Diltiazem Hydrochloride Extended-Release Capsules
» Diltiazem Hydrochloride Extended-Release Capsules contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of diltiazem hydrochloride (C22H26N2O4S·HCl).
Packaging and storage— Preserve in tight containers.
Labeling— The labeling indicates the Dissolution Test with which the product complies.
USP Reference standards 11—
USP Desacetyl Diltiazem Hydrochloride RS
    C20H24N2O3S·HCl    408.95
USP Diltiazem Hydrochloride RS Click to View Structure
Identification—
A: Transfer 17.4 g of ammonium thiocyanate and 2.8 g of cobalt chloride to a 100-mL volumetric flask, add about 50 mL of water, and sonicate for 10 minutes. Dilute with water to volume, and mix (Indicator solution). Grind the contents of 1 Capsule, and transfer to a 15-mL screw-capped test tube. Add 10 mL of 0.1 N hydrochloric acid, shake, and filter. Add 2 mL of Indicator solution to 2 mL of the filtrate, and shake. Add 5 mL of chloroform, and shake: a blue color develops in the chloroform layer.
B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
Dissolution 711—
for products labeled for dosing every 12 hours—
test 1— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 1. Proceed as directed for Extended-Release Dosage Forms.
Medium: water; 900 mL.
Apparatus 2: 100 rpm.
Times: 3, 9, and 12 hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 237 nm on filtered portions of the solution under test, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RS in the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2 O4S·HCl dissolved at the times specified conform to the Acceptance Table given.
Time (hours) Amount dissolved
3 between 10% and 25%
9 between 45% and 85%
12 not less than 70%
Acceptance Table
Level Number
Tested		 Criteria
L1 6 No individual value lies outside each of the stated ranges, and no individual value is less than the stated amount at the final test time.
L2 6 The average value of the 12 units (L1 + L2) lies within each of the stated ranges and is not less than the stated amount at the final test time. At 3 hours none of the units is outside the range of 10% to 35% of labeled content; at 9 hours none of the units is outside the range of 45% to 95% of labeled content; and at 12 hours none of the units is less than 65% of labeled content at the final test time.
L3 12 The average value of the 24 units (L1 + L2 + L3) lies within each of the stated ranges and is not less than the stated amount at the final test time. At 3 hours not more than 2 of the 24 units are outside the range of 10% to 35% of labeled content, and these two units must be within the range of 5% to 45% of labeled content; at 9 hours not more than 2 of the 24 units are outside the range of 45% to 95% of labeled content, and these two units must be within the range of 35% to 100% of labeled content; at 12 hours not more than 2 of the 24 units are less than 65% of labeled content at the final test time, and these two units cannot be less than 60% of labeled content at the final test time.
test 4— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.
Medium, Apparatus, and Procedure— Proceed as directed under Test 1.
Times: 4, 8, 12, and 24 hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
4 between 10% and 25%
8 between 35% and 60%
12 between 55% and 80%
24 not less than 80%
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.
Procedure— Proceed as directed under Test 1.
Times: 1, 3, and 8 hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 not more than 15%
3 between 45% and 70%
8 not less than 80%
test 10— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 10.
Medium: 0.05 M phosphate buffer, pH 6.5; 900 mL. Prepare the buffer employing the following method. 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.
Apparatus 1: 100 rpm.
Procedure— Proceed as directed under Test 1.
Times: 1, 6, 9, and 24 hours.
Tolerances— The percentages of the labeled amount of C22H26 N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 not more than 10%
6 between 10% and 30%
9 between 34% and 60%
24 not less than 80%
for products labeled for dosing every 24 hours—
test 2— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
Medium, Apparatus, and Procedure— Proceed as directed under Test 1.
Times: 1, 4, 10, and 15 hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 5% and 20%
4 between 30% and 50%
10 between 70% and 90%
15 not less than 80%
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 hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 237 nm on filtered portions of the solution under test, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RS in the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2 O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
6 between 20% and 45%
12 between 25% and 50%
18 between 35% and 70%
24 not less than 70%
30 not less than 85%
test 6— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.
Medium and Procedure— Proceed as directed under Test 1.
Apparatus 1: 100 rpm.
Times: 2, 4, 8, 12, and 16 hours.
Tolerances— The percentages of the labeled amount of C22H26N2 O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
2 not more than 25%
4 between 25% and 50%
8 between 60% and 85%
12 not less than 70%
16 not less than 80%
test 7— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.
Medium: pH 4.2 acetate buffer; 900 mL. Prepare the buffer by employing the following method. Transfer 115 mL of acetic acid to a 10-L volumetric flask, dilute with water to volume, and mix (Solution A). Transfer 165.4 g of anhydrous sodium acetate 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 necessary, with the addition of Solution A or Solution B to a pH of 4.2 ± 0.05.
Apparatus 2: 100 rpm.
Times: 1, 4, 10, and 15 hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 237 nm on filtered portions of the solution under test, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RS in the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2 O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 not more than 10%
4 between 15% and 35%
10 between 65% and 85%
15 not less than 80%
test 8— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8.
Medium, Apparatus, and Procedure— Proceed as directed under Test 1.
Times: 1, 4, 10, and 15 hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 between 5% and 20%
4 between 30% and 50%
10 between 60% and 90%
15 not less than 80%
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 fluid 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 hours.
Times for Medium 2: 2, 12, 18, and 24 hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 237 nm on filtered portions of the solution under test, suitably diluted with the appropriate Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RS in the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
(Medium 1)		 Amount dissolved
(Medium 2)
2 between 0% and 5% between 20% and 45%
12   between 35% and 55%
18   not less than 60%
24   not less than 80%
test 11— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 11.
Medium, Apparatus, and Procedure— Proceed as directed under Test 3.
Times: 1, 6, 12, and 18 hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
1 not more than 10%
6 between 30% and 40%
12 between 36% and 58%
18 not less than 85%
test 12— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 12. Proceed as directed for Extended-Release Dosage Forms.
Medium and Procedure— Proceed as directed under Test 1.
Apparatus 1: 100 rpm.
Times: 2, 8, 14, and 24 hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
2 not more than 20%
8 between 30% and 55%
14 not less than 65%
24 not less than 80%
test 13— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 13. Proceed as directed for Extended-Release Dosage Forms.
Medium and Procedure— Proceed as directed under Test 1.
Apparatus 1: 100 rpm.
Times: 2, 8, 14, and 24 hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
2 not more than 20%
8 between 30% and 55%
14 between 60% and 80%
24 not less than 80%
test 14— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 14. Proceed as directed for Extended-Release Dosage Forms.
Medium, Apparatus, Times, and Procedure— Proceed as directed under Test 3.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
6 between 20% and 45%
12 between 25% and 50%
18 between 35% and 70%
24 not less than 70%
30 not less than 80%
test 15— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 15. Proceed as directed for 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 hours.
Procedure— Proceed as directed under Test 1.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved
2 not more than 25%
4 between 20% and 40%
8 between 60% and 85%
12 not less than 70%
16 not less than 80%
Uniformity of dosage units 905: meet the requirements.
Assay—
Buffer— Dissolve 6.9 g of monobasic potassium phosphate in 1000 mL of water, adjust with 0.1 N hydrochloric acid to a pH of 3.0, add 0.50 mL of triethylamine, and mix.
Mobile phase— Prepare a filtered and degassed mixture of Buffer and acetonitrile (50:50). Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard preparation— Prepare a solution in methanol having an accurately known concentration of about 1.2 mg of USP Diltiazem Hydrochloride RS per mL and a concentration of about 0.02 mg of USP Desacetyl Diltiazem Hydrochloride RS per mL. Pipet a 2.0-mL aliquot of this solution into a 100-mL volumetric flask, dilute with Mobile phase to volume, and mix to obtain a Standard preparation having a known concentration of about 0.024 mg of USP Diltiazem Hydrochloride RS per mL.
Assay preparation— Weigh and mix the contents of not fewer than 20 Capsules. Grind the contents thoroughly, and transfer an accurately weighed portion, equivalent to about 120 mg of diltiazem hydrochloride, to a 100-mL volumetric flask. Add approximately 60 mL of methanol, and shake by mechanical means for 30 minutes. Sonicate the resulting solution for 10 minutes to complete the extraction. Dilute with methanol to volume, and mix. Pipet a 2.0-mL aliquot into a 100-mL volumetric flask, dilute with Mobile phase to volume, mix, and filter.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 240-nm detector and a 4.6-mm × 15-cm column that contains 5-µm packing L7. The flow rate is about 1 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative retention times are about 0.7 for desacetyl diltiazem and 1.0 for diltiazem; the resolution, R, between desacetyl diltiazem and diltiazem is not less than 2.0; and the relative standard deviation for replicate injections is not more than 2.0% for diltiazem.
Procedure— Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of diltiazem hydrochloride (C22 H26N2O4S·HCl) in the portion of Capsules taken by the formula:
5000C(rU / rS)
in which C is the concentration, in mg per mL, of USP Diltiazem Hydrochloride RS in the Standard preparation; and rU and rS are the diltiazem peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Sujatha Ramakrishna, Ph.D.
Senior Scientific Liaison
1-301-816-8349		 (SM22010) Monographs - Small Molecules 2
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
711 Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison
1-301-816-8106		 (GCDF2010) General Chapters - Dosage Forms
USP35–NF30 Page 2917
Pharmacopeial Forum: Volume No. 32(6) Page 1673