Identification, Infrared Absorption 
197F
—
Prepare analytical specimens as follows.
Test specimen—
Crush 1 Tablet, and transfer the powder to a volumetric flask of suitable size so that the final concentration is about 1.2 mg of verapamil hydrochloride per mL. Add 0.05 N hydrochloric acid to about 75% of the final volume, and dissolve by heating, with stirring, for 40 minutes. Cool, and dilute with 0.05 N 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 minutes. 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 minutes.
Standard specimen—
Dissolve about 48 mg of
USP Verapamil Hydrochloride RS, accurately weighed, in 25 mL of water. Transfer to a 125-mL separatory funnel, add 2 mL of 1 N sodium hydroxide, and extract with 25 mL of chloroform, shaking for two minutes. Proceed as directed for the
Test specimen, beginning with “Pass the chloroform extract.”
Drug release 724—
Test 1—
If the product complies with this test, the labeling indicates that it meets USP
Drug Release Test 1. Proceed as directed for
Method B under
Delayed-Release (
Enteric-Coated)
Articles—
General Drug Release Standard.
Apparatus 2:
50 rpm.
Times:
Acid stage—1 hour; Buffer stage—2, 3.5, 5, and 8 hours.
Procedure—
Wrap each Tablet in a wire helix to prevent the Tablets from floating. After 1 hour 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.
[NOTE—Use only filters that have been shown not to absorb verapamil.
] Dilute, if necessary, the filtered portions of the solutions under test with water at the 1-hour interval and with 0.1 N hydrochloric acid at the 2-, 3.5-, 5-, and 8-hour intervals. Determine the amounts of C
27H
38N
2O
4·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 278 nm, using 0.01 N hydrochloric acid as the blank, by comparison with a Standard solution having a known concentration of
USP Verapamil Hydrochloride RS in 0.01 N hydrochloric acid.
Tolerances—
The percentage of the labeled amount of C
27 H
38N
2O
4·HCl dissolved at the times specified conforms to
Acceptance Table 1.
FOR PRODUCTS LABELED TO CONTAIN 180 MG OR 240 MG:
| Time (hours) |
 Amount dissolved |
| 1 |
between 7% and 15% |
| 2 |
between 16% and 30% |
| 3.5 |
between 31% and 50% |
| 5 |
between 51% and 75% |
| 8 |
not less than 85% |
FOR PRODUCTS LABELED TO CONTAIN 120 MG:
| Time (hours) |
Amount dissolved |
| 1 |
between 10% and 21% |
| 2 |
between 18% and 33% |
| 3.5 |
between 35% and 60% |
| 5 |
between 50% and 82% |
| 8 |
not less than 85% |
Test 2—
If the product complies with this test, the labeling indicates that it meets USP
Drug Release Test 2. Proceed as directed for
Test 1, except that under
Procedure, the Tablet is not required to be wrapped in a wire helix.
Times and Tolerances:
FOR PRODUCTS LABELED TO CONTAIN 240 MG:
| Time (hours) |
Amount dissolved |
| 1 |
between 8% and 20% |
| 2 |
between 15% and 35% |
| 3.5 |
between 35% and 65% |
| 5 |
between 55% and 85% |
| 8 |
not less than 80% |
FOR PRODUCTS LABELED TO CONTAIN 180 MG:
| Time (hours) |
Amount dissolved |
| 1 |
between 10% and 25% |
| 2 |
between 20% and 40% |
| 3.5 |
between 40% and 75% |
| 8 |
not less than 80% |
Test 3—
If the product complies with this test, the labeling indicates that it meets USP
Drug Release Test 3. Proceed as directed for
Test 1.
Times and Tolerances:
| Time (hours) |
Amount dissolved |
| 1 |
between 8% and 20% |
| 2 |
between 15% and 35% |
| 3.5 |
between 27% and 57% |
| 5 |
between 45% and 75% |
| 8 |
not less than 80% |
Test 4—
If the product complies with this test, the labeling indicates that it meets USP
Drug Release Test 4.
Phosphate buffer solution—
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, dilute with water to 1000 mL, and mix.
Medium: Phosphate buffer solution;
50 mL.
Apparatus 7:
20 cycles per minute.
Procedure—
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 to 30 cycles per minute. 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 then dilute with water to 50 mL. Stir and mix each tube thoroughly. Determine the amount of C
27H
38N
2O
4·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 278 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 Verapamil Hydrochloride RS in the same
Medium.
Times and Tolerances—
The percentages of the labeled amount of C
27H
38N
2O
4·HCl dissolved at the times specified conform to
Acceptance Table 1.
| Time (hours) |
Amount dissolved |
| 3 |
not more than 10% |
| 6 |
between 20% and 50% |
| 9 |
between 52.5% and 82.5% |
| 14 |
not less than 85% |
Test 5—
If the product complies with this test, the labeling indicates that it meets USP
Drug Release Test 5.
Phosphate buffer solution—
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, dilute with water to 1000 mL, and mix.
Medium: Phosphate buffer solution;
900 mL.
Apparatus 2:
50 rpm.
Procedure—
Determine the amount of C
27H
38N
2O
4·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 278 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 Verapamil Hydrochloride RS in the same
Medium.
Times and Tolerances—
The percentages of the labeled amount of C
27H
38N
2O
4·HCl dissolved at the times specified conform to
Acceptance Table 1.
| Time (hours) |
Amount dissolved |
| 1 |
between 2% and 12% |
| 2 |
between 10% and 25% |
| 4 |
between 25% and 50% |
| 8 |
not less than 80% |
Dissolution 711—
Test 1—
If the product complies with this test, the labeling indicates that it meets USP
Dissolution Test 1. Proceed as directed for
Procedure for
Method B under
Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms.
Apparatus 2:
50 rpm.
Times:
Acid stage—1 hour; Buffer stage—2, 3.5, 5, and 8 hours.
Procedure—
Wrap each Tablet in a wire helix to prevent the Tablets from floating. After 1 hour 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.
[NOTE—Use only filters that have been shown not to absorb verapamil.
] Dilute, if necessary, the filtered portions of the solutions under test with water at the 1-hour interval and with 0.1 N hydrochloric acid at the 2-, 3.5-, 5-, and 8-hour intervals. Determine the amounts of C
27H
38N
2O
4·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 278 nm, using 0.01 N hydrochloric acid as the blank, by comparison with a Standard solution having a known concentration of
USP Verapamil Hydrochloride RS in 0.01 N hydrochloric acid.
Tolerances—
The percentage of the labeled amount of C
27 H
38N
2O
4·HCl dissolved at the times specified conforms to
Acceptance Table 2.
FOR PRODUCTS LABELED TO CONTAIN 180 MG OR 240 MG:
| Time (hours) |
Amount dissolved |
| 1 |
between 7% and 15% |
| 2 |
between 16% and 30% |
| 3.5 |
between 31% and 50% |
| 5 |
between 51% and 75% |
| 8 |
not less than 85% |
FOR PRODUCTS LABELED TO CONTAIN 120 MG:
| Time (hours) |
Amount dissolved |
| 1 |
between 10% and 21% |
| 2 |
between 18% and 33% |
| 3.5 |
between 35% and 60% |
| 5 |
between 50% and 82% |
| 8 |
not less than 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
Procedure, the Tablet is not required to be wrapped in a wire helix.
Times and Tolerances—
The percentage of the labeled amount of C
27H
38N
2O
4·HCl dissolved at the times specified conforms to
Acceptance Table 2.
FOR PRODUCTS LABELED TO CONTAIN 240 MG:
| Time (hours) |
Amount dissolved |
| 1 |
between 8% and 20% |
| 2 |
between 15% and 35% |
| 3.5 |
between 35% and 65% |
| 5 |
between 55% and 85% |
| 8 |
not less than 80% |
FOR PRODUCTS LABELED TO CONTAIN 180 MG:
| Time (hours) |
Amount dissolved |
| 1 |
between 10% and 25% |
| 2 |
between 20% and 40% |
| 3.5 |
between 40% and 75% |
| 8 |
not less than 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 C
27H
38N
2O
4·HCl dissolved at the times specified conforms to
Acceptance Table 2.
| Time (hours) |
Amount dissolved |
| 1 |
between 8% and 20% |
| 2 |
between 15% and 35% |
| 3.5 |
between 27% and 57% |
| 5 |
between 45% and 75% |
| 8 |
not less than 80% |
Test 4—
If the product complies with this test, the labeling indicates that it meets USP
Dissolution Test 4.
Phosphate buffer solution—
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, dilute with water to 1000 mL, and mix.
Medium:
Phosphate buffer solution; 50 mL.
Procedure—
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 to 30 cycles per minute. 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 C
27H
38N
2O
4·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 278 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 Verapamil Hydrochloride RS in the same
Medium.
Times and Tolerances—
The percentages of the labeled amount of C
27H
38N
2O
4·HCl dissolved at the times specified conform to
Acceptance Table 2.
| Time (hours) |
Amount dissolved |
| 3 |
not more than 10% |
| 6 |
between 20% and 50% |
| 9 |
between 52.5% and 82.5% |
| 14 |
not less than 85% |
Test 5—
If the product complies with this test, the labeling indicates that it meets USP
Dissolution Test 5.
Phosphate buffer solution—
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, dilute with water to 1000 mL, and mix.
Medium:
Phosphate buffer solution; 900 mL.
Apparatus 2:
50 rpm.
Procedure—
Determine the amount of C
27H
38N
2O
4·HCl dissolved by employing UV absorption at the wavelength of maximum absorbance at about 278 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 Verapamil Hydrochloride RS in the same
Medium.
Times and Tolerances—
The percentages of the labeled amount of C
27H
38N
2O
4·HCl dissolved at the times specified conform to
Acceptance Table 2.
| Time (hours) |
Amount dissolved |
| 1 |
between 2% and 12% |
| 2 |
between 10% and 25% |
| 4 |
between 25% and 50% |
| 8 |
not less than 80% |
(Official April 1, 2006)
Chromatographic purity—
Buffer solution, Mobile phase, Standard preparation, System suitability solution, and Chromatographic system—
Proceed as directed in the
Assay.
Procedure—
Proceed as directed for
Procedure in the
Assay. Calculate the percentage of each impurity in the portion of Tablets taken by the formula:
100(ri / rs),
in which
ri is the peak response for each impurity, and
rs is the sum of the responses of all of the peaks: not more than 0.5% of any individual impurity is found, and the sum of all impurities is not more than 1.0%.
Assay—
Buffer solution—
Transfer 0.82 g of sodium acetate to a 1000-mL volumetric flask, add 33 mL of glacial acetic acid, dilute with water to volume, and mix.
Mobile phase—
Prepare a filtered and degassed mixture of
Buffer solution, acetonitrile, and 2-aminoheptane (70:30:0.5). Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Standard preparation—
Dissolve an accurately weighed quantity of
USP Verapamil Hydrochloride RS in
Mobile phase, and dilute quantitatively, and stepwise if necessary, with
Mobile phase to obtain a solution having a known concentration of about 1.2 mg per mL.
Assay preparation—
Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 240 mg of verapamil hydrochloride, to a 200-mL volumetric flask, and add about 160 mL of Mobile phase. Sonicate for 15 minutes, stir for 15 minutes, dilute with Mobile phase to volume, and mix. Centrifuge a portion for 20 minutes, and use as the Assay preparation.
Chromatographic system
(see
Chromatography 621)—The liquid chromatograph is equipped with a 278-nm detector and a 4.6-mm × 15-cm column that contains packing L1. The flow rate is about 1.0 mL per minute. Chromatograph the
System suitability solution, and record the peak responses as directed for
Procedure: the resolution,
R, between verapamil and verapamil related compound B is not less than 1.5. Chromatograph the
Standard preparation, and record the peak responses as directed for
Procedure: the relative standard deviation for replicate injections is not more than 2.0%.
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 verapamil hydrochloride (C
27H
38N
2O
4·HCl) in the portion of Tablets taken by the formula:
200C(rU / rS),
in which
C is the concentration, in mg per mL, of
USP Verapamil Hydrochloride RS in the
Standard preparation; and
rU and
rS are the peak responses obtained from the
Assay preparation and the
Standard preparation, respectively.
