Verapamil Hydrochloride Extended-Release Tablets
DEFINITION
Verapamil Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of verapamil hydrochloride (C27H38N2O4·HCl).
IDENTIFICATION
• Infrared Absorption 
197F
197F
Standard:
1.92 mg/mL of USP Verapamil Hydrochloride RS, in water. Transfer 25 mL of this solution to a 125-mL separatory funnel. Add 2 mL of 1 N sodium hydroxide, and extract with 25 mL of chloroform, shaking for 2 min. Pass the chloroform extract through a filter containing anhydrous sodium sulfate, and collect the filtrate in a porcelain dish. Rinse with an additional 10 mL of chloroform, collecting the rinsing in the same porcelain dish. Evaporate on a steam bath with the aid of a current of air to dryness, and dry the oily residue at 105
for 30 min.
for 30 min.
Sample:
1.2 mg/mL of Verapamil Hydrochloride in 50 mM hydrochloric acid, prepared as follows: crush 1 Tablet, and transfer the powder to a volumetric flask of suitable size. Add 50 mM hydrochloric acid to about 75% of the final volume, and dissolve by heating, with stirring, for 40 min. Cool, and dilute with 50 mM hydrochloric acid to volume. Filter, and transfer 40 mL of the filtrate to a 125-mL separatory funnel. Add 4 mL of 1 N sodium hydroxide, and extract with 20 mL of chloroform, shaking for 2 min. Pass the chloroform extract through a filter containing anhydrous sodium sulfate, and collect the filtrate in a porcelain dish. Rinse with an additional 10 mL of chloroform, collecting the rinsing in the same porcelain dish. Evaporate on a steam bath with the aid of a current of air to dryness, and dry the oily residue at 105 for 30 min.
for 30 min.
Acceptance criteria:
Meets the requirements
ASSAY
• Procedure
Solution A:
To 0.82 g of sodium acetate add 33 mL of glacial acetic acid, and dilute with water to 1000 mL.
Mobile phase:
Acetonitrile, 2-aminoheptane, and Solution A (60:1:140)
System suitability solution:
2.5 mg/mL of USP Verapamil Hydrochloride RS and 2.0 mg/mL of USP Verapamil Related Compound B RS in Mobile phase
Standard solution:
1.2 mg/mL of USP Verapamil Hydrochloride RS in Mobile phase
Sample solution:
Transfer an equivalent to 240 mg of verapamil hydrochloride, from powdered Tablets (NLT 20), to a 200-mL volumetric flask, and add about 160 mL of Mobile phase. Sonicate for 15 min, stir for 15 min, dilute with Mobile phase to volume, and mix. Centrifuge a portion for 20 min, and use the supernatant as the Sample solution.
Chromatographic system
Mode:
LC
Detector:
UV 278 nm
Column:
4.6-mm × 15-cm; packing L1
Flow rate:
1 mL/min
Injection size:
10 µL
System suitability
Samples:
Standard solution and System suitability solution
Suitability requirements
Resolution:
NLT 1.5 between verapamil and verapamil related compound B, System suitability solution
Relative standard deviation:
NMT 2.0%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C27H38N2O4·HCl in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Verapamil Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = concentration of verapamil hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 711
711
Test 1:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 1. Proceed as directed for Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms, Method B, Procedure.
Acid stage:
Using 900 mL of simulated gastric fluid TS (without enzyme), conduct this stage of the test for 1 h.
Buffer stage:
Using 900 mL of simulated intestinal fluid TS (without enzyme), conduct this stage of the test for 7 h.
Apparatus 2:
50 rpm
Times:
Acid stage: 1 h; Buffer stage: 2, 3.5, 5, and 8 h.
Analysis:
Wrap each Tablet in a wire helix to prevent the Tablets from floating. After 1 h in the Acid stage, withdraw a specimen for analysis, and carefully transfer the dosage form, including the wire helix, to a vessel containing the Buffer stage medium, which has been previously warmed to 37 ± 0.5. Filter a portion of the solution under test at each time interval, using a suitable glass microfiber filter paper. Dilute, if necessary, the filtered portions of the solutions under test with water at the 1-h interval and with 0.1 N hydrochloric acid at the 2-, 3.5-, 5-, and 8-h intervals. Determine the amounts of C27H38N2O4·HCl dissolved for the filtered portions of the solution under test, using 0.01 N hydrochloric acid as the blank.
. Filter a portion of the solution under test at each time interval, using a suitable glass microfiber filter paper. Dilute, if necessary, the filtered portions of the solutions under test with water at the 1-h interval and with 0.1 N hydrochloric acid at the 2-, 3.5-, 5-, and 8-h intervals. Determine the amounts of C27H38N2O4·HCl dissolved for the filtered portions of the solution under test, using 0.01 N hydrochloric acid as the blank.
[Note—Use only filters that have been shown not to absorb verapamil. ]
Detector:
UV 278 nm
Standard solution:
USP Verapamil Hydrochloride RS in 0.01 N hydrochloric acid
Sample solution:
Sample per Dissolution 711.
711.
Tolerances:
The percentage of the labeled amount of C27H38N2O4·HCl dissolved at the times specified conforms to Acceptance Table 2.
For Products Labeled to Contain 180 or 240 mg
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 7%–15% |
| 2 | 16%–30% |
| 3.5 | 31%–50% |
| 5 | 51%–75% |
| 8 | NLT 85% |
For Products Labeled to Contain 120 mg
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 10%–21% |
| 2 | 18%–33% |
| 3.5 | 35%–60% |
| 5 | 50%–82% |
| 8 | NLT 85% |
Test 2:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2. Proceed as directed for Test 1, except that under Analysis, the Tablet is not required to be wrapped in a wire helix.
Times and Tolerances:
The percentage of the labeled amount of C27H38N2O4·HCl dissolved at the times specified conforms to Acceptance Table 2.
For Products Labeled to Contain 240 mg
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 8%–20% |
| 2 | 15%–35% |
| 3.5 | 35%–65% |
| 5 | 55%–85% |
| 8 | NLT 80% |
For Products Labeled to Contain 180 mg
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 10%–25% |
| 2 | 20%–40% |
| 3.5 | 40%–75% |
| 8 | NLT 80% |
For Products Labeled to Contain 120 mg
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 10%–25% |
| 2 | 20%–40% |
| 3.5 | 35%–70% |
| 5 | 55%–85% |
| 8 | NLT 80% |
Test 3:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3. Proceed as directed for Test 1.
Times and Tolerances:
The percentage of the labeled amount of C27H38N2O4·HCl dissolved at the times specified conforms to Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 8%–20% |
| 2 | 15%–35% |
| 3.5 | 27%–57% |
| 5 | 45%–75% |
| 8 | NLT 80% |
Test 4:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.
Medium:
Simulated intestinal fluid TS (without enzyme); 50 mL
Apparatus 7:
20 cycles/min (see Drug Release 724)
724)
Detector:
UV 278 nm
Standard solution:
USP Verapamil Hydrochloride RS in Medium
Analysis:
Scrape about 2 mm × 2 mm of the coating from the side edge of the Tablet under test. Glue the system to a plastic rod sample holder at the area where the color has been removed. Attach each plastic sample holder to an arm of the apparatus, which reciprocates at an amplitude of about 2 cm and 15–30 cycles/min. The Tablet is continuously immersed in tubes containing 50 mL of Medium at 37. At the end of each specified test interval, the systems are transferred to the next row of new test tubes containing 50 mL of fresh Medium. Remove the tubes after the last test interval, and allow them to cool to room temperature. Add 2.0 mL of 1.0 M phosphoric acid to each tube, and dilute with water to 50 mL. Stir and mix each tube thoroughly. Determine the amount of C27H38N2O4·HCl dissolved for the filtered portions of the solution under test, suitably diluted with Medium.
. At the end of each specified test interval, the systems are transferred to the next row of new test tubes containing 50 mL of fresh Medium. Remove the tubes after the last test interval, and allow them to cool to room temperature. Add 2.0 mL of 1.0 M phosphoric acid to each tube, and dilute with water to 50 mL. Stir and mix each tube thoroughly. Determine the amount of C27H38N2O4·HCl dissolved for the filtered portions of the solution under test, suitably diluted with Medium.
Times and Tolerances:
The percentages of the labeled amount of C27H38N2O4·HCl dissolved at the times specified conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 3 | NMT 10% |
| 6 | 20%–50% |
| 9 | 52.5%–82.5% |
| 14 | NLT 85% |
Test 5:
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.
Phosphate buffer:
Dissolve 6.8 g of monobasic potassium phosphate in 250 mL of water. Add 190 mL of 0.2 N sodium hydroxide in 400 mL of water, adjust with 0.2 N sodium hydroxide to a pH of 7.5 ± 0.1, and dilute with water to 1000 mL.
Medium:
Phosphate buffer; 900 mL
Apparatus 2:
50 rpm.
Detector:
UV 278 nm
Sample solution:
Sample per Dissolution 711.
711.
Standard solution:
USP Verapamil Hydrochloride RS in Medium
Analysis:
Determine the amount of C27H38N2O4·HCl dissolved for the filtered portions of the solution under test, suitably diluted with Medium.
Times and Tolerances:
The percentages of the labeled amount of C27H38N2O4·HCl dissolved at the times specified conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 2%–12% |
| 2 | 10%–25% |
| 4 | 25%–50% |
| 8 | NLT 80% |
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
Solution A, Mobile phase, Standard solution, System suitability solution, Sample solution, Chromatographic system, and System suitability:
Proceed as directed in the Assay.
Analysis
Sample:
Sample solution
Calculate the percentage of each impurity in the portion of Tablets taken:
Result = (rU/rT) × 100
| rU | = | = peak response for each impurity from the Sample solution |
| rT | = | = sum of the responses for all peaks from the Sample solution |
Acceptance criteria
Individual impurities:
NMT 0.5% each
Total impurities:
NMT 1.0%
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight, light-resistant containers.
• Labeling:
The labeling indicates the Dissolution Test with which the product complies.
• USP Reference Standards 11
11
USP Verapamil Hydrochloride RS 
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USP Verapamil Related Compound B RS
Benzeneacetonitrile,
-[2-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]ethyl]-3,4-dimethoxy--(1-methylethyl)-, monohydrochloride.
C26H36N2O4·HCl 477.05
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Benzeneacetonitrile,
-[2-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]ethyl]-3,4-dimethoxy--(1-methylethyl)-, monohydrochloride.
C26H36N2O4·HCl 477.05
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 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 5015
Pharmacopeial Forum: Volume No. 33(4) Page 683