. Table Interim Revision Announcement Official November 1, 2017 Amlodipine 1 Amlodipine, Valsartan, and Hydrochlorothiazide Tablets 2 (Continued) Tablet Strength Nominal Amlodipine/ Nominal Concentra- DEFINITION Valsartan/ Concentra- Nominal tion Amlodipine, Valsartan, and Hydrochlorothiazide Tablets Hydrochlo- tion Concentra- of Hydrocontain NLT 92.5% and NMT 107.5% each of the la- rothiazide of tion chlorothia- beled amounts of amlodipine (C 20H 25ClN 2O 5), valsartan (mg/mg/ Amlodipine of Valsartan zide (C 24H 29N 5O 3), and hydrochlorothiazide (C 7H 8ClN 3O 4S 2). mg) (mg/ml) (mg/ml) (mg/ml) 5/160/25 0.1 3.2 0.5 IDENTIFICATION 10/160/25 0.2 3.2 0.5 A. The UV absorption spectra of the amlodipine, val- 10/320/25 0.1 3.2 0.25 sartan, and hydrochlorothiazide peaks of Sample A, Sample B, and Sample C, and those of Sample A: Nominally equivalent to 0.1 mg/ the Standard exhibit maxima and minima at the ml of amlodipine in Diluent from Sample stock same wavelengths, as obtained in the Assay. Sample B: Nominally equivalent to 0.064 mg/ B. The retention times of the amlodipine, valsartan, and ml of valsartan in Diluent from Sample stock hydrochlorothiazide peaks of Sample A, Sample Sample C: Nominally equivalent to B, and Sample C correspond to those of 0.025 mg/ml of hydrochlorothiazide in Diluent from the Standard, as obtained in the Assay. Sample stock ASSAY PROCEDURE Use amber glassware for all s containing drug Detector: UV 225 nm. For Identification A, use a disubstances. ode array detector in the range of 200 400 nm. Solution A: Acetonitrile, water, and phosphoric acid Column: 4.6-mm 15-cm; 3-µm packing L1 (50:950:1) Column temperature: 40 Solution B: Acetonitrile, water, and phosphoric acid Flow rate: 1.5 ml/min (950:50:1) Injection volume: 10 µl Mobile phase: See Table 1. Sample: Standard Table 1 Time Solution A Solution B Tailing factor: NMT 2.0 for amlodipine, valsartan, and hydrochlorothiazide Relative standard deviation: NMT 2.0% for 0 95 5 amlodipine, valsartan, and hydrochlorothiazide 3 50 50 6 40 60 Samples: Standard, Sample A, Sample 10 5 95 B, and Sample C 10.1 95 5 15 95 5 amlodipine (C 20H 25ClN 2O 5) in the portion of Tablets taken: Diluent: Acetonitrile and water (500:500) 0.1% Phosphoric acid: Water and phosphoric acid Result = (r U/r S) (C S/C U) (M r1/m r2) 100 (1000:1) Standard : 0.14 mg/ml of USP Amlodipine r U = peak response of amlodipine from Sample Besylate RS, 0.064 mg/ml of USP Valsartan RS, and A 0.025 mg/ml of USP Hydrochlorothiazide RS in Diluent r S = peak response of amlodipine from the Sample stock : Transfer NLT 10 Tablets into a Standard suitable volumetric flask. Add 0.1% Phosphoric acid to 4% of the total volume to disperse the Tablets. Soni- in the Standard (mg/ml) cate for 10 min. Add 4% of the total volume of aceto- C U = nominal concentration of amlodipine in nitrile, swirl to mix, and add 60% of the total volume Sample A (mg/ml) 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 super- natant. valsartan (C 24H 29N 5O 3) in the portion of Tablets taken: Table 2 r U Tablet Strength Nominal Amlodipine/ Nominal Concentra- Valsartan/ Concentra- Nominal tion Hydrochlo- tion Concentra- of Hydrorothiazide of tion chlorothia- (mg/mg/ Amlodipine of Valsartan zide mg) (mg/ml) (mg/ml) (mg/ml) 5/160/12.5 0.1 3.2 0.25 10/160/12.5 0.2 3.2 0.25 r S C S C U = peak response of valsartan from Sample B = peak response of valsartan from the Standard = concentration of USP Valsartan RS in the Standard (mg/ml) = nominal concentration of valsartan in Sample B (mg/ml)
2 Amlodipine Official November 1, 2017 hydrochlorothiazide (C 7H 8ClN 3O 4S 2) in the portion of Detector: UV 250 nm Tablets taken: Column: 4.6-mm 5-cm; 3-µm packing L1 Column temperature: 30 Flow rate: 1.5 ml/min Injection volume r U = peak response of hydrochlorothiazide from For 10/320/25 (mg/mg/mg) of Tablet strengths Sample C (amlodipine/valsartan/hydrochlorothiazide): r S = peak response of hydrochlorothiazide from the 5 µl Standard For 5/160/12.5, 10/160/12.5, 5/160/25, and 10/ C S = concentration of USP Hydrochlorothiazide RS 160/25 (mg/mg/mg) of Tablet strengths in the Standard (mg/ml) (amlodipine/valsartan/hydrochlorothiazide): C U = nominal concentration of hydrochlorothiazide 10 µl in Sample C (mg/ml) Acceptance criteria: 92.5% 107.5% Sample: Standard PERFORMANCE TESTS Re: NLT 3.0 between amlodipine and valsartan Change to read: Tailing factor: NMT 2.0 for amlodipine, valsartan, and hydrochlorothiazide DISSOLUTION 711 Relative standard deviation: NMT 2.0% for Test 1 amlodipine, valsartan, and hydrochlorothiazide Buffer: Dissolve 6.805 g of monobasic potassium phosphate and 0.896 g of sodium hydroxide in Samples: Standard and Sample 1000 ml of water. Adjust with 0.2 N sodium hydroxamlodipine (C 20H 25ClN 2O 5) dissolved: ide or 1 M phosphoric acid to a ph of 6.8. Medium: Buffer; 900 ml Apparatus 2 Result = (r U/r S) C S V (M r1/m r2) (1/L 1) 100 For 5/160/12.5, 10/160/12.5, 5/160/25, and 10/ 160/25 (mg/mg/mg) of Tablet strengths r U = peak response of amlodipine from the Sample (amlodipine/valsartan/hydrochlorothiazide): 50 rpm r S = peak response of amlodipine from the For 10/320/25 (mg/mg/mg) of Tablet strengths Standard (amlodipine/valsartan/hydrochlorothiazide): 55 rpm in the Standard (mg/ml) Time: 30 min Solution A: Acetonitrile, water, and phosphoric acid (50:950:1) Solution B: Acetonitrile, water, and phosphoric acid (950:50:1) L 1 = label claim of amlodipine (mg/tablet) Mobile phase: See Table 3. valsartan (C 24H 29N 5O 3) dissolved: Table 3 Result = (r U/r S) C S V (1/L 2) 100 Time Solution A Solution B r U = peak response of valsartan from the Sample 0.00 67 33 r S = peak response of valsartan from the Standard 2.50 23 77 2.51 67 33 C S = concentration of USP Valsartan RS in the 4.00 67 33 Standard (mg/ml) Diluent: 1 mg/ml of polysorbate 80 in Buffer L 2 = label claim of valsartan (mg/tablet) Standard stock A: 0.07 mg/ml of USP Amlodipine Besylate and 0.124 mg/ml of USP Hydro- hydrochlorothiazide (C 7H 8ClN 3O 4S 2) dissolved: chlorothiazide RS. Initially dissolve with 4% of the total volume of methanol, and dilute with Diluent to Result = (r U/r S) C S V (1/L 3) 100 volume. Standard stock B: 3.2 mg/ml of USP Val- r U = peak response of hydrochlorothiazide from the sartan RS in methanol Sample Standard : 0.014 mg/ml of USP Amlodipine r S = peak response of hydrochlorothiazide from the Besylate RS, 0.16 mg/ml of USP Valsartan RS, and Standard 0.0248 mg/ml of USP Hydrochlorothiazide RS in Diluin the Standard (mg/ml) C S = concentration of USP Hydrochlorothiazide RS ent from Standard stock A and Standard stock B, respectively Sample : Pass a portion of the under L 3 = label claim of hydrochlorothiazide (mg/tablet) test through a suitable filter of 0.45-µm pore size. Disamlodipine (C 20H 25ClN 2O 5) is dissolved, NLT 80% (Q) Tolerances: NLT 75% (Q) of the labeled amount of card at least the first 10 ml of the filtrate. of the labeled amount of valsartan (C 24H 29N 5O 3) is dis- solved, and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C 7H 8ClN 3O 4S 2) is dissolved.
Official November 1, 2017 Amlodipine 3 Samples: Standard and Sample amlodipine (C 20H 25ClN 2O 5) dissolved: Result = (r U/r S) C S V (M r1/m r2) (1/L 1) 100 Test 2: If the product complies with this test, the labeling indicates that the product meets USP Dis Test 2. Medium: Proceed as directed under Dis Test 1; 900 ml. Apparatus 2 For Tablets labeled to contain amlodipine/val- sartan/hydrochlorothiazide, 5/160/12.5, 10/160/ 12.5, 5/160/25, 10/160/25, and 5/80/12.5 (mg/ mg/mg): 50 rpm For Tablets labeled to contain amlodipine/valsartan/hydrochlorothiazide, 10/320/25 (mg/mg/ mg): 55 rpm Times For valsartan and hydrochlorothiazide: 30 min For amlodipine: 45 min Buffer: Mix 7.0 ml of triethylamine with 1000 ml of water. Adjust with phosphoric acid to a ph of 3.0. Solution A: Acetonitrile and Buffer (10:90) Solution B: Acetonitrile and Buffer (90:10) Mobile phase: See Table 4. r U = peak response of amlodipine from the Sample r S = peak response of amlodipine from the Standard in the Standard (mg/ml) L 1 = label claim of amlodipine (mg/tablet) valsartan (C 24H 29N 5O 3) dissolved: Result = (r U/r S) C S V (1/L 2) 100 Table 4 r U = peak response of valsartan from the Sample Time Solution A Solution B r S = peak response of valsartan from the Standard 0 90 10 C S = concentration of USP Valsartan RS in the 7 30 70 Standard (mg/ml) 8 90 10 15 90 10 L 2 = label claim of valsartan (mg/tablet) Standard stock A: 0.35 mg/ml of USP hydrochlorothiazide (C 7H 8ClN 3O 4S 2) dissolved: Amlodipine Besylate RS, prepared as follows. Initially dissolve in 10% of the final volume of methanol and dilute with Medium to volume. Result = (r U/r S) C S V (1/L 3) 100 Standard stock B: 1.6 mg/ml of USP Val- r U = peak response of hydrochlorothiazide from the sartan RS in methanol Sample Standard stock C: 0.7 mg/ml of USP Hydro- r S = peak response of hydrochlorothiazide from the chlorothiazide RS, prepared as follows. Initially dis- Standard solve in 25% of the final volume of methanol and C S = concentration of USP Hydrochlorothiazide RS dilute with Medium to volume. in the Standard (mg/ml) Standard : (L 1/1000) mg/ml of amlodipine, (L 2/1000) mg/ml of valsartan, and (L 3/1000) mg/ml L 3 = label claim of hydrochlorothiazide (mg/tablet) of hydrochlorothiazide in.medium (IRA 1-Nov-2017) from Tolerances: NLT 75% (Q) of the labeled amount of Standard stock A, Standard stock B, amlodipine (C 20H 25ClN 2O 5) is dissolved, NLT 80% (Q) and Standard stock C, where L 1 is the label of the labeled amount of valsartan (C 24H 29N 5O 3) is disclaim of amlodipine in mg/tablet, L 2 is the label claim of valsartan in mg/tablet, and L 3 is the label claim of solved, and NLT 80% (Q) of the labeled amount of hydrochlorothiazide (C 7H 8ClN 3O 4S 2) is dissolved. hydrochlorothiazide in mg/tablet Test 3: If the product complies with this test, the label- Sample : Pass a portion of the under ing indicates that the product meets USP Dis test through a suitable filter of 1-µm pore size. Test 3. Medium: Dissolve 6.80 g of monobasic potassium phosphate in 1000 ml of water. Adjust with 10% so- dium hydroxide to a ph of 6.8; 1000 ml for Detector: UV 237 nm valsartan and hydrochlorothiazide; 900 ml for Column: 4.6-mm 15-cm; 5-µm packing L1 amlodipine. Temperatures Apparatus 2 Autosampler: 10 For valsartan and hydrochlorothiazide: 50 rpm Column: 50 For amlodipine in Tablets labeled to contain Flow rate: 1.5 ml/min amlodipine/valsartan/hydrochlorothiazide, 10/ Injection volume: 20 µl 320/25 (mg/mg/mg): 55 rpm For amlodipine in Tablets labeled to contain Sample: Standard amlodipine/valsartan/hydrochlorothiazide, 5/160/ 12.5, 10/160/12.5, 5/160/25, 10/160/25, and 5/ Tailing factor: NMT 2.0 for each peak 80/12.5 (mg/mg/mg): 50 rpm Relative standard deviation: NMT 2.0% for each Times peak For valsartan and hydrochlorothiazide: 30 min For amlodipine: 45 min Solution A: Acetonitrile, trifluoroacetic acid and water (10: 0.1: 90)
4 Amlodipine Official November 1, 2017 Solution B: Acetonitrile, trifluoroacetic acid and water (90: 0.1: 10) valsartan (C 24H 29N 5O 3) dissolved: Mobile phase: See Table 5. Result = (r U/r S) C S V (1/L 2) 100 Table 5 r U = peak response of valsartan from the Sample Time Solution A Solution B r S = peak response of valsartan from the Standard 0.01 90 10 2.5 10 90 C S = concentration of USP Valsartan RS in the Standard (mg/ml) 3.0 90 10 V = volume of Medium, 1000 ml 5.0 90 10 L 2 = label claim of valsartan (mg/tablet) Diluent: Acetonitrile and water (50:50) hydrochlorothiazide (C 7H 8ClN 3O 4S 2) dissolved: Standard stock A: 0.15 mg/ml of USP Amlodipine Besylate RS in Medium, prepared as follows. Initially dissolve and sonicate in 5% of the final Result = (r U/r S) C S V (1/L 3) 100 volume of Diluent, and dilute with Medium to volume. r U = peak response of hydrochlorothiazide from the Standard stock B: 1.6 mg/ml of USP Val- Sample sartan RS in Medium, prepared as follows. Initially dis- r S = peak response of hydrochlorothiazide from the solve and sonicate in 20% of the final volume of Dilu- Standard ent, and dilute with Medium to volume. C S = concentration of USP Hydrochlorothiazide RS Standard stock C: 0.25 mg/ml of USP Hy- in the Standard (mg/ml) drochlorothiazide RS in Medium, prepared as follows. V = volume of Medium, 1000 ml Initially dissolve and sonicate in 10% of the final vol- L 3 = label claim of hydrochlorothiazide (mg/tablet) ume of Diluent, and dilute with Medium to volume. Tolerances Standard : (L 1/1000) mg/ml of amlodipine, For Tablets labeled to contain amlodipine/ (L 2/1000) mg/ml of valsartan, and (L 3/1000) mg/ml valsartan/hydrochlorothiazide, 5/160/12.5, 10/ of hydrochlorothiazide in Diluent from Standard stock 160/12.5, 5/160/25, and 10/160/25 (mg/mg/ A, Standard stock B, and Standard mg): NLT 75% (Q) of the labeled amount of stock C, where L 1 is the label claim of amlodipine (C 20H 25ClN 2O 5) is dissolved, NLT 80% (Q) amlodipine in mg/tablet, L 2 is the label claim of val- of the labeled amount of valsartan (C 24H 29N 5O 3) is sartan in mg/tablet, and L 3 is the label claim of hy- dissolved, and NLT 80% (Q) of the labeled amount drochlorothiazide in mg/tablet of hydrochlorothiazide (C 7H 8ClN 3O 4S 2) is dissolved. Sample : Pass a portion of the under For Tablets labeled to contain amlodipine/valtest through a suitable filter of 0.45-µm pore size. Dis- sartan/hydrochlorothiazide, 5/160/25, and 10/ card at least the first few milliliters of the filtrate. 320/25 (mg/mg/mg): NLT 70% (Q) of the labeled amount of amlodipine (C 20H 25ClN 2O 5) is dissolved, NLT 80% (Q) of the labeled amount of valsartan (C 24H 29N 5O 3) is dissolved, and NLT 80% (Q) of the Detectors labeled amount of hydrochlorothiazide For amlodipine: UV 237 nm (C 7H 8ClN 3O 4S 2) is dissolved. For valsartan and hydrochlorothiazide: UV 270 UNIFORMITY OF DOSAGE UNITS 905 : Meet the nm requirements Column: 4.6-mm 10-cm; 5-µm packing L1 Flow rate: 1.5 ml/min Injection volume: 10 µl IMPURITIES Sample: Standard Change to read: Tailing factor: NMT 2.0 for each peak ORGANIC IMPURITIES Relative standard deviation: NMT 2.0% for each Use amber glassware for all s containing drug peak substances. Mobile phase, Diluent, Sample A, Sample so- Samples: Standard and Sample lution B, Sample C, and Chromatographic system: Proceed as directed in the Assay. amlodipine (C 20H 25ClN 2O 5) dissolved: : 0.02 mg/ml each of USP Benzothiadiazine Related Compound A RS and USP Valsartan Result = (r U/r S) C S V (M r1/m r2) (1/L 1) 100 Related Compound B RS, 0.005 mg/ml of USP Amlodipine Related Compound A RS, 0.14 mg/ml of r U = peak response of amlodipine from the Sample USP Amlodipine Besylate RS, 0.064 mg/ml of USP Val sartan RS, and 0.025 mg/ml of USP Hydrochlorothia- r S = peak response of amlodipine from the zide RS in Diluent Standard Sensitivity : 0.14 µg/ml of USP Amlodipine Besylate RS, 0.064 µg/ml of USP Valsartan RS, and in the Standard (mg/ml) 0.025 µg/ml of USP Hydrochlorothiazide RS in Diluent Standard : 0.0005 mg/ml of USP Amlodipine Related Compound A RS, 0.0001 mg/ml of USP Benzothiadiazine Related Compound A RS, 0.0003 mg/ ml of USP Amlodipine Besylate RS, 0.00015 mg/ml of = label claim of amlodipine (mg/tablet) L 1
Official November 1, 2017 Amlodipine 5 USP Valsartan RS, and 0.00005 mg/ml of USP Hydro- r U = peak response of chlorothiazide or chlorothiazide RS in Diluent hydrochlorothiazide dimer from Sample C Samples:, Sensitivity, r S = peak response of hydrochlorothiazide from the and Standard Standard C S = concentration of USP Hydrochlorothiazide RS Re: NLT 2.0 between any adjacent peaks of in the Standard (mg/ml) benzothiadiazine related compound A, hydrochloro- C U = nominal concentration of hydrochlorothiazide thiazide, amlodipine related compound A, in Sample C (mg/ml) amlodipine, valsartan related compound B, and val- Calculate the percentage of each unspecified sartan, degradation product in the portion of Tablets taken: Relative standard deviation: NMT 5.0% for amlodipine related compound A, benzothiadiazine Result = (r U/r S) (C S/C U) (M r1/m r2) 100 related compound A, amlodipine, valsartan, and hyr U = peak response of each unspecified degradation drochlorothiazide, Standard Signal-to-noise ratio: NLT 10 for amlodipine, valr S = peak response of amlodipine from the product from Sample A sartan, and hydrochlorothiazide, Sensitivity Standard Samples: Sample A, Sample B, Sample C, and Standard in the Standard (mg/ml) Calculate the percentage of amlodipine related com- C U = nominal concentration of amlodipine in pound A in the portion of Tablets taken: Sample A (mg/ml) Result = (r U/r S) (C S/C U) (M r1/m r2) 100 r U = peak response of amlodipine related Acceptance criteria: See Table 6. Disregard the compound A from Sample A amlodipine ethyl analog peak, the valsartan related r S = peak response of amlodipine related compound B peak, and any peaks below 0.1%. compound A from the Standard C S = concentration of USP Amlodipine Related Table 6 Compound A RS in the Standard (mg/ml) Relative Acceptance C U = nominal concentration of amlodipine in Retention Criteria, Sample A (mg/ml) Name Time NMT (%) M r1 = molecular weight of amlodipine related Benzothiadiazine related compound A free base, 406.86 compound A a. 0.60 1.0 M r2 = molecular weight of amlodipine related Chlorothiazide 0.62 0.50 b. compound A fumarate, 522.93 Hydrochlorothiazide 0.64 Calculate the percentage of any valsartan related Devaleryl valsartan 0.71 0.2 degradation product in the portion of Tablets taken: c. Hydrochlorothiazide dimer d. 0.89 0.50 Amlodipine related r U = peak response of any valsartan related compound A e. 0.96 0.5 degradation product from Sample B Amlodipine 1.00 r S = peak response of valsartan from the Standard Valsartan related degradation C S = concentration of USP Valsartan RS in the product 1 1.04 0.2 Standard (mg/ml) f. Amlodipine ethyl C U = nominal concentration of valsartan in Sample analog 1.08 B (mg/ml) g. Calculate the percentage of benzothiadiazine related Valsartan related compound A in the portion of Tablets taken: compound B 1.22 h. a.4-amino-6-chloro-1,3-benzenedisulfonamide. b.6-chloro-2h-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. r U c.n-{[2 -(1H-Tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valine. = peak response of benzothiadiazine related d.6-chloro-n-[(6-chloro-7-sulfamoyl-2,3-dihydro-4h-1,2,4- compound A from Sample C benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4- r S = peak response of benzothiadiazine related benzothiadiazine-7-sulfonamide 1,1-dioxide. e compound A from the Standard.3-Ethyl 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-meth- yl-3,5-pyridinedicarboxylate]. C S = concentration of USP Benzothiadiazine Related f. These are specified unidentified degradation products. No information is Compound A RS in the Standard available about chemical structures or chemical names for these impuri- (mg/ml) ties. C U = nominal concentration of hydrochlorothiazide g.diethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4- in Sample C (mg/ml) dihydropyridine-3,5-dicarboxylate. Process related impurity given for in- Calculate the percentage of chlorothiazide and formation only. h hydrochlorothiazide dimer in the portion of Tablets..N-Butyryl-N-{[2 -(1H-tetrazole-5-yl)biphenyl-4-yl]-methyl}-L-valine. (IRA 1-Nov-2017) Process related impurity given for information only. taken: i. Benzenesulfonic acid is the counter ion to the amlodipine, and peaks at RRT of 0.33 and 0.42 are not considered as degradation products.
6 Amlodipine Official November 1, 2017 Table 6 (Continued) Samples: and Standard Relative Acceptance Retention Criteria, [NOTE The relative retention times of valsartan related Name Time NMT (%) compound A and valsartan are about 0.65 and 1.0, Valsartan related respectively.] degradation product 2 1.27 0.2 Re: NLT 2.0 between valsartan and valsartan f. Valsartan 1.36 related compound A, Valsartan related Relative standard deviation: NMT 5.0% for valdegradation sartan related compound A, Standard product 3 f. 1.51 0.2 Valsartan related Samples: Standard and Sample degradation Calculate the percentage of the valsartan related com- product 4 f. 1.62 0.2 pound A in the portion of Tablets taken: Any other unspecified degradation product 0.2 i. Total degradation r U = peak response of valsartan related compound products 2.0 A from the Sample a.4-amino-6-chloro-1,3-benzenedisulfonamide. r S = peak response of valsartan related compound b.6-chloro-2h-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. A from the Standard c.n-{[2 -(1H-Tetrazole-5-yl)biphenyl-4-yl]methyl}-L-valine. C S = concentration of USP Valsartan Related d.6-chloro-n-[(6-chloro-7-sulfamoyl-2,3-dihydro-4h-1,2,4- Compound A RS in the Standard benzothiadiazine-4-yl 1,1-dioxide)methyl]3,4-dihydro-2H-1,2,4- benzothiadiazine-7-sulfonamide 1,1-dioxide. (mg/ml) e.3-ethyl 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-meth- C U = nominal concentration of valsartan in the yl-3,5-pyridinedicarboxylate]. Sample (mg/ml) Acceptance criteria: NMT 1.0 % (IRA 1-Nov-2017) f. These are specified unidentified degradation products. No information is available about chemical structures or chemical names for these impurities. ADDITIONAL REQUIREMENTS g.diethyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4- PACKAGING AND STORAGE: Store at controlled room temdihydropyridine-3,5-dicarboxylate. Process related impurity given for in- perature in tight containers in a dry place. formation only. LABELING: When more than one Dis test is given, h..n-butyryl-n-{[2 -(1H-tetrazole-5-yl)biphenyl-4-yl]-methyl}-L-valine. (IRA the labeling states the Dis test used only if Test 1 1-Nov-2017) Process related impurity given for information only. is not used. i. Benzenesulfonic acid is the counter ion to the amlodipine, and peaks at RRT of 0.33 and 0.42 are not considered as degradation products. Add the following:. LIMIT OF VALSARTAN RELATED COMPOUND A [NOTE Valsartan related compound A is a process impurity and a formulation specific degradation product.] Mobile phase: n-hexane, 2-propanol, and trifluoroacetic acid (850:150:1) : 0.04 mg/ml each of USP Valsartan Related Compound A and USP Valsartan RS in Mobile phase Standard : 0.001 mg/ml of USP Valsartan Related Compound A RS in Mobile phase Sample : Nominally 0.5 mg/ml of valsartan in Mobile phase from a suitable amount of finely crushed powder from NLT 20 Tablets. Sonication may be necessary for complete dis. Pass through a suitable filter of 0.45-µm pore size. Detector: UV 230 nm Column: 4.6-mm 25-cm; 5-µm packing L40 Temperatures Autosampler: 10 Column: 30 Flow rate: 0.8 ml/min Injection volume: 20 µl Run time: NLT 3.5 times the retention time of valsartan related compound A Change to read: USP REFERENCE STANDARDS 11 USP Amlodipine Besylate RS USP Amlodipine Related Compound A RS 3-Ethyl 5-methyl [2-(2-aminoethoxymethyl)- 4-(2-chlorophenyl)-6-methyl-3,5-pyridinedicarboxy- late] fumarate. C 20H 23ClN 2O 5 C 4H 4O 4 522.93 USP Benzothiadiazine Related Compound A RS 4-Amino-6-chloro-1,3-benzenedisulfonamide. C 6H 8ClN 3O 4S 2 285.73 USP Hydrochlorothiazide RS USP Valsartan RS.USP Valsartan Related Compound A RS N-Valeryl-N-{[2 -(1H-tetrazole-5-yl)biphenyl- 4-yl]methyl}-D-valine. C 24H 29N 5O 3 435.52 USP Valsartan Related Compound B RS (IRA 1-Nov-2017)