures contain amlodipine/valsartan/hydrochlorothiazide, 10/ Autosampler: /25 (mg/mg/mg); and 50 rpm for amlodipine in Column: 50 Tablets labeled to contain amlodipine/valsartan/hydro- Flow rate: 1.5 ml/min chlorothiazide, 5/160/12.5, 10/160/12.5, 5/160/25, Injection volume: 20 µl 10/160/25, and 5/80/12.5 (mg/mg/mg) System suitability Times: 30 min for valsartan and hydrochlorothiazide, Sample: 45 min for amlodipine Suitability requirements Solution A: Acetonitrile, trifluoroacetic acid and water Tailing factor: NMT 2.0 for each peak (10:0.1:90) Relative standard deviation: NMT 2.0% for each Solution B: Acetonitrile, trifluoroacetic acid and water peak (90:0.1:10) Mobile phase: See Table 5. Samples: and Sample amlodipine (C 20H 25ClN 2O 5) dissolved: Table 5 Result = (r U/r S) C S V (M r1/m r2) (1/L 1)

5 4 Amlodipine Official June 1, 2016 Table 5 (Continued) C S = concentration of USP Valsartan RS in the (mg/ml) V = volume of Medium, 1000 ml L 2 = label claim for valsartan (mg/tablet) hydrochlorothiazide (C 7H 8ClN 3O 4S 2) dissolved: Diluent: Acetonitrile and water (50:50) Result = (r U/r S) C S V (1/L 3) 100 Standard stock A: 0.15 mg/ml of USP Amlodipine Besylate RS in Medium prepared as fol- r U = peak response of hydrochlorothiazide from the lows. Initially dissolve and sonicate in 5% of the final Sample volume of Diluent and dilute with Medium to volume. r S = peak response of hydrochlorothiazide from the Standard stock B: 1.6 mg/ml of USP Val- sartan RS in Medium prepared as follows. Initially dis- C S = concentration of USP Hydrochlorothiazide RS solve and sonicate in 20% of the final volume of Dilu- in the (mg/ml) ent and dilute with Medium to volume. V = volume of Medium, 1000 ml Standard stock C: 0.25 mg/ml of USP Hy- L 3 = label claim for hydrochlorothiazide (mg/ drochlorothiazide RS in Medium prepared as follows. Tablet) Initially dissolve and sonicate in 10% of the final vol- Tolerances ume of Diluent and dilute with Medium to volume. For Tablets labeled to contain amlodipine/ : (L 1/1000) mg/ml of amlodipine, valsartan/hydrochlorothiazide, 5/160/12.5, 10/ (L 2/1000) mg/ml of valsartan, and (L 3/1000) mg/ml 160/12.5, 5/160/25, and 10/160/25 (mg/mg/ of hydrochlorothiazide in Diluent from Standard stock mg): NLT 75% (Q) of the labeled amount of A, Standard stock B, and Standard amlodipine (C 20H 25ClN 2O 5) is dissolved, NLT 80% (Q) stock C, where L 1 is the label claim of of the labeled amount of valsartan (C 24H 29N 5O 3) is amlodipine in mg/tablet, L 2 is the label claim of Val- dissolved, and NLT 80% (Q) of the labeled amount sartan in mg/tablet, and L 3 is the label claim of hy- of hydrochlorothiazide (C 7H 8ClN 3O 4S 2) is dissolved. drochlorothiazide in mg/tablet. For Tablets labeled to contain amlodipine/val- Sample : Pass a portion of the under sartan/hydrochlorothiazide, 5/160/25, and 10/ test through a suitable filter of 0.45-µm pore size. Dis- 320/25 (mg/mg/mg): NLT 70% (Q) of the labeled card at least the first few ml of the filtrate. amount of amlodipine (C 20H 25ClN 2O 5) is dissolved, Chromatographic system NLT 80% (Q) of the labeled amount of valsartan (C 24H 29N 5O 3) is dissolved, and NLT 80% (Q) of the Mode: LC labeled amount of hydrochlorothiazide Detector: UV 237 for amlodipine and UV 270 nm (C 7H 8ClN 3O 4S 2) is dissolved. (RB 1-Jun-2016) for valsartan and hydrochlorothiazide UNIFORMITY OF DOSAGE UNITS 905 : Meet the Column: 4.6-mm 10-cm; 5-µm packing L1 requirements Flow rate: 1.5 ml/min Injection volume: 10 µl IMPURITIES System suitability Sample: Change to read: Suitability requirements Tailing factor: NMT 2.0 for each peak Relative standard deviation: NMT 2.0% for each ORGANIC IMPURITIES peak Use amber glassware for all s containing drug substances. Samples: and Sample Mobile phase, Diluent, Sample A, Sample so- lution B, Sample C, and Chromatographic amlodipine (C 20H 25ClN 2O 5) dissolved: system: Proceed as directed in the Assay. System suitability : 0.02 mg/ml each of USP Result = (r U/r S) C S V (M r1/m r2) (1/L 1) 100 Benzothiadiazine Related Compound A RS and USP Valsartan Related Compound B RS, mg/ml of USP r U = peak response of amlodipine from the Sample Amlodipine Related Compound A RS, 0.14 mg/ml of USP Amlodipine Besylate RS, mg/ml of USP Valr S = peak response of amlodipine from the sartan RS, and mg/ml of USP Hydrochlorothia- zide RS in Diluent C S = concentration of USP Amlodipine Besylate RS Sensitivity : 0.14 µg/ml of USP Amlodipine in the (mg/ml) Besylate RS, µg/ml of USP Valsartan RS, and V = volume of Medium, 900 ml µg/ml of USP Hydrochlorothiazide RS in Diluent M r1 = molecular weight of amlodipine, : mg/ml of USP Amlodipine Related Compound A RS, mg/ml of USP Benzothiadiazine Related Compound A RS, mg/ L 1 = label claim for amlodipine (mg/tablet) ml of USP Amlodipine Besylate RS, mg/ml of USP Valsartan RS, and mg/ml of USP Hydrovalsartan (C 24H 29N 5O 3) dissolved: chlorothiazide RS in Diluent System suitability Result = (r U/r S) C S V (1/L 2) 100 Samples: System suitability, Sensitivity, and r U = peak response of valsartan from the Sample Suitability requirements Signal-to-noise ratio: NLT 10 for amlodipine, valr S = peak response of valsartan from the Standard sartan, and hydrochlorothiazide, Sensitivity

6 Official June 1, 2016 Amlodipine 5 Re: NLT 2.0 between any adjacent peaks of Calculate the percentage of each unspecified benzothiadiazine related compound A, hydrochloro- product in the portion of Tablets taken: thiazide, amlodipine related compound A, amlodipine, valsartan related compound B, and valsartan, Result = (r U/r S) (C S/C U) (M r1/m r2) 100 System suitability Relative standard deviation: NMT 5.0% for r U = peak response of each unspecified amlodipine related compound A, benzothiadiazine product from Sample A related compound A, amlodipine, valsartan, and hy- r S = peak response of amlodipine from the drochlorothiazide, C S = concentration of USP Amlodipine Besylate RS Samples: Sample A, Sample B, Sample in the (mg/ml) C, and C U = nominal concentration of amlodipine in Calculate the percentage of amlodipine related com- Sample A (mg/ml) pound A in the portion of Tablets taken: M r1 = molecular weight of amlodipine, Result = (r U/r S) (C S/C U) (M r1/m r2) 100 Acceptance criteria: See.Table 6. (RB 1-Jun-2016) Disrer U = peak response of amlodipine related gard amlodipine ethyl analog peak, valsartan related compound A from Sample A compound B peak, and any peaks below 0.1%. r S = peak response of amlodipine related compound A from the.table 6 (RB 1-Jun-2016) C S = concentration of USP Amlodipine Related Compound A RS in the Relative Acceptance (mg/ml) Retention Criteria, C U = nominal concentration of amlodipine in Name Time NMT (%) Sample A (mg/ml) Benzothiadiazine related compound A = molecular weight of amlodipine related (RB 1-Jun-2016) a. compound A free base, Chlorothiazide (RB 1-Jun- 2016) = molecular weight of amlodipine related (RB 1-Jun-2016) b. compound A fumarate, Hydrochlorothiazide 0.64 Calculate the percentage of any valsartan related Devaleryl valsartan product in the portion of Tablets taken: c..hydrochlorothiazide dimer (RB (RB 1-Jun-2016) 1-Jun-2016)d. Amlodipine related compound A r U = peak response of any valsartan related e. product from Sample B Amlodipine 1.00 r S = peak response of valsartan from the Standard Valsartan related C S = concentration of USP Valsartan RS in the product 1 f (mg/ml) Amlodipine ethyl ana- C U = nominal concentration of valsartan in Sample log 1.08 g. B (mg/ml) Valsartan related Calculate the percentage of benzothiadiazine related compound B 1.22 compound A in the portion of Tablets taken: h. Valsartan related product f. r U = peak response of benzothiadiazine related Valsartan 1.36 compound A from Sample C Valsartan related r S = peak response of benzothiadiazine related compound A from the product 3 f C S = concentration of USP Benzothiadiazine Related a. 4-Amino-6-chloro-1,3-benzenedisulfonamide. Compound A RS in the.b.6-chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. (RB 1- (mg/ml) Jun-2016) C U = nominal concentration of hydrochlorothiazide c. N-{[2 -(1H-Tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valine. in Sample C (mg/ml).d.6-chloro-n-[(6-chloro-7-sulfamoyl-2,3-dihydro-4h-1,2,4- Calculate the percentage of.chlorothiazide and benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4- hydrochlorothiazide dimer benzothiadiazine-7-sulfonamide 1,1-dioxide. (RB 1-Jun-2016) (RB 1-Jun-2016) in the portion e. of Tablets taken: 3-Ethyl, 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-meth- yl-3,5-pyridinedicarboxylate]. f. These are specified unidentified products. No information is available about chemical structures or chemical names for these impurities. r U = peak response of.chlorothiazide or g. Diethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4- hydrochlorothiazide dimer (RB 1-Jun-2016) from dihydropyridine-3,5-dicarboxylate..process related impurity given for information only. (RB 1-Jun-2016) Sample C h. (S)-N-Butyryl-N-{[2 -(1-H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine.. r S = peak response of hydrochlorothiazide from the Process related impurity given for information only. (RB 1-Jun-2016) i. C S = concentration of USP Hydrochlorothiazide RS Benzenesulfonic acid is the counter ion to the amlodipine, and peaks at RRT of 0.33 and 0.42 are not considered as products. in the (mg/ml) C U = nominal concentration of hydrochlorothiazide in Sample C (mg/ml)

7 6 Amlodipine Official June 1, 2016.Table 6 (RB 1-Jun-2016) (Continued) Add the following: Relative Acceptance Retention Criteria,. LABELING: When more than one Dis test is Name Time NMT (%) given, the labeling states the Dis test used only if Valsartan related Test 1 is not used. (RB 1-Jun-2016) USP REFERENCE STANDARDS 11 product USP Amlodipine Besylate RS USP Amlodipine Related Compound A RS f. Any other unspecified 3-Ethyl, 5-methyl [2-(2-aminoethoxymethyl)- product (2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxy- i. Total late] fumarate. products.2.0 (RB 1-Jun-2016) C 20H 23ClN 2O 5 C 4H 4O a. 4-Amino-6-chloro-1,3-benzenedisulfonamide. USP Benzothiadiazine Related Compound A RS.b.6-Chloro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. (RB 1-4-Amino-6-chloro-1,3-benzenedisulfonamide. Jun-2016) C 6H 8ClN 3O 4S c. N-{[2 -(1H-Tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valine. USP Hydrochlorothiazide RS.d.6-Chloro-N-[(6-chloro-7-sulfamoyl-2,3-dihydro-4H-1,2,4- USP Valsartan RS benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4- benzothiadiazine-7-sulfonamide 1,1-dioxide. (RB 1-Jun-2016) e. 3-Ethyl, 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxylate]. f. These are specified unidentified products. No information is available about chemical structures or chemical names for these impurities. g. Diethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate..process related impurity given for information only. (RB 1-Jun-2016). h. (S)-N-Butyryl-N-{[2 -(1-H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine. Process related impurity given for information only. (RB 1-Jun-2016) i. Benzenesulfonic acid is the counter ion to the amlodipine, and peaks at RRT of 0.33 and 0.42 are not considered as products. ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Store at controlled room temperature in tight containers in a dry place.