Diltiazem Hydrochloride Extended-Release Capsules. Type of Posting Posting Date Official Date

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1 Diltiazem Hydrochloride Extended-Release Capsules Type of Posting Posting Date Official Date Revision Bulletin 17 Nov Dec 2017 Expert Committee Chemical Medicines Monographs 2 Reason for Revision Compliance In accordance with the Rules and Procedures of the Council of Experts, the Monographs Chemical Medicines 2 Expert Committee has revised the Diltiazem Hydrochloride Extended-Release Capsules The purpose for the revision is to add Dis Test 18 to accommodate the FDA approved drug products with different dis conditions and tolerance than the existing dis test The Diltiazem Hydrochloride Extended-Release Capsules Revision Bulletin supersedes the currently official Diltiazem Hydrochloride Extended-Release Capsules The Revision Bulletin will be incorporated in the Second Supplement to USP 41 NF 36 Should you have any questions, please contact Edith Chang, Scientific Liaison ( or yec@usporg)

2 Column: Revision Bulletin Official December 1, 2017 Diltiazem 1 21-mm 15-cm; 17-µm packing L1 Diltiazem Hydrochloride Extended- Flow rate: 03 ml/min Injection volume: 20 µl Release Capsules System suitability Sample: Standard DEFINITION Suitability requirements Diltiazem Hydrochloride Extended-Release Capsules contain Tailing factor: NMT 20 NLT 900% and NMT 1100% of the labeled amount of Relative standard deviation: NMT 10% diltiazem hydrochloride (C 22H 26N 2O 4S HCl) Analysis Samples: Standard and Sample IDENTIFICATION Calculate the percentage of the labeled amount of dil- A The UV-Vis spectrum of the major peak of the Sample tiazem hydrochloride (C 22H 26N 2O 4S HCl) in the por corresponds to that of the Standard, as tion of Capsules taken: obtained in the Assay B The retention time of the major peak of the Sample Result = (r U/r S) (C S/C U) 100 corresponds to that of the Standard, as obtained in the Assay r U = peak response of diltiazem from the Sample ASSAY r S = peak response of diltiazem from the Standard PROCEDURE Solution A: 079 g/l of ammonium bicarbonate in C S = concentration of USP Diltiazem Hydrochloride water Adjust with diluted ammonia or acetic RS in the Standard (mg/ml) acid to a ph of 80 C U = nominal concentration of diltiazem Solution B: Acetonitrile hydrochloride in the Sample Mobile phase: See Table 1 (mg/ml) Acceptance criteria: 900% 1100% Table 1 Solution A Solution B PERFORMANCE TESTS (min) (%) (%) Change to read: DISSOLUTION 711 For products labeled for dosing every 12 h Test 1: If the product complies with this test, the la beling indicates that it meets USP Dis Test s: 3, 9, and 12 h Diluent: Acetonitrile and water (40:60) Standard : 005 mg/ml of USP Diltiazem Hy- drochloride RS in Diluent Sample : Sample per Dis 711 Di- Sample stock : Nominally 05 mg/ml of dilthat tiazem hydrochloride from the Capsules in Diluent prepared of the Standard as follows Transfer a portion of finely powdered Tolerances: See contents of NLT 20 Capsules to a suitable volumetric flask Add Diluent equivalent to 80% of the flask vol- Table 2 ume, mechanically shake for 30 min, and sonicate for 60 min Dilute with the Diluent to volume Centrifuge and use the supernatant Sample : Nominally 005 mg/ml of diltiazem hydrochloride prepared in Diluent from Sample stock NLT 70 Chromatographic system (See Chromatography 621, System Suitability) Mode: LC Detector: UV 240 nm For Identification A, use a diode array detector in the range of nm tance Test 4: If the product complies with this test, the labeling indicates that it meets USP Dis Test 4 s: 4, 8, 12, and 24 h Sample : Sample per Dis 711 Dilute Tolerances: See Table The United States Pharmacopeial Convention All Rights Reserved

3 2 Diltiazem Official December 1, 2017 Table 3 s: 1, 4, 10, and 15 h Sample : Sample per Dis 711 Dilute 24 NLT 80 Tolerances: See Table 6 Table 6 Test 5: If the product complies with this test, the la- beling indicates that it meets USP Dis Test 5 Medium: 005 M phosphate buffer, ph 72; 900 ml Apparatus 2: 50 rpm s: 1, 3, and 8 h NLT 80 Sample : Sample per Dis 711 Di- times specified conform to Dis 711, Accepthat of the Standard tance Tolerances: See Table 4 Test 3: If the product complies with this test, the labeling indicates that it meets USP Dis Test 3 Table 4 Medium: 01 N hydrochloric acid; 900 ml s: 6, 12, 18, 24, and 30 h 1 NMT NLT 80 Sample : Sample per Dis 711 Dilute Tolerances: See Table 7 Test 10: If the product complies with this test, the Table 7 labeling indicates that it meets USP Dis Test 10 Buffer: Dissolve 71 g of anhydrous dibasic sodium phosphate in 1000 ml of water, and adjust with phosphoric acid to a ph of Medium: Buffer; 900 ml 24 NLT 70 s: 1, 6, 9, and 24 h 30 NLT 85 Sample : Sample per Dis 711 Ditance times specified conform to Dis 711, Acceplute Test 6: If the product complies with this test, the la- Tolerances: See Table 5 beling indicates that it meets USP Dis Test 6 Table 5 s: 2, 4, 8, 12, and 16 h 1 NMT 10 Sample : Sample per Dis 711 Di NLT 80 Tolerances: See Table 8 Table 8 tance For products labeled for dosing every 24 h 2 NMT 25 Test 2: If the product complies with this test, the la beling indicates that it meets USP Dis Test The United States Pharmacopeial Convention All Rights Reserved

4 Official December 1, 2017 Diltiazem 3 Table 8 (Continued) Test 9: If the product complies with this test, the la- beling indicates that it meets USP Dis Test [NOTE Perform the test separately in each of the two 12 NLT 70 media] 16 NLT 80 Medium 1: 01 N hydrochloric acid; 900 ml Medium 2: Simulated intestinal fluid TS, prepared without enzyme and adjusted to a ph of 75 ± 01; 900 ml Apparatus 2: 75 rpm tance for Medium 1: 2 h Test 7: If the product complies with this test, the la- s for Medium 2: 2, 12, 18, and 24 h beling indicates that it meets USP Dis Test 7 Buffer: Transfer 115 ml of acetic acid to a 10-L volu- metric flask, dilute with water to volume, and mix (Solution A) Transfer 1654 g of anhydrous sodium Sample : Sample per Dis 711 Diacetate to a 10-L volumetric flask, dilute with water to volume, and mix (Solution B) Mix 4410 ml of Solution A with 1590 ml of Solution B Adjust, if nec- Tolerances: See Table 11 essary, with the addition of Solution A or Solution B to a ph of 42 ± 005 Medium: Buffer; 900 ml Table 11,, s: 1, 4, 10, and 15 h Medium 1 Medium 2 (%) Sample : Sample per Dis 711 Di- 18 NLT NLT 80 Tolerances: See Table 9 Table 9 Test 11: If the product complies with this test, the labeling indicates that it meets USP Dis Test 1 NMT Medium: 01 N hydrochloric acid; 900 ml NLT 80 s: 1, 6, 12, and 18 h Sample : Sample per Dis 711 Ditance Test 8: If the product complies with this test, the la- beling indicates that it meets USP Dis Test 8 Tolerances: See Table 12 s: 1, 4, 10, and 15 h Table 12 1 NMT 10 Sample : Sample per Dis 711 Di Tolerances: See Table NLT 85 Table 10 tance Test 12: If the product complies with this test, the labeling indicates that it meets USP Dis Test Proceed as directed for Extended-Release Dosage Forms in Procedure, Apparatus 1 and Apparatus 2 15 NLT The United States Pharmacopeial Convention All Rights Reserved

5 4 Diltiazem Official December 1, 2017 Table 15 s: 2, 8, 14, and 24 h Sample : Sample per Dis 711 Dilute NLT NLT 80 Tolerances: See Table 13 Table 13 tance Test 15: If the product complies with this test, the 2 NMT 20 labeling indicates that it meets USP Dis Test Proceed as directed for Extended-Release Dosage 14 NLT 65 Forms in Procedure, Apparatus 1 and Apparatus 2 24 NLT 80 Medium: 005 M phosphate buffer, ph 75; 900 ml Apparatus 2: 75 rpm s: 2, 4, 8, 12, and 16 h times specified conform to Dis 711, Accepin Medium tance Test 13: If the product complies with this test, the Sample : Sample per Dis 711 Dilabeling indicates that it meets USP Dis Test 13 Proceed as directed for Extended-Release Dosage Forms in Procedure, Apparatus 1 and Apparatus 2 Tolerances: See Table 16 Table 16 s: 2, 8, 14, and 24 h 2 NMT 25 Sample : Sample per Dis 711 Dilute NLT 70 Tolerances: See Table NLT 80 Table 14 tance 2 NMT 20 Test 16: If the product complies with this test, the labeling indicates that it meets USP Dis Test NLT 80 Medium, Apparatus 2, s, Standard, and Sample : Proceed as directed for Test 3 Detector: UV 238 nm Tolerances: See Table 17 Test 14: If the product complies with this test, the Table 17 labeling indicates that it meets USP Dis Test 14 Proceed as directed for Extended-Release Dosage Forms in Procedure, Apparatus 1 and Apparatus 2 Medium: 01 N hydrochloric acid; 900 ml s: 6, 12, 18, 24, and 30 h NLT NLT 80 Sample : Sample per Dis 711 Di- Tolerances: See Table 15 tance Test 17: If the product complies with this test, the labeling indicates that it meets USP Dis Test The United States Pharmacopeial Convention All Rights Reserved

6 Official December 1, 2017 Diltiazem 5 Medium: 01 N hydrochloric acid; 900 ml Calculate the percentage of the labeled amount of, with wire helix sinkers diltiazem hydrochloride (C 22H 26N 2O 4S HCl) s: 6, 12, and 30 h dissolved at each time point i: Detector: UV 238 nm Result 1 = C 1 V (1/L) 100 Sample : Dilute with Medium, if necessary, to a concentration that is similar to that of the Standard Result 2 = [(C 2 V) + (C 1 V S)] (1/L) 100 Blank: Medium Tolerances: See Table 18 Result 3 = {(C 3 V ) + [(C 2 + C 1) V S]} (1/L) 100 Table 18 Result 4 = {(C 4 V) + [(C 3 + C 2 + C 1) V S]} (1/L) 100 C i = concentration of diltiazem hydrochloride in the Sample withdrawn at the specified time point (mg/ml) 30 NLT 80 V L = volume of Medium, 900 ml = label claim (mg/capsule) V S = volume of the Sample withdrawn at each time point (ml) Tolerances: See Table 19 (RB 10-Oct-2017) Test 18: If the product complies with this test, the Table 19 labeling indicates that it meets USP Dis Test 18 Point (i) 1 2 NMT 20 s: 2, 4, 8, and 12 h Standard stock : 028 mg/ml of USP Dil NLT 80 tiazem Hydrochloride RS prepared as follows To a suitable amount of USP Diltiazem Hydro- chloride RS in a suitable volumetric flask, add Medium to 50% of the volume of the flask and soni- times specified conform to Dis 711, Accepcate for 5 min to dissolve Dilute with Medium to tance (RB 1-Dec-2017) volume UNIFORMITY OF DOSAGE UNITS 905 : Meet the Standard : 0014 mg/ml of USP Diltiazem requirements Hydrochloride RS from the Standard stock Sample : At the times specified, withdraw IMPURITIES 10 ml of the under test Replace the aliquots withdrawn for analysis with equal volumes of Change to read: fresh portions of Medium maintained at 37 Pass the through a PVDF filter of 045-µm pore size ORGANIC IMPURITIES Discard the first 2 ml of filtrate Dilute with Medium Solution A, Solution B, Mobile phase, Diluent, and to a concentration that is similar to that of the Stan- Chromatographic system: Proceed as directed in the dard Assay Analysis Standard : 25 µg/ml each of USP Desacetyl Samples: Standard and Sample Diltiazem Hydrochloride RS and USP Diltiazem Hydro- Calculate the concentration of diltiazem hydrochlo- chloride RS in Diluent ride (C 22H 26N 2O 4S HCl) in the sample withdrawn Sample : Nominally 05 mg/ml of diltiazem from the vessel at each time point i: hydrochloride from the Capsules in Diluent prepared as follows Transfer a portion of the finely powdered contents Result = (A U/A S) C S D of NLT 20 Capsules to a suitable volumetric flask Add Diluent equivalent to 80% of the flask volume, A U = absorbance of diltiazem from the Sample mechanically shake for 30 min, and sonicate for 60 at each time point min Dilute with Diluent to volume Centrifuge and use A S = absorbance of diltiazem from the Standard the supernatant System suitability C S = concentration of USP Diltiazem Hydrochloride Sample: Standard RS in the Standard (mg/ml) [NOTE For relative retention times see Table 20 (RB 1- D = dilution factor of the Sample Dec-2017)] Suitability requirements Re: NLT 20 between desacetyl diltiazem and diltiazem 2017 The United States Pharmacopeial Convention All Rights Reserved

7 g g Revision Bulletin 6 Diltiazem Official December 1, 2017 Relative standard deviation: NMT 30% Table 20 (RB 1-Dec-2017) (Continued) Analysis Relative Acceptance Samples: Standard and Sample Retention Criteria, Calculate the percentage of desacetyl diltiazem hy- Name NMT (%) drochloride (RB 10-Oct-2017) in the portion of Capsules Diltiazem related compound C d taken: 058 b, Diltiazem related compound D e 061 b, Result = (r U/r S) (C S/C U) 100 Diltiazem related compound E 066 b,f Desacetyl g diltiazem (RB 1-Dec-2017) r U = peak response of desacetyl diltiazem from the Diltiazem related compound A h Sample b, (RB 1-Dec-2017) 083 r S = peak response of desacetyl diltiazem from the Diltiazem related compound B i Standard b, (RB 1-Dec-2017) 089 C S = concentration of USP Desacetyl Diltiazem Diltiazem 10 Hydrochloride RS in the Standard Any individual unspecified impurity 02 (µg/ml) C U = nominal concentration of diltiazem Total impurities 20 hydrochloride in the Sample (µg/ml) a (2S,3S)-5-(2-Aminoethyl)-3-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-1, Calculate the percentage of any individual unspecified 5-benzothiazepine-4(5H)-one b impurity in the portion of Capsules taken: These are impurities related to the drug substance They are not to be reported for the drug product and should not be included in the total Result = (r U/r S) (C S/C U) 100 impurities c (2S,3S)-3-Hydroxy-2-(3-methoxyphenyl)-5-(2-(methylamino)ethyl)-2,3- r U dihydrobenzo[b][1,4]thiazepin-4(5h)-one = peak response of each unspecified impurity d (2S,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-hydroxyphenyl)-4-oxo-2,3,4,5- from the Sample tetrahydro-1,5-benzothiazepin-3-yl acetate r S = peak response of diltiazem from the Standard e (2S,3S)-2-(4-Methoxyphenyl)-5-[2-(methylamino)ethyl]-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-3-yl acetate f C S = concentration of USP Diltiazem Hydrochloride (2S,3S)-3-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5- RS in the Standard (µg/ml) benzothiazepine-4(5h)-one C U = nominal concentration of diltiazem d-cis-3-hydroxy-2,3-dihydro-5-[2-dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5h)-one The acceptance criteria for this hydrochloride in the Sample (µg/ml) impurity is based on the hydrochloride form Acceptance criteria: See Table 20 (RB 1-Dec-2017) Disre- h (RB 1-Dec-2017) (2R,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-methoxyphenyl)-4- gard limit: 005% oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-yl acetate i (RB 1-Dec-2017) (2S,3S)-2-(4-Methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1, 5-benzothiazepine-3-yl acetate Table 20 (RB 1-Dec-2017) Relative Acceptance ADDITIONAL REQUIREMENTS Retention Criteria, PACKAGING AND STORAGE: Preserve in tight containers Name NMT (%) Store at controlled room temperature LABELING: The labeling indicates the Dis test with Diltiazem related compound H b 044 which the product complies a, Diltiazem related compound G c 052 b, a (2S,3S)-5-(2-Aminoethyl)-3-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-1, 5-benzothiazepine-4(5H)-one Change to read: b These are impurities related to the drug substance They are not to be reported for the drug product and should not be included in the total USP REFERENCE STANDARDS 11 impurities USP Desacetyl Diltiazem Hydrochloride RS c (2S,3S)-3-Hydroxy-2-(3-methoxyphenyl)-5-(2-(methylamino)ethyl)-2,3- d-cis-3-hydroxy-2,3-dihydro-5-[2-dimethylamidihydrobenzo[b][1,4]thiazepin-4(5h)-one no)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepind tetrahydro-1,5-benzothiazepin-3-yl (2S,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-hydroxyphenyl)-4-oxo-2,3,4,5- acetate 4(5H)-one hydrochloride (RB 1-Dec-2017) C 20H 24N 2O 3S HCl e (2S,3S)-2-(4-Methoxyphenyl)-5-[2-(methylamino)ethyl]-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-3-yl acetate USP Diltiazem Hydrochloride RS f (2S,3S)-3-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5- benzothiazepine-4(5h)-one d-cis-3-hydroxy-2,3-dihydro-5-[2-dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5h)-one The acceptance criteria for this impurity is based on the hydrochloride form h (RB 1-Dec-2017) (2R,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-methoxyphenyl)-4- oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-yl acetate i (RB 1-Dec-2017) (2S,3S)-2-(4-Methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1, 5-benzothiazepine-3-yl acetate 2017 The United States Pharmacopeial Convention All Rights Reserved