. olumn: Inteim Revision Announcement Official Novembe 1, 2017 Amlodipine 1 Amlodipine and Valsatan Tablets DEFINITION Amlodipine and Valsatan Tablets contain NLT 90.0% and NT 110.0% of the labeled amount of amlodipine ( 20H 25lN 2O 5) and valsatan ( 24H 29N 5O 3). IDENTIFIATION A. The UV absoption specta of the majo peaks of Sample A and Sample B and those of the Standad exhibit maxima and minima at the same wavelengths, as obtained in the Assay. B. The etention times of the majo peaks of Sample A and Sample B coespond to those of the Standad, as obtained in the Assay. ASSAY PROEDURE Solution A: Wate and tiethylamine (1000:10). Adjust with phosphoic acid to a ph of 2.8. Solution B: ethanol and acetonitile (700:300) obile phase: See Table 1. 3.9-mm 15-cm; 5-µm packing L1 Tempeatues Autosample: 10 olumn: 30 Flow ate: 1.0 ml/min Sample: Standad Tailing facto: NT 1.5 fo both amlodipine and valsatan amlodipine and valsatan Samples: Standad, Sample A, and Sample B amlodipine ( 20H 25lN 2O 5) in the potion of Tablets taken: Result = ( U/ S) ( S/ U) ( 1/ 2) 100 U = peak esponse of amlodipine fom Sample A Table 1 S = peak esponse of amlodipine fom the Standad Time Solution A Solution B S = concentation of USP Amlodipine Besylate RS in the Standad (mg/ml) 0 50 50 U = nominal concentation of amlodipine in Sample A (mg/ml) 3 50 50 1 = molecula weight of amlodipine, 408.88 15 30 70 2 = molecula weight of amlodipine besylate, 20 30 70 20.1 50 50 25 50 50 valsatan ( 24H 29N 5O 3) in the potion of Tablets taken: Diluent: Solution A and Solution B (50:50) Result = ( U/ S) ( S/ U) 100 Standad : 0.14 mg/ml of USP Amlodipine Besylate RS and 0.16 mg/ml of USP Valsatan RS. Add U = peak esponse of valsatan fom Sample methanol to 5% of the final volume to dissolve, and B dilute with Diluent to volume. S = peak esponse of valsatan fom the Standad Sample stock : Tansfe NLT 10 Tablets into a suitable volumetic flask. Initially add wate to 10% of S = concentation of USP Valsatan RS in the the final volume, and sonicate to dispese as needed. Standad (mg/ml) Add Diluent, using about 70% of the final volume, and U = nominal concentation of valsatan in Sample shake fo up to 45 min to dispese. Following dispe- B (mg/ml) sion, sonicate fo 15 min, and shake fo 30 min. Dilute Acceptance citeia: 90.0% 110.0% with Diluent to volume to obtain a containing known nominal concentations of 0.1 0.2 mg/ml of PERFORANE TESTS amlodipine and 1.6 6.4 mg/ml of valsatan. entifuge the fo about 10 min at 3000 pm. hange to ead: Sample A: Nominally equivalent to 0.1 mg/ ml of amlodipine in Diluent fom the Sample stock DISSOLUTION 711 Test 1 Sample B: Nominally equivalent to 0.16 mg/ Buffe: Dissolve 6.805 g of monobasic potassium ml of valsatan in Diluent fom the Sample stock phosphate and 0.896 g of sodium hydoxide in wate, and dilute with wate to 1000 ml. Adjust with 0.2 N homatogaphic system sodium hydoxide o 1 phosphoic acid to a ph of (See homatogaphy 621, System Suitability.) 6.8. edium: Buffe; 1000 ml Detecto: UV 237 nm. Fo Identification A, use a di- Appaatus 2: 75 pm ode aay detecto in the ange of 200 400 nm. Time: 30 min obile phase: Acetonitile, wate, and tifluooacetic acid (500:500:2) Diluent: 1 mg/ml of polysobate 80 in Buffe : 0.4 mg/ml each of USP Amlodipine Besylate RS and USP Valsatan RS, pepaed as follows. Initially dissolve in methanol to 40% of the total volume, and dilute with Buffe to volume. Standad stock A: 0.072 mg/ml of USP Amlodipine Besylate RS, pepaed as follows. Initially
Inteim Revision Announcement 2 Amlodipine Official Novembe 1, 2017 dissolve in methanol to 4% of the final volume, and Appaatus 2: 50 pm dilute with Diluent to volume. Buffe: ix 7.0 ml of tiethylamine with 1000 ml of Standad stock B: 2.2 mg/ml of USP Val- wate. Adjust with phosphoic acid to a ph of 3.0. satan RS in methanol Solution A: Acetonitile and Buffe (10:90) Standad : (L 1/1000) mg/ml of amlodipine Solution B: Acetonitile and Buffe (90:10) and (L 2/1000) mg/ml of valsatan in Diluent fom obile phase: See Table 2. Standad stock A and Standad stock B, whee L 1 is the label claim of amlodipine in mg/tablet, and L 2 is the label claim of valsatan in mg/tablet Table 2 Sample : Pass a potion of the unde Time Solution A Solution B test though a suitable filte of 0.45-µm poe size. Dis- cad the fist 10 ml of the filtate. 0 80 20 homatogaphic system 7 30 70 (See homatogaphy 621, System Suitability.) 8 80 20 10 80 20 Detecto: UV 230 nm olumn: 4.6-mm 15-cm; 4-µm packing L11 Standad stock A: 0.14 mg/ml of USP olumn tempeatue: 40 Amlodipine Besylate RS, pepaed as follows. Initially Flow ate: 1.2 ml/min dissolve in 10% of the final volume of methanol, and dilute with edium to volume. Run time: NLT 2 times the etention time of Standad stock B: 1.6 mg/ml of USP Valamlodipine satan RS in methanol Standad : (L 1/1000) mg/ml of amlodipine Samples: and Standad and (L 2/1000) mg/ml of valsatan in.edium (IRA 1- Nov-2017) fom Standad stock A and Standad stock B, whee L 1 is the label claim of Re: NLT 2.0 between amlodipine and val- amlodipine in mg/tablet, and L 2 is the label claim of satan, valsatan in mg/tablet Tailing facto: NT 2.0 fo amlodipine and val- Sample : Pass a potion of the unde satan, Standad test though a suitable filte of 1-µm poe size. homatogaphic system amlodipine and valsatan, Standad (See homatogaphy 621, System Suitability.) Samples: Standad and Sample Detecto: UV 237 nm olumn: 4.6-mm 15-cm; 5-µm packing L1 amlodipine ( 20H 25lN 2O 5) dissolved: Tempeatues Result = ( U/ S) S V ( 1/ 2) (1/L 1) 100 Autosample: 10 olumn: 50 Flow ate: 1.5 ml/min U = peak esponse of amlodipine fom the Sample Injection volume: 20 µl S = peak esponse of amlodipine fom the Standad Sample: Standad S = concentation of USP Amlodipine Besylate RS in the Standad (mg/ml) Tailing facto: NT 2.0 fo amlodipine and valsatan 1 = molecula weight of amlodipine, 408.88 amlodipine and valsatan 2 = molecula weight of amlodipine besylate, L Samples: Standad and Sample 1 = label claim of amlodipine (mg/tablet) valsatan ( amlodipine ( 20H 25lN 2O 5) dissolved: 24H 29N 5O 3) dissolved: Result = ( U/ S) S V (1/L 2) 100 Result = ( U/ S) S V ( 1/ 2) (1/L 1) 100 U = peak esponse of amlodipine fom the Sample U = peak esponse of valsatan fom the Sample S = peak esponse of amlodipine fom the S = peak esponse of valsatan fom the Standad Standad S = concentation of USP Amlodipine Besylate RS S = concentation of USP Valsatan RS in the Standad (mg/ml) in the Standad (mg/ml) L 1 = molecula weight of amlodipine, 408.88 2 = label claim of valsatan (mg/tablet) Toleances: NLT 80% (Q) of the labeled amount of 2 = molecula weight of amlodipine besylate, amlodipine ( 20H 25lN 2O 5) and valsatan ( 24H 29N 5O 3) is dissolved. L 1 = label claim of amlodipine (mg/tablet) Test 2: If the poduct complies with this test, the labelvalsatan ( 24H 29N 5O 3) dissolved: ing indicates that the poduct meets USP Dis Test 2. edium and Time: Poceed as diected in Dis Result = ( U/ S) S V (1/L 2) 100 Test 1; 1000 ml. U = peak esponse of valsatan fom the Sample
Inteim Revision Announcement Official Novembe 1, 2017 Amlodipine 3 S = peak esponse of valsatan fom the Standad S = peak esponse of amlodipine fom the Standad S = concentation of USP Valsatan RS in the S = concentation of USP Amlodipine Besylate RS Standad (mg/ml) in the Standad (mg/ml) L 2 = label claim of valsatan (mg/tablet) 1 = molecula weight of amlodipine, 408.88 Toleances: NLT 75% (Q) of the labeled amount of 2 = molecula weight of amlodipine besylate, amlodipine ( 20H 25lN 2O 5) is dissolved and NLT 80% (Q) of the labeled amount of valsatan ( 24H 29N 5O 3) is L 1 = label claim of amlodipine (mg/tablet) dissolved. Test 3: If the poduct complies with this test, the label- valsatan ( 24H 29N 5O 3) dissolved: ing indicates that the poduct meets USP Dis Test 3. Result = ( U/ S) S V (1/L 2) 100 edium, Appaatus 2, and Time: Poceed as di U = peak esponse of valsatan fom the Sample ected in Dis Test 1. Solution A: Acetonitile, tifluooacetic acid, and wate (10: 0.1: 90) S = peak esponse of valsatan fom the Standad Solution B: Acetonitile, tifluooacetic acid, and wate (90: 0.1: 10) S = concentation of USP Valsatan RS in the obile phase: See Table 3. Standad (mg/ml) Table 3 L 2 = label claim of valsatan (mg/tablet) Toleances: NLT 75% (Q) of the labeled amount of Time Solution A Solution B amlodipine ( 20H 25lN 2O 5) is dissolved and NLT 80% (Q) of the labeled amount of valsatan ( 24H 29N 5O 3) is 0.01 90 10 dissolved. 2.5 10 90 UNIFORITY OF DOSAGE UNITS 905 : eet the equiements 3.0 90 10 5.0 90 10 IPURITIES Diluent: Acetonitile and wate (50:50) Standad stock A: 0.14 mg/ml of USP hange to ead: Amlodipine Besylate RS, pepaed as follows. Initially dissolve in Diluent about 4% of the final volume, and ORGANI IPURITIES dilute with edium to volume. obile phase, Diluent, Sample A, Sample so- Standad stock B: 1.6 mg/ml of USP Valdiected lution B, and homatogaphic system: Poceed as satan RS, pepaed as follows. Initially dissolve in in the Assay. about 20% of the final volume of Diluent, and dilute Standad stock A: Pepae as diected fo the with edium to volume. Standad in the Assay. Standad : (L 1/1000) mg/ml of amlodipine : Dissolve a suitable quanand (L 2/1000) mg/ml of valsatan in edium fom tity of USP Valsatan Related ompound B RS in Stan- Standad stock A and Standad stock B, dad stock A to obtain a containing whee L 1 is the label claim of amlodipine in mg/tab- 0.08 mg/ml of USP Valsatan Related ompound B RS, let, and L 2 is the label claim of valsatan in mg/tablet 0.14 mg/ml of USP Amlodipine Besylate RS, and Sample : Pass a potion of the unde 0.16 mg/ml of USP Valsatan RS. test though a suitable filte of 0.45-µm poe size and Sensitivity : 0.14 µg/ml of USP Amlodipine discad the fist few millilites of the filtate. Besylate RS and 0.16 µg/ml of USP Valsatan RS in Dil- homatogaphic system uent fom Standad stock A (See homatogaphy 621, System Suitability.) Standad stock B: 0.1 mg/ml of USP Amlodipine Related ompound A RS as fee base, pe- Detecto: UV 237 nm fo amlodipine and UV 270 paed as follows. Add methanol to 5% of the final volnm fo valsatan ume to dissolve, and dilute with Diluent to volume. olumn: 4.6-mm 10-cm; 5-µm packing L1 Standad : 0.0005 mg/ml of USP Amlodipine Flow ate: 1.5 ml/min Related ompound A RS as fee base, and 0.0003 mg/ ml each of USP Amlodipine Besylate RS and USP Val- satan RS in Diluent fom Standad stock A and Sample: Standad Standad stock B, espectively Tailing facto: NT 2.0 fo amlodipine and Samples:, Sensitivity, valsatan and Standad amlodipine and valsatan Re: oe than 4.0 between amlodipine and valsatan elated compound B and moe than 4.0 Samples: Standad and Sample between valsatan elated compound B and val- satan, amlodipine ( 20H 25lN 2O 5) dissolved: Relative standad deviation: NT 5.0% fo amlodipine elated compound A, amlodipine, and Result = ( U/ S) S V ( 1/ 2) (1/L 1) 100 valsatan, Standad U Signal-to-noise atio: NLT 10 fo amlodipine and = peak esponse of amlodipine fom the Sample valsatan, Sensitivity
Inteim Revision Announcement 4 Amlodipine Official Novembe 1, 2017 Table 4 Samples: Sample A, Sample B, and Relative Acceptance Standad Retention iteia, alculate the pecentage of amlodipine elated com- Name Time NT (%) pound A fee base in the potion of Tablets taken: Devaleyl valsatan 0.24 0.2 a. Result = ( U/ S) ( S/ U) ( 1/ 2) 100 Amlodipine elated compound A 0.50 0.5 b. U = peak esponse of amlodipine elated Valsatan elated degadation compound A fom Sample A poduct 1 0.54 0.2 S = peak esponse of amlodipine elated Valsatan elated degadation compound A fom the Standad poduct 2 0.81 0.2 S = concentation of USP Amlodipine Related Amlodipine 1.00 ompound A RS in the Standad (mg/ml) Valsatan elated compound B 1.34 d. U = nominal concentation of amlodipine in Valsatan elated degadation Sample A (mg/ml) poduct 3 1.44 0.2 1 = molecula weight of amlodipine elated Valsatan 1.74 compound A fee base, 406.86 Valsatan elated degadation 2 = molecula weight of amlodipine elated poduct 4 2.06 0.2 compound A fumaate, 522.93 Valsatan ethyl este 2.32 0.2 alculate the pecentage of valsatan elated e. Any othe unspecified degadation.poducts othe than valsatan elated degadation poduct 0.2 compound A (IRA 1-Nov-2017) in the potion of Tablets taken: 1.2;.2.0, if valsatan elated compound Result = ( U/ S) ( S/ U) 100 A is a potential degadation Total degadation f poducts.. poduct (IRA 1- U = peak esponse of valsatan elated degadation (IRA 1-Nov-2017) poduct fom Sample B Nov-2017) a S = peak esponse of valsatan fom the Standad.N-{[2 -(1H-Tetazole-5-yl)biphenyl-4-yl]methyl}-L-valine. b.3-ethyl 5-methyl [2-(2-aminoethoxymethyl)-4-(2-chloophenyl)-6-meth- yl-3,5-pyidinedicaboxylate]. S = concentation of USP Valsatan RS in the c.these ae specified unidentified degadation poducts. No infomation is Standad (mg/ml) available about chemical stuctues o chemical names fo these impui- U = nominal concentation of valsatan in Sample ties. B (mg/ml) d.n-butyyl-n-{[2 -(1H-tetazole-5-yl)biphenyl-4-yl]methyl}-L-valine. alculate the pecentage of each unspecified e.n-valeyl-n-{[2 -(1H-tetazole-5-yl)biphenyl-4-yl]methyl}-L-valine ethyl este. degadation poduct in the potion of Tablets taken:.f.if valsatan elated compound A is a potential degadation poduct, Result = ( U/ S) ( S/ U) ( 1/ 2) 100 the total degadation poducts limit does not include valsatan elated compound A and amlodipine elated compound A. (IRA 1-Nov-2017) U = peak esponse of each unspecified degadation Add the following: poduct fom Sample A S = peak esponse of amlodipine fom the. LIIT OF VALSARTAN RELATED OPOUND Standad A [NOTE Valsatan elated compound A is a pocess impu- S = concentation of USP Amlodipine Besylate RS in the Standad (mg/ml) ity and a fomulation-specific degadation poduct.] obile phase: n-hexane, 2-popanol, and tifluooace- U = nominal concentation of amlodipine in Sample A (mg/ml) tic acid (850:150:1) : 0.04 mg/ml each of USP 1 = molecula weight of amlodipine, 408.88 Valsatan Related ompound A and USP Valsatan RS in 2 = molecula weight of amlodipine besylate, obile phase Acceptance citeia: See Table 4. Disegad valsatan Standad : 0.001 mg/ml of USP Valsatan Reelated compound B, the benzenesulfonic acid peak at lated ompound A RS in obile phase elative etention time 0.19, and any peaks below Sample : Nominally 0.5 mg/ml of valsatan in 0.1%. obile phase fom a suitable amount of finely cushed powde fom NLT 20 Tablets. Sonication may be necessay fo complete dis. Pass though a suitable filte of 0.45-µm poe size. homatogaphic system (See homatogaphy 621, System Suitability.) Detecto: UV 230 nm olumn: 4.6-mm 25-cm; 5-µm packing L40 Tempeatues Autosample: 10 olumn: 30 Flow ate: 0.8 ml/min Injection volume: 20 µl Run time: NLT 3.5 times the etention time of valsatan elated compound A
Inteim Revision Announcement Official Novembe 1, 2017 Amlodipine 5 LABELING: When moe than one Dis test is given, Samples: and Standad the labeling states the Dis test used only if Test 1 is not used. [NOTE The elative etention times fo valsatan elated compound A and valsatan ae about 0.7 and 1.0, espectively.] hange to ead: Re: NLT 2.0 between valsatan and valsatan USP REFERENE STANDARDS 11 elated compound A, USP Amlodipine Besylate RS Relative standad deviation: NT 5.0% fo val- USP Amlodipine Related ompound A RS satan elated compound A, Standad 3-Ethyl 5-methyl [2-(2-aminoethoxymethyl)- 4-(2-chloophenyl)-6-methyl-3,5-pyidinedicaboxy- Samples: Standad and Sample late] fumaate. alculate the pecentage of valsatan elated com- 20H 23lN 2O 5 4H 4O 4 522.93 pound A in the potion of Tablets taken: USP Valsatan RS.USP Valsatan Related ompound A RS Result = ( U/ S) ( S/ U) 100 N-Valeyl-N-{[2 -(1H-tetazole-5-yl)biphenyl- 4-yl]methyl}-D-valine. 24H 29N 5O 3 435.52 U = peak esponse of valsatan elated compound (IRA 1-Nov-2017) A fom the Sample USP Valsatan Related ompound B RS S = peak esponse of valsatan elated compound N-Butyyl-N-{[2 -(1H-tetazole-5-yl)biphenyl- A fom the Standad 4-yl]methyl}-L-valine. S = concentation of USP Valsatan Related 23H 27N 5O 3 421.49 ompound A RS in the Standad (mg/ml) U = nominal concentation of valsatan in the Sample (mg/ml) Acceptance citeia: NT 1.0 % (IRA 1-Nov-2017) ADDITIONAL REQUIREENTS PAKAGING AND STORAGE: Stoe at contolled oom tempeatue, in tight containes, and in a dy place.