Diltiazem Hydrochloride Extended-Release Capsules
»Diltiazem Hydrochloride Extended-Release Capsules contain not less than 90.0percent and not more than 110.0percent of the labeled amount of diltiazem hydrochloride (C22H26N2O4S·HCl).
Packaging and storage— Preserve in tight containers.
Labeling— The labeling indicates the Drug Release Testwith which the product complies.
Identification—
A: Transfer 17.4g of ammonium thiocyanate and 2.8g of cobalt chloride to a 100-mLvolumetric flask,add about 50mLof water,and sonicate for 10minutes.Dilute with water to volume,and mix (Indicator solution).Grind the contents of 1Capsule,and transfer to a 15-mLscrew-capped test tube.Add 10mLof 0.1Nhydrochloric acid,shake,and filter.Add 2mLof Indicator solutionto 2mLof the filtrate,and shake.Add 5mLof 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 preparationcorresponds to that in the chromatogram of the Standard preparation,as obtained in the Assay.
Drug release á724ñ—
FORPRODUCTS LABELED FOR DOSING EVERY12HOURS—
Test 1: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 1.Proceed as directed for Extended-Release Articles—General Drug Release Standard á724ñ.
Medium: water;900mL.
Apparatus 2: 100rpm.
Times: 3,9,and 12hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 237nm on filtered portions of the solution under test,suitably diluted with Dissolution Medium,if necessary,in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RSin the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to the Acceptance Tablegiven.
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 12units (L1+L2)lies within each of the stated ranges and is not less than the stated amount at the final test time.At 3hours none of the units is outside the range of 10%to 35%of labeled content;at 9hours none of the units is outside the range of 45%to 95%of labeled content;and at 12hours none of the units is less than 65%of labeled content at the final test time.
L3 12 The average value of the 24units (L1+L2+L3)lies within each of the stated ranges and is not less than the stated amount at the final test time.At 3hours not more than 2of the 24units 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 9hours not more than 2of 24of the 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 12hours not more than 2of the 24units 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 USPDrug Release Test 4.
Medium,Apparatus,andProcedure— Proceed as directed under Test 1.
Times: 4,8,12,and 24hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 5.
Medium: 0.05Mphosphate buffer,pH7.2;900mL.
Apparatus 2: 50rpm.
Procedure— Proceed as directed under Test 1.
Times: 1,3,and 8hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 10.
Medium: 0.05Mphosphate buffer,pH6.5;900mL.Prepare the buffer employing the following method.Dissolve 7.1g of anhydrous dibasic sodium phosphate in 1000mLof water,and adjust with phosphoric acid to a pHof 6.5.
Apparatus 1: 100rpm.
Procedure— Proceed as directed under Test 1.
Times: 1,6,9,and 24hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
Time (hours) Amount dissolved
1 not more than 10%
6 between 10%and 30%
9 between 34%and 60%
24 not less than 80%
FORPRODUCTS LABELED FOR DOSING EVERY24HOURS—
Test 2: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 2.
Medium,Apparatus,and Procedure— Proceed as directed under Test 1.
Times: 1,4,10,and 15hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 3.
Medium: 0.1Nhydrochloric acid;900mL.
Apparatus 2: 100rpm.
Times: 6,12,18,24,and 30hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 237nm on filtered portions of the solution under test,suitably diluted with Dissolution Medium,if necessary,in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RSin the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 6.
Medium and Procedure— Proceed as directed under Test 1.
Apparatus 1: 100rpm.
Times: 2,4,8,12,and 16hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 7.
Medium: pH4.2acetate buffer;900mL.Prepare the buffer by employing the following method.Transfer 115mLof acetic acid to a 10-liter volumetric flask,dilute with water to volume,and mix (Solution A).Transfer 165.4g of anhydrous sodium acetate to a 10-liter volumetric flask,dilute with water to volume,and mix (Solution B).Mix 4410mLof Solution Awith 1590mLof Solution B.Adjust,if necessary,with the addition of Solution Aor Solution Bto a pHof 4.2±0.05.
Apparatus 2: 100rpm.
Times: 1,4,10,and 15hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 237nm on filtered portions of the solution under test,suitably diluted with Dissolution Medium,if necessary,in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RSin the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 8.
Medium,Apparatus,andProcedure— Proceed as directed under Test 1.
Times: 1,4,10,and 15hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 9.
NOTE—Perform the test separately in each of the two media.
Medium 1: 0.1Nhydrochloric acid;900mL.
Medium 2: simulated intestinal fluid TS,prepared without enzyme and adjusted to a pHof 7.5±0.1;900mL.
Apparatus 2: 75rpm.
Time for Medium 1: 2hours.
Times for Medium 2: 2,12,18,and 24hours.
Procedure— Determine the amount of C22H26N2O4S·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 237nm on filtered portions of the solution under test,suitably diluted with the appropriate Dissolution Medium,if necessary,in comparison with a Standard solution having a known concentration of USP Diltiazem Hydrochloride RSin the same Medium.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1.
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 USPDrug Release Test 11.
Medium,Apparatus,andProcedure— Proceed as directed under Test 3.
Times: 1,6,12,and 18hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 12.Proceed as directed for Extended-Release Articles—General Drug Release Standard á724ñ.
Medium andProcedure— Proceed as directed under Test 1.
Apparatus 1: 100rpm.
Times: 2,8,14,and 24hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
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 USPDrug Release Test 13.Proceed as directed for Extended-Release Articles—General Drug Release Standard á724ñ.
Medium andProcedure— Proceed as directed under Test 1.
Apparatus 1: 100rpm.
Times: 2,8,14,and 24hours.
Tolerances— The percentages of the labeled amount of C22H26N2O4S·HCl dissolved at the times specified conform to Acceptance Table 1under Drug Release á724ñ.
Time (hours) Amount dissolved
2 not more than 20%
8 between 30%and 55%
14 between 60%and 80%
24 not less than 80%
Uniformity of dosage units á905ñ: meet the requirements.
Assay—
Buffer— Dissolve 6.9g of monobasic potassium phosphate in 1000mLof water,adjust with 0.1Nhydrochloric acid to a pHof 3.0,add 0.50mLof triethylamine,and mix.
Mobile phase— Prepare a filtered and degassed mixture of Bufferand acetonitrile (50:50).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Standard preparation— Prepare a solution in methanol having an accurately known concentration of about 1.2mg of USP Diltiazem Hydrochloride RSper mLand a concentration of about 0.02mg of USP Desacetyl Diltiazem Hydrochloride RSper mL.Pipet a 2.0-mLaliquot of this solution into a 100-mLvolumetric flask,dilute with Mobile phaseto volume,and mix to obtain a Standard preparationhaving a known concentration of about 0.024mg of USP Diltiazem Hydrochloride RSper mL.
Assay preparation— Weigh and mix the contents of not fewer than 20Capsules.Grind the contents thoroughly,and transfer an accurately weighed portion,equivalent to about 120mg of diltiazem hydrochloride,to a 100-mLvolumetric flask.Add approximately 60mLof methanol,and shake by mechanical means for 30minutes.Sonicate the resulting solution for 10minutes to complete the extraction.Dilute with methanol to volume,and mix.Pipet a 2.0-mLaliquot into a 100-mLvolumetric flask,dilute with Mobile phaseto volume,mix,and filter.
Chromatographic system (see Chromatography á621ñ)— 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 1mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the relative retention times are about 0.7for desacetyl diltiazem and 1.0for 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 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of C22H26N2O4S·HCl in the portion of Capsules taken by the formula:
5000C(rU/rS),
in which Cis the concentration,in mg per mL,of USP Diltiazem Hydrochloride RSin the Standard preparation,and rUand rSare the diltiazem peak responses obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(PA5)Pharmaceutical Analysis 5
USP28–NF23Page 655
Pharmacopeial Forum:Volume No.30(2)Page 478
Phone Number:1-301-816-8305