Diltiazem Hydrochloride Extended-Release Capsules

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition
Issued and maintained by the United States Pharmacopeial Convention (USP)
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1 DEFINITION

Diltiazem Hydrochloride Extended-Release Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl). 

2 IDENTIFICATION 

A. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

3 ASSAY 

3.1 Procedure 

Solution A: 0.79 g/L of ammonium bicarbonate in water. Adjust with diluted ammonia solution or acetic acid to a pH of 8.0.

Solution B: Acetonitrile 

Mobile phase: See Table 1. 

Table 1 

Diluent: Acetonitrile and water (40:60) 

Standard solution: 0.05 mg/mL of USP Diltiazem Hydrochloride RS in Diluent 

Sample stock solution: Nominally 0.5 mg/mL of diltiazem hydrochloride from the Capsules in Diluent prepared as follows. Transfer a portion of nely powdered contents of NLT 20 Capsules to a suitable volumetric ask. Add Diluent equivalent to 80% of the ask volume, mechanically shake for 30 min, and sonicate for 60 min. Dilute with the Diluent to volume. Centrifuge and use the supernatant. 

Sample solution: Nominally 0.05 mg/mL of diltiazem hydrochloride prepared in Diluent from Sample stock solution Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 240 nm. For Identication A, use a diode array detector in the range of 190–400 nm. 

Column: 2.1-mm × 15-cm; 1.7-µm packing L1 

Flow rate: 0.3 mL/min 

Injection volume: 2.0 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 1.0% 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the portion of Capsules taken: 

Result = (r_u/r_s) × (C_s/C_u) × 100 

r_u = peak response of diltiazem from the Sample solution 

r_s = peak response of diltiazem from the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

C_u = nominal concentration of diltiazem hydrochloride in the Sample solution (mg/mL) 

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

4.1 Dissolution 〈711〉 

For products labeled for dosing every 12 h 

Test 1: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 1. 

Medium: Water; 900 mL 

Apparatus 2: 100 rpm 

Times: 3, 9, and 12 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. 

Tolerances: See Table 2. 

Table 2 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4. 

Medium: Water; 900 mL 

Apparatus 2: 100 rpm 

Times: 4, 8, 12, and 24 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 3. 

Table 3 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 5: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5. 

Medium: 0.05 M phosphate buffer, pH 7.2; 900 mL 

Apparatus 2: 50 rpm 

Times: 1, 3, and 8 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 4. 

Table 4 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 10: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 10. 

Buffer: Dissolve 7.1 g of anhydrous dibasic sodium phosphate in 1000 mL of water, and adjust with phosphoric acid to a pH of 6.5. 

Medium: Buffer; 900 mL 

Apparatus 1: 100 rpm 

Times: 1, 6, 9, and 24 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 5. 

Table 5 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

For products labeled for dosing every 24 h 

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2. 

Medium: Water; 900 mL 

Apparatus 2: 100 rpm 

Times: 1, 4, 10, and 15 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 6. 

Table 6 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3. 

Medium: 0.1 N hydrochloric acid; 900 mL 

Apparatus 2: 100 rpm 

Times: 6, 12, 18, 24, and 30 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 7. 

Table 7 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 6: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6. 

Medium: Water; 900 mL 

Apparatus 1: 100 rpm 

Times: 2, 4, 8, 12, and 16 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 8. 

Table 8 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 7: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7. 

Buffer: Transfer 115 mL of acetic acid to a 10-L volumetric ask, dilute with water to volume, and mix (Solution A). Transfer 165.4 g of anhydrous sodium acetate to a 10-L volumetric ask, dilute with water to volume, and mix (Solution B). Mix 4410 mL of Solution A with 1590 mL of Solution B. Adjust, if necessary, with the addition of Solution A or Solution B to a pH of 4.2 ± 0.05. 

Medium: Buffer; 900 mL 

Apparatus 2: 100 rpm 

Times: 1, 4, 10, and 15 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 9. 

Table 9 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 8: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8. 

Medium: Water; 900 mL 

Apparatus 2: 100 rpm 

Times: 1, 4, 10, and 15 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 10. 

Table 10 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 9: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 9. 

[Note—Perform the test separately in each of the two media.] 

Medium 1: 0.1 N hydrochloric acid; 900 mL 

Medium 2: Simulated intestinal uid TS, prepared without enzyme and adjusted to a pH of 7.5 ± 0.1; 900 mL 

Apparatus 2: 75 rpm 

Time for Medium 1: 2 h 

Times for Medium 2: 2, 12, 18, and 24 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution.

Tolerances: See Table 11. 

Table 11 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 11: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 11. 

Medium: 0.1 N hydrochloric acid; 900 mL 

Apparatus 2: 100 rpm 

Times: 1, 6, 12, and 18 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. 

Tolerances: See Table 12. 

Table 12 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 12: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 12. Proceed as directed in Dissolution 〈711〉, Procedure, Apparatus 1 and Apparatus 2, Extended-Release Dosage Forms. 

Medium: Water; 900 mL 

Apparatus 1: 100 rpm 

Times: 2, 8, 14, and 24 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 13. 

Table 13 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 13: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 13. Proceed as directed in Dissolution 〈711〉, Procedure, Apparatus 1 and Apparatus 2, Extended-Release Dosage Forms. 

Medium: Water; 900 mL 

Apparatus 1: 100 rpm 

Times: 2, 8, 14, and 24 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 14. 

Table 14

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 14: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 14. Proceed as directed in Dissolution 〈711〉, Procedure, Apparatus 1 and Apparatus 2, Extended-Release Dosage Forms. 

Medium: 0.1 N hydrochloric acid; 900 mL 

Apparatus 2: 100 rpm 

Times: 6, 12, 18, 24, and 30 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. Tolerances: See Table 15. 

Table 15 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 15: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 15. Proceed as directed in Dissolution 〈711〉, Procedure, Apparatus 1 and Apparatus 2, Extended-Release Dosage Forms. 

Medium: 0.05 M phosphate buffer, pH 7.5; 900 mL 

Apparatus 2: 75 rpm 

Times: 2, 4, 8, 12, and 16 h 

Detector: UV 237 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Sample per Dissolution 〈711〉. Dilute with Medium to a concentration that is similar to that of the Standard solution. www.webofpharma.com

2/17/25, 10:59 PM USP-NF Diltiazem Hydrochloride Extended-Release Capsules Tolerances: See Table 16. 

Table 16 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 16: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 16. 

Medium, Apparatus 2, Times, Standard solution, and Sample solution: Proceed as directed for Test 3. 

Detector: UV 238 nm 

Tolerances: See Table 17. 

Table 17 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 17: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 17. 

Medium: 0.1 N hydrochloric acid; 900 mL 

Apparatus 2: 100 rpm, with wire helix sinkers 

Times: 6, 12, and 30 h 

Detector: UV 238 nm 

Standard solution: USP Diltiazem Hydrochloride RS in Medium 

Sample solution: Dilute with Medium, if necessary, to a concentration that is similar to that of the Standard solution. Blank: Medium 

Tolerances: See Table 18. 

Table 18 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 18: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 18. 

Medium: Water; 900 mL 

Apparatus 1: 100 rpm 

Times: 2, 4, 8, and 12 h 

Detector: UV 237 nm 

Standard stock solution: 0.28 mg/mL of USP Diltiazem Hydrochloride RS in Medium prepared as follows. To a suitable amount of USP Diltiazem Hydrochloride RS in a suitable volumetric ask, add Medium to 50% of the volume of the ask and sonicate for 5 min to dissolve. Dilute with Medium to volume. 

Standard solution: 0.014 mg/mL of USP Diltiazem Hydrochloride RS in Medium from the Standard stock solution 

Sample solution: At the times specied, withdraw 10 mL of the solution under test. Replace the aliquots withdrawn for analysis with equal volumes of fresh portions of Medium maintained at 37°. Pass the solution through a PVDF lter of 0.45-µm pore size. Discard the rst 2 mL of ltrate. Dilute with Medium to a concentration that is similar to that of the Standard solution. 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time point i: 

Result = (A_u/A_s) × C_s × D 

A_u = absorbance of diltiazem from the Sample solution at each time point  

A_s = absorbance of diltiazem from the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

D = dilution factor for the Sample solution 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point i: 

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = [(C₂ × V) + (C₁ × V_S)] × (1/L) × 100 

Result₃ = {(C₃ × V) + [(C₂ + C₁) × V_S]} × (1/L) × 100 

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁) × V_S)]} × (1/L) × 100 

C_i = concentration of diltiazem hydrochloride in the Sample solution withdrawn at the specied time point (mg/mL) 

V = volume of Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample withdrawn at each time point (mL) 

Tolerances: See Table 19. 

Table 19 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to 22 26 2 4 

Dissolution 〈711〉, Acceptance Table 2. 

Test 19: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 19. 

Medium: 0.1 N hydrochloric acid; 900 mL 

Temperature: 37.0°–37.5° 

Apparatus 2: 100 rpm, with a suitable sinker 

Times: 1, 4, 12, 18, and 24 h 

Detector: UV 238 nm 

Cell: 0.5 mm 

Standard solution: 0.4 mg/mL of USP Diltiazem Hydrochloride RS in Medium 

Sample solution: A portion of the solution under test at the time points specied 

Analysis 

Samples: Standard solution and Sample solution 

Use an automatic dissolution system with an appropriate dissolution software. 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point i: 

Result = (A_u/A_s) × (C_s /L) × V × 100 

A_u = absorbance of diltiazem from the Sample solution at each time point 

A_s = absorbance of diltiazem from the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

L = label claim (mg/Capsule) 

V = volume of Medium, 900 mL 

Tolerances: See Table 20. 

Table 20 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 20: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 20. 

Dissolution Test 20 is suitable for products labeled to contain 360 mg of diltiazem hydrochloride. 

Medium: 0.1 N hydrochloric acid; 900 mL 

Apparatus 2: 100 rpm 

Times: 6, 12, 18, and 24 h 

Detector: UV 237 nm 

Cell: 0.05 cm 

Standard solution: 0.4 mg/mL of USP Diltiazem Hydrochloride RS prepared as follows. Transfer a suitable amount of USP Diltiazem Hydrochloride RS into a suitable volumetric ask, and add methanol to 5% of the total volume of the ask to dissolve. Dilute with Medium to volume. 

Sample solution: Pass a portion of the solution under test through a suitable lter at the time points specied. 

Blank: Medium 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time point (i): 

Result = (A_u/A_s) × C_s

A_u = absorbance of diltiazem from the Sample solution at each time point 

A_s = absorbance of diltiazem from the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100 

Result₃ = ({C₃ × [V − (2 × V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100 

Result₄ = ({C₄ × [V − (3 × V_S)]} + [(C₃ + C₂ + C₁) × V_S)] × (1/L) × 100 

C_i = concentration of diltiazem hydrochloride in the Sample solution withdrawn at the specied time point (mg/mL) 

V = volume of Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample withdrawn at each time point (mL) 

Tolerances: See Table 21. 

Table 21 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 21: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 21. 

Medium: 0.1 N hydrochloric acid; 900 mL, deaerated 

Apparatus 2: 100 rpm 

Times: 2, 4, 14, 18, and 24 h 

Standard stock solution: 1.33 mg/mL of USP Diltiazem Hydrochloride RS in Medium 

Standard solution: (L/900) mg/mL of USP Diltiazem Hydrochloride RS from the Standard stock solution in Medium, where L is the label claim in mg/Capsule 

Sample solution: Pass a portion of the solution under test at the time points specied through a suitable lter. 

Instrumental conditions 

(See Ultraviolet-Visible Spectroscopy 〈857〉.) 

Mode: UV 

Analytical wavelength: 237 nm for 120 mg, 180 mg, and 240 mg strength capsules. 

260 nm for 300 mg and 360 mg strength capsules. 

Cell: 1 mm for 120 mg, 180 mg, and 240 mg strength capsules. 

2 mm for 300 mg and 360 mg strength capsules. 

Blank: Medium 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i):

Result = (A_u/A_s) × (C_s/L) × V × 100 

A_u = absorbance of diltiazem from the Sample solution at each time point 

A_s = absorbance of diltiazem from the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

L = label claim (mg/Capsule) 

V = volume of Medium, 900 mL 

Tolerances: See Table 22. 

Table 22 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 24: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 24. 

Medium: Water; 900 mL, degassed 

Apparatus 1: 100 rpm 

Times: 2, 6, 16, and 24 h 

Mobile phase: Methanol and water (53:47). Add 1 mL of triuoroacetic acid to each liter of the mixture. 

Standard solution: 0.3 mg/mL of USP Diltiazem Hydrochloride RS in Medium 

Sample solution: At the specied times, withdraw 10 mL of the solution under test and pass through a suitable lter of 0.45-µm pore size, discarding the rst 3 mL of ltrate. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 270 nm 

Column: 4.6-mm × 7.5-cm; 3.5-µm packing L1 

Column temperature: 40° 

Flow rate: 1.1 mL/min 

Injection volume: 10 µL 

Run time: NLT 3 times the retention time of diltiazem 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 3.0% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration (C_i) of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time 

point (i): 

C = (r_u/r_s) × C_s

r_u = peak response of diltiazem from the Sample solution 

r_s = peak response of diltiazem from the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i): 22 26 2 4 

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100 

Result₃ = ({C₃ × [V − (2 × V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100 

Result₄ = ({C₄ × [V − (3 × V_S)]} + [(C₃ + C₂ + C₁) × V_S)] × (1/L) × 100  

C_i = concentration of diltiazem hydrochloride in the portion of sample withdrawn at the specied time point (mg/mL) 

V = volume of Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample solution withdrawn at each time point (mL) 

Tolerances: See Table 23. 

Table 23 

The percentages of the labeled amount of diltiazem hydrochloride dissolved at the times specied conform to Dissolution 〈711〉, 

Acceptance Table 2. 

Test 25: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 25. Medium: Water, deaerated, if necessary; 900 mL 

Apparatus 1: 100 rpm 

Times: 2, 4, 8, 12 and 16 h 

Standard solution: 0.01 mg/mL of USP Diltiazem Hydrochloride RS in Medium. Sonicate to dissolve. 

Sample solution: At the times specied, withdraw 10 mL of the solution under test and replace with an equal volume of fresh Medium. Centrifuge the solution and use the clear supernatant. Dilute with Medium to a concentration similar to that of the Standard solution, if necessary. [Note—A centrifuge speed of 2500 rpm for 10 min may be suitable.] 

Instrumental conditions 

(See Ultraviolet-Visible Spectroscopy 〈857〉.) 

Mode: UV 

Analytical wavelength: 237 nm 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration (C_i) of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time point (i): 

Result = (A_u/A_s) × C_s × D 

A_u = absorbance of the Sample solution 

A_s = absorbance of the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

D = dilution factor for the Sample solution, if necessary 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i): 

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = [(C₂ × V) + (C₁ × V_S)] × (1/L) × 100 

Result₃ = {(C₃ × V) + [(C₂ + C₁) × V_S]} × (1/L) × 100 

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁) × V_S)]} × (1/L) × 100 

Result₅ = {(C₅ × V) + [(C₄ + C₃ + C₂ + C₁) × V_S]) × (1/L) × 100 

C_i = concentration of diltiazem hydrochloride in the Sample solution withdrawn at the specied time point i (mg/mL) 

V = volume of the Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL) 

Tolerances: See Table 24. 

Table 24 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 26: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 26. 

Medium: Water, deaerated; 900 mL 

Apparatus 1: 100 rpm 

Times: 2, 8, 14 and 24 h 

Standard solution: 0.01 mg/mL of USP Diltiazem Hydrochloride RS in Medium. Sonicate to dissolve. 

Sample solution: At the times specied, withdraw 10 mL of the solution under test and replace with an equal volume of fresh Medium. Pass the solution through a suitable lter of 0.45-μm pore size, discarding the rst 2-3 mL of the ltrate. Dilute with Medium to a concentration similar to that of the Standard solution, if necessary. 

Instrumental conditions 

(See Ultraviolet-Visible Spectroscopy 〈857〉.) 

Mode: UV 

Analytical wavelength: 237 nm 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration (C_i) of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time point (i): 

Result_i = (A_u/A_s) × C_s × D 

A_u = absorbance of the Sample solution 

A_s = absorbance of the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

D = dilution factor for the Sample solution, if necessary 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i): 

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = [(C₂ × V) + (C₁ × V_S)] × (1/L) × 100 

Result₃ = {(C₃ × V) + [(C₂ + C₁) × V_S]} × (1/L) × 100 

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁) × V_S)]} × (1/L) × 100 

C_i = concentration of diltiazem hydrochloride in the Sample solution withdrawn at the specied time point i (mg/mL)

V = volume of the Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL) 

Tolerances: See Table 25. 

Table 25 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl)) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 27: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 27. 

Medium: pH 6.0 phosphate buffer prepared as follows. Transfer 250 mL of solution containing 27.22 g/L of monobasic potassium 

phosphate in water to a 1000-mL volumetric ask. Add 28 mL of 0.2 N sodium hydroxide solution and dilute with water to volume; 900 OFFICIAL 

mL, deaerated, if necessary. 

Apparatus 2: 100 rpm, with a suitable sinker 

Times: 4, 8, 12, and 24 h 

Standard solution: 0.1 mg/mL of USP Diltiazem Hydrochloride RS in Medium. Sonicate to dissolve, if necessary. 

Sample solution: At the times specied, withdraw a portion of the solution under test and pass through a suitable lter of 10-μm pore size. Instrumental conditions 

(See Ultraviolet-Visible Spectroscopy 〈857〉.) 

Mode: UV 

Analytical wavelength: 237 nm 

Cell: 1 mm 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration (C_i) of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time point (i): 

Result_i = (A_u/A_s) × C_s

A_u = absorbance of the Sample solution 

A_s = absorbance of the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i):  

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100 

Result₃ = ({C₃ × [V − (2 × V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100 

Result₄ = ({C₄ × [V − (3 × V_S)]} + [(C₃ + C₂ + C₁) × V_S)] × (1/L) × 100  

C_i = concentration of diltiazem hydrochloride in the portion of sample withdrawn at the specied time point (mg/mL) i 

V = volume of Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample solution withdrawn at each time point (mL) 

Tolerances: See Table 26. 

Table 26 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 28: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 28. 

Medium: Water; 900 mL, deaerated, if necessary 

Apparatus 2: 100 rpm 

Times: 1, 4, and 10 h 

Standard solution: 0.027 mg/mL of USP Diltiazem Hydrochloride RS in Medium. Sonicate to dissolve, if necessary. Sample stock solution: At the times specied, withdraw a portion of the solution under test and pass through a suitable lter of 10-μm pore size. 

Sample solution: Transfer 2.5 mL of the Sample stock solution to 25-mL volumetric ask and dilute with Medium to volume. 

Instrumental conditions 

(See Ultraviolet-Visible Spectroscopy 〈857〉.) 

Mode: UV 

Analytical wavelength: 237 nm 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration (C_i) of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time i point (i): 

Result_i = (A_u/A_s) × C_s× D 

A_u = absorbance of the Sample solution 

A_s = absorbance of the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

D = dilution factor for the Sample solution, 10 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100 

Result₃ = ({C₃ × [V − (2 × V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100 

C_i = concentration of diltiazem hydrochloride in the portion of sample withdrawn at the specied time point (mg/mL) 

V = volume of Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample solution withdrawn at each time point (mL) 

Tolerances: See Table 27. 

Table 27 

The percentages of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

Test 29: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 29. 

Medium: 0.1 N hydrochloric acid; 900 mL, deaerated, if necessary 

Apparatus 2: 100 rpm 

Times: 6, 12, 18, 24, and 30 h 

Solution A: 1 mL/L of phosphoric acid in water 

Mobile phase: Acetonitrile and Solution A (28:72) 

Standard solution: 0.016 mg/mL of USP Diltiazem Hydrochloride RS in Medium 

Sample solution: At the times specied, withdraw a portion of the solution under test and pass through a suitable lter of 0.45-µm pore size, discarding an appropriate volume of ltrate so that a consistent result can be obtained. Dilute with Medium to a concentration similar to that of the Standard solution. Filter through a suitable lter of 0.45-μm pore size, discarding an appropriate volume of ltrate so that a consistent result can be obtained. 

Chromatographic system  

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 237 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L11 

Column temperature: 40° 

Flow rate: 2 mL/min 

Injection volume: 40 µL 

Run time: NLT 1.2 times the retention time of diltiazem 

System suitability 

Sample: Standard solution 

[Note—The relative retention times for desacetyl diltiazem and diltiazem are 0.56 and 1.0, respectively.] 

Suitability requirements 

Tailing factor: NMT 2.0 for diltiazem 

Relative standard deviation: NMT 2.0% for sum of the peak responses of desacetyl diltiazem and diltiazem Analysis 

Samples: Standard solution and Sample solution 

Calculate the concentration (C_i) of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) in the sample withdrawn from the vessel at each time point (i): 

C_{i =} (r_u/r_s) × C_s × D 

r_u = sum of the peak responses of desacetyl diltiazem and diltiazem from the Sample solution 

r_s = sum of the peak responses of desacetyl diltiazem and diltiazem from the Standard solution 

C_s = concentration of USP Diltiazem Hydrochloride RS in the Standard solution (mg/mL) 

D = dilution factor for the Sample solution 

Calculate the percentage of the labeled amount of diltiazem hydrochloride (C₂₂H₂₆N₂O₄S. HCl) dissolved at each time point (i): 

Result₁ = C₁ × V × (1/L) × 100 

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100 

Result₃ = ({C₃ × [V − (2 × V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100 

Result₄ = ({C₄ × [V − (3 × V_S)]} + [(C₃ + C₂ + C₁) × V_S)] × (1/L) × 100 

Result₅ = ({C₅ × [V − (4 × V_S)]} + [(C₄ + C₃ + C₂ + C₁) × V_S]) × (1/L) × 100 

C_i = concentration of diltiazem hydrochloride in the portion of sample withdrawn at the specied time point (mg/mL) 

V = volume of Medium, 900 mL 

L = label claim (mg/Capsule) 

V_S = volume of the Sample solution withdrawn at each time point (mL) 

Tolerances: See Table 28. 

Table 28 

The percentages of the labeled amount of diltiazem hydrochloride dissolved at the times specied conform to Dissolution 〈711〉, Acceptance Table 2. 

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements 

5 IMPURITIES 

5.1 Organic Impurities 

Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay. 

Standard solution: 2.5 µg/mL each of USP Desacetyl Diltiazem Hydrochloride RS and USP Diltiazem Hydrochloride RS in Diluent Sample solution: Nominally 0.5 mg/mL of diltiazem hydrochloride from the Capsules in Diluent prepared as follows. Transfer a portion of the nely powdered contents of NLT 20 Capsules to a suitable volumetric ask. Add Diluent equivalent to 80% of the ask volume, mechanically shake for 30 min, and sonicate for 60 min. Dilute with Diluent to volume. Centrifuge and use the supernatant. 

System suitability 

Sample: Standard solution 

[Note—For relative retention times, see Table 29.] 

Suitability requirements 

Resolution: NLT 2.0 between desacetyl diltiazem and diltiazem 

Relative standard deviation: NMT 3.0% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of desacetyl diltiazem hydrochloride in the portion of Capsules taken: 

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of desacetyl diltiazem from the Sample solution

r_s = peak response of desacetyl diltiazem from the Standard solution

C_s = concentration of USP Desacetyl Diltiazem Hydrochloride RS in the Standard solution (mg/mL)

C_u = cnominal concentration of diltiazem hydrochloride in the Sample solution (µg/mL)

Calculate the percentage of any individual unspecied impurity in the portion of Capsules taken: 

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of each unspecied impurity from the Sample solution

r_s = peak response of diltiazem from the Standard solution

C_s = cconcentration of USP Diltiazem Hydrochloride RS in the Standard solution (µg/mL)

C_u = nominal concentration of diltiazem hydrochloride in the Sample solution (µg/mL)

Acceptance criteria: See Table 29. Disregard limit: 0.05%. 

Table 29 

a (2S,3S)-5-(2-Aminoethyl)-3-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one. 

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 impurities. 

c(2S,3S)-3-Hydroxy-2-(3-methoxyphenyl)-5-(2-(methylamino)ethyl)-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one. 

d (2S,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-hydroxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate. e(2S,3S)-2-(4-Methoxyphenyl)-5-[2-(methylamino)ethyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-yl acetate. f (2S,3S)-3-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one. 

g 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 (2R,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-yl acetate.

i (2S,3S)-2-(4-Methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-yl acetate. 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature. 

Labeling: The labeling indicates the Dissolution test with which the product complies. 

Change to read: 

USP Reference Standards 〈11〉 

USP Desacetyl Diltiazem Hydrochloride RS 

d-cis-3-Hydroxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride.

C₂₀H₂₄N₂O₃S. HCl              408.94 (CN 1-Dec-2024) 

USP Diltiazem Hydrochloride RS