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
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.
Acceptance Table
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.
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.
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.
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.
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.
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.
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.
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.
test 9
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 9.
[notePerform 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.
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.
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.
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.
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.
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.
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
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USP35NF30 Page 2917
Pharmacopeial Forum: Volume No. 32(6) Page 1673
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