Verapamil Hydrochloride Extended-Release Tablets
»Verapamil Hydrochloride Extended-Release Tablets contain not less than 90.0percent and not more than 110.0percent of the labeled amount of verapamil hydrochloride (C27H38N2O4·HCl).
Packaging and storage—
Preserve in tight,light-resistant containers.
Labeling—
The labeling indicates the Drug Release Testwith which the product complies.
Identification,Infrared Absorption á197Fñ—
Prepare analytical specimens as follows.
Test specimen—
Crush 1Tablet,and transfer the powder to a volumetric flask of suitable size so that the final concentration is about 1.2mg of verapamil hydrochloride per mL.Add 0.05Nhydrochloric acid to about 75%of the final volume,and dissolve by heating,with stirring,for 40minutes.Cool,and dilute with 0.05Nhydrochloric acid to volume.Filter,and transfer 40mLof the filtrate to a 125-mLseparatory funnel.Add 4mLof 1Nsodium hydroxide,and extract with 20mLof chloroform,shaking for two minutes.Pass the chloroform extract through a filter containing anhydrous sodium sulfate,and collect the filtrate in a porcelain dish.Rinse with an additional 10mLof 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 30minutes.
for 30minutes.
Standard specimen—
Dissolve about 48mg of USP Verapamil Hydrochloride RS,accurately weighed,in 25mLof water.Transfer to a 125-mLseparatory funnel,add 2mLof 1Nsodium hydroxide,and extract with 25mLof chloroform,shaking for two minutes.Proceed as directed for the Test specimenbeginning with “Pass the chloroform extract.”
Drug release á724ñ—
Test 1—
If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 1.Proceed as directed for Method Bunder Delayed-Release(Enteric-Coated)Articles—General Drug Release Standard.
Acid stage—
Using 900mLof simulated gastric fluid TS(without enzyme),conduct this stage of the test for 1hour.
Buffer stage—
Using 900mLof simulated intestinal fluid TS(without enzyme),conduct this stage of the test for 7hours.
Apparatus 2:
50rpm.
Times:
Acid stage—1hour;Buffer stage—2hours,3.5hours,5hours,and 8hours.
Procedure—
Wrap each Tablet in a wire helix to prevent the Tablets from floating.After 1hour 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 stagemedium,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 0.1Nhydrochloric acid at the 2-,3.5-,5-,and 8-hour intervals.Determine the amounts of C27H38N2O4·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 278nm,using 0.01Nhydrochloric acid as the blank,by comparison with a Standard solution having a known concentration of USP Verapamil Hydrochloride RSin 0.01Nhydrochloric acid.
.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 0.1Nhydrochloric acid at the 2-,3.5-,5-,and 8-hour intervals.Determine the amounts of C27H38N2O4·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 278nm,using 0.01Nhydrochloric acid as the blank,by comparison with a Standard solution having a known concentration of USP Verapamil Hydrochloride RSin 0.01Nhydrochloric acid.
Tolerances—
The percentage of the labeled amount of C27H38N2O4·HCl dissolved at the times specified conforms to Acceptance Table 1.
FOR PRODUCTS LABELED TO CONTAIN180MG OR240MG:
| 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 CONTAIN120MG:
| 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 USPDrug 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.
Timesand Tolerances:
FOR PRODUCTS LABELED TO CONTAIN240MG:
| 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 CONTAIN180MG:
| 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 USPDrug Release Test 3.Proceed as directed for Test 1.
Timesand 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 USPDrug Release Test 4.
Phosphate buffer solution—
Dissolve 6.8g of monobasic potassium phosphate in 250mLof water.Add 190mLof 0.2Nsodium hydroxide in 400mLof water,adjust with 0.2Nsodium hydroxide to a pHof 7.5±0.1,dilute with water to 1000mL,and mix.
Medium:Phosphate buffer solution;
50mL.
Apparatus 7:
20cycles per minute.
Procedure—
Scrape about 2mm ×2mm 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 2cm and 15to 30cycles per minute.The tablet is continuously immersed in tubes containing 50mLof Mediumat 37.At the end of each specified test interval,the systems are transferred to the next row of new test tubes containing 50mLof fresh Medium.Remove the tubes after the last test interval and allow them to cool to room temperature.Add 2.0mLof 1.0Mphosphoric acid to each tube and then dilute with water to 50mL.Stir and mix each tube thoroughly.Determine the amount of C27H38N2O4·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 278nm 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 RSin the same Medium.
.At the end of each specified test interval,the systems are transferred to the next row of new test tubes containing 50mLof fresh Medium.Remove the tubes after the last test interval and allow them to cool to room temperature.Add 2.0mLof 1.0Mphosphoric acid to each tube and then dilute with water to 50mL.Stir and mix each tube thoroughly.Determine the amount of C27H38N2O4·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 278nm 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 RSin the same Medium.
Timesand Tolerances—
The percentages of the labeled amount of C27H38N2O4·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 USPDrug Release Test 5.
Phosphate buffer solution—
Dissolve 6.8g of monobasic potassium phosphate in 250mLof water.Add 190mLof 0.2Nsodium hydroxide in 400mLof water,adjust with 0.2Nsodium hydroxide to a pHof 7.5±0.1,dilute with water to 1000mL,and mix.
Medium:Phosphate buffer solution;
900mL.
Apparatus 2:
50rpm.
Procedure—
Determine the amount of C27H38N2O4·HCl dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 278nm 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 RSin the same Medium.
Timesand Tolerances—
The percentages of the labeled amount of C27H38N2O4·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% |
Uniformity of dosage units á905ñ:
meet the requirements.
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 Procedurein the Assay.Calculate the percentage of each impurity in the portion of Tablets taken by the formula:
100(ri/rs),
in which riis the peak response for each impurity,and rsis 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 0.82g of sodium acetate to a 1000-mLvolumetric flask,add 33mLof 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 Suitabilityunder Chromatography á621ñ).
Standard preparation—
Dissolve an accurately weighed quantity of USP Verapamil Hydrochloride RSin Mobile phase,and dilute quantitatively,and stepwise if necessary,with Mobile phaseto obtain a solution having a known concentration of about 1.2mg per mL.
System suitability solution—
Dissolve suitable quantities of USP Verapamil Hydrochloride RSand USP Verapamil Related Compound B RSin Mobile phaseto obtain a solution containing about 2.5and 2.0mg per mL,respectively.
Assay preparation—
Weigh and finely powder not fewer than 20Tablets.Transfer an accurately weighed portion of the powder,equivalent to about 240mg of verapamil hydrochloride,to a 200-mLvolumetric flask,and add about 160mLof Mobile phase.Sonicate for 15minutes,stir for 15minutes,dilute with Mobile phaseto volume,and mix.Centrifuge a portion for 20minutes,and use as the Assay preparation.
Chromatographic system
(see Chromatography á621ñ)—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 1.0mLper minute.Chromatograph the System suitability solution,and record the peak responses as directed for Procedure:the resolution,R,between verapamil and verapamil related compound Bis 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 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 verapamil hydrochloride (C27H38N2O4·HCl)in the portion of Tablets taken by the formula:
200C(rU/rS),
in which Cis the concentration,in mg per mL,of USP Verapamil Hydrochloride RSin the Standard preparation;and rUand rSare the 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 2019
Phone Number:1-301-816-8305