Nifedipine Extended-Release Tablets
»Nifedipine Extended-Release Tablets contain not less than 90.0percent and not more than 110.0percent of the labeled amount of nifedipine (C17H18N2O6).
Packaging and storage—
Preserve in tight,light-resistant containers,and store at controlled room temperature.
Labeling—
The labeling indicates the Drug Release Testwith which the product complies.
USP Reference standards á11ñ—
USP Nifedipine RS.USP Nifedipine Nitrophenylpyridine Analog RS.USP Nifedipine Nitrosophenylpyridine Analog RS.
NOTE—Nifedipine,when exposed to daylight and certain wavelengths of artificial light,readily converts to a nitrosophenylpyridine derivative.Exposure to UVlight leads to the formation of a nitrophenylpyridine derivative.Perform assays and tests in the dark or under golden fluorescent or other low-actinic light.Use low-actinic glassware.
Identification—
A:
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.
B:Ultraviolet Absorption á197Uñ—
Solutions—
Prepare a test solution as directed for the Assay preparationin the Assay,except to dilute further with Mobile phaseto obtain a solution having a concentration of about 0.02mg per mL.Prepare the Standard solution as directed for the Standard preparationin the Assayunder Nifedipine,except to dilute further with Mobile phaseto obtain a solution having a known concentration of about 0.02mg per mL.
Drug release á724ñ—
Test 1:
If the product complies with this test,the labeling indicates that the product meets USPDrug Release Test 1.
Medium:
water;50mL.
Apparatus 7—
Do not use the reciprocating disk,but use a 25-cm plexiglas rod,the perimeter of the Tablets being affixed to the rod with a water-insoluble glue.The solution containers are 25-mm test tubes,150to 200mm in length,and the water bath is maintained at 37±0.5
.
.
Times:
4,12,and 24hours.
Diluting solution 1:
a mixture of methanol and acetonitrile (1:1).
Diluting solution 2:
a mixture of Diluting solution 1and water (1:1).
Standard solutions—
Transfer about 50mg of USP Nifedipine RS,accurately weighed,to a 100-mLvolumetric flask;dissolve in 50mLof Diluting solution 1;dilute with water to volume;and mix to obtain a Standard stock solution.Quantitatively dilute this Standard stock solution with Diluting solution 2to obtain solutions having known concentrations of 0.01mg per mL,0.05mg per mL,and 0.20mg per mLthat are used at 4hours,12hours,and 24hours,respectively.
Procedure—
[NOTE—For the 4-hour time period,filter,determine the absorbance at 456nm,and use this determination to correct for excipient interference at the other time periods.]Determine the amount of C17H18N2O6released at each 4-hour interval by employing UVabsorption at the wavelength of maximum absorbance at about 338nm,in 0.5-cm cells.Use test solutions that are suitably diluted,if necessary,with Diluting solution 1and water to obtain a final mixture of water,methanol,and acetonitrile (2:1:1)in comparison with the appropriate Standard solution,using Diluting solution 2as the blank.
Tolerances—
The cumulative percentages of the labeled amount of nifedipine (C17H18N2O6),released in vivo and dissolved at the times specified,conform to Acceptance Table 1.
| Time (hours) | Amount dissolved |
| 4 | between 5%and 17% |
| 12 | between 43%and 80% |
| 24 | not less than 80% |
Test 2:
If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 2.
Buffer concentrate—
Transfer 330.9g of dibasic sodium phosphate and 38g of citric acid to a 1-Lvolumetric flask,add water to dissolve,add 10mLof phosphoric acid,dilute with water to volume,and mix.
Medium—
Mix 125.0mLof Buffer concentrateand 1Lof 10%sodium lauryl sulfate solution,and dilute to 10L.Adjust if necessary to a pHof 6.8;900mL.
Apparatus 2:
50rpm,with sinkers (see Fig.1).
;)
Fig.1(printed with permission of the Japanese Pharmacopoeia)
Times:
3,6,and 12hours.
Determine the amount of nifedipine (C17H18N2O6)dissolved by employing the following method.
Mobile phase—
Prepare a filtered and degassed mixture of acetonitrile and water (70:30).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Standard solution—
Dissolve an accurately weighed quantity of USP Nifedipine RSin methanol to obtain a solution having a known concentration of about 1.11mg per mL.Dilute quantitatively and stepwise with Dissolution Mediumto obtain a solution having a known concentration of 0.1mg per mL.
Chromatographic system—
The liquid chromatograph is equipped with a 350-nm detector and a 4.0-mm ×125-mm column that contains 3-µm packing L1.The flow rate is about 1.5mLper minute.The column temperature is maintained at about 40.Chromatograph the Standard solution,and record the peak responses as directed for Procedure:the column efficiency is not less than 2000theoretical plates;the tailing factor is not more than 1.5;and the relative standard deviation for replicate injections is not more than 2.0%.
.Chromatograph the Standard solution,and record the peak responses as directed for Procedure:the column efficiency is not less than 2000theoretical plates;the tailing factor is not more than 1.5;and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure—
Separately inject equal volumes (about 20µL)of filtered portions of the Standard solutionand the solution under test into the chromatograph,record the chromatograms,and measure the responses for the major peaks.Determine the amount of nifedipine (C17H18N2O6)dissolved.
Tolerances—
The percentages of the labeled amount of nifedipine (C17H18N2O6)released in vivo and dissolved at the times specified conform to Acceptance Table 1.
| Time (hours) | Amount dissolved |
| 3 | between 10%and 30% |
| 6 | between 40%and 65% |
| 12 | not less than 80% |
Test 3:
If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 3.
FOR TABLETS LABELED TO CONTAIN30MG OF NIFEDIPINE—
Phase 1:
Medium:
0.05Mphosphate buffer,pH7.5.
Apparatus 2:
100rpm.
Time:
1hour.
Standard solution—
Prepare a solution in Mediumhaving an accurately known concentration of about 0.034mg of USP Nifedipine RSper mL.If necessary,a volume of methanol,not exceeding 10%of the final volume,can be used to help solubilize nifedipine.
Procedure—
[NOTE—After the run,take the Tablet out of the dissolution vessel,adapt a sinker to it,and transfer the Tablet with the sinker to the dissolution vessel containing the Dissolution Mediumfor Phase 2.]Determine the amount of C17H18N2O6released in Phase 1from UVabsorbances at the wavelength of maximum absorbance at about 238nm using filtered portions of the solution under test,in comparison with the Standard solution,using theDissolution Mediumas the blank.
Phase 2:
Medium:
0.5%sodium lauryl sulfate in simulated gastric fluid without enzyme,pH1.2;900mL.
Apparatus 2:
100rpm.
Times:
1,4,8,and 12hours.
Standard solution—
Prepare a solution in Medium having an accurately known concentration of about 0.034mg of USP Nifedipine RSper mL.If necessary,a volume of methanol,not exceeding 10%of the final volume,can be used to help solubilize nifedipine.
Procedure—
Determine the amount of C17H18N2O6released in Phase 2from UVabsorbances at the wavelength of maximum absorbance at about 238nm using filtered portions of the solution under test,in comparison with the Standard solution,using Dissolution Medium as the blank.
Tolerances—
The cumulative percentages of the labeled amount of nifedipine (C17H18N2O6),released in vivo and dissolved at the times specified,conform to Acceptance Table 1.
| Time (hours) | Amount dissolved* |
| 1 | not more than 30% |
| 4 | between 30%and 55% |
| 8 | not less than 60% |
| 12 | not less than 80% |
|
*
For each dosage unit,add the amount dissolved in phosphate buffer,pH7.5from Phase 1to the amount dissolved at each time point in Phase 2.
|
|
FOR TABLETS LABELED TO CONTAIN60MG OF NIFEDIPINE—
Phase 1:
Medium:
0.05Mphosphate buffer,pH7.5.
Apparatus 2:
100rpm.
Time:
25minutes.
Standard solution—
Prepare a solution in Mediumhaving an accurately known concentration of about 0.067mg of USP Nifedipine RSper mL.If necessary,a volume of methanol,not exceeding 10%of the final volume,can be used to help solubilize nifedipine.
Procedure—
[NOTE—After the run,take the Tablet out of the dissolution vessel,adapt a sinker to it,and transfer the Tablet with the sinker to the dissolution vessel containing the Dissolution Mediumfor Phase 2.]Determine the amount of C17H18N2O6released in Phase 1from UVabsorbances at the wavelength of maximum absorbance at about 238nm using filtered portions of the solution under test,in comparison with the Standard solution,using Dissolution Mediumas the blank.
Phase 2:
Medium:
0.5%sodium lauryl sulfate in simulated gastric fluid without enzyme,pH1.2;900mL.
Apparatus 2:
100rpm.
Times:
1,4,8,and 12hours.
Standard solution—
Prepare a solution in Mediumhaving an accurately known concentration of about 0.067mg of USP Nifedipine RSper mL.If necessary,a volume of methanol,not exceeding 10%of the final volume,can be used to help solubilize nifedipine.
Procedure—
Determine the amount of C17H18N2O6released in Phase 2from UVabsorbances at the wavelength of maximum absorbance at about 238nm using filtered portions of the solution under test,in comparison with the Standard solution,using Dissolution Mediumas the blank.
Tolerances—
The cumulative percentages of the labeled amount of nifedipine (C17H18N2O6),released in vivo and dissolved at the times specified,conform to Acceptance Table 1.
| Time (hours) | Amount dissolved* |
| 1 | not more than 30% |
| 4 | between 40%and 70% |
| 8 | not less than 70% |
| 12 | not less than 80% |
|
*
For each dosage unit,add the amount dissolved in phosphate buffer,pH7.5from Phase 1to the amount dissolved at each time point in Phase 2.
|
|
Test 4:
If the product complies with this test,the labeling indicates that the product meets USPDrug Release Test 4.
Medium:
0.5%sodium lauryl sulfate in simulated gastric fluid without enzyme,pH1.2;900mL.
Apparatus 2:
100rpm.
Times:
1,4,and 12hours.
Standard solution—
Prepare a solution in Mediumhaving an accurately known concentration of about 0.067mg of USP Nifedipine RSper mLfor Tablets labeled to contain 60mg,and of about 0.034mg of USP Nifedipine RSper mLfor Tablets labeled to contain 30mg.If necessary,a volume of methanol,not exceeding 10%of the final volume,can be used to help solubilize nifedipine.
Procedure—
Determine the amount of C17H18N2O6released from UVabsorbances at the wavelength of maximum absorbance at about 238nm using filtered portions of the solution under test,in comparison with the Standard solution,using Dissolution Mediumas the blank.
Tolerances—
The cumulative percentages of the labeled amount of nifedipine (C17H18N2O6),released at the times specified,conform to Acceptance Table 1.
FOR TABLETS LABELED TO CONTAIN30MG OF NIFEDIPINE
| Time (hours) | Amount dissolved |
| 1 | between 12%and 35% |
| 4 | between 44%and 67% |
| 12 | not less than 80% |
FOR TABLETS LABELED TO CONTAIN60MG OF NIFEDIPINE
| Time (hours) | Amount dissolved |
| 1 | between 10%and 30% |
| 4 | between 40%and 63% |
| 12 | not less than 80% |
Uniformity of dosage units á905ñ:
meet the requirements.
Related compounds—
[NOTE—Conduct this test promptly after preparation of the Standard nifedipine solutionand the Test solution.]
Standard nifedipine solution,Reference solution 1,and Reference solution 2—
Prepare as directed in the test for Related compoundsunder Nifedipine,except to obtain solutions having known concentrations of about 6µg per mLand 1.5µg per mLfor Reference solution 1and Reference solution 2,respectively.
System suitability solution—
Mix equal volumes of the Standard nifedipine solution,Reference solution 1,and Reference solution 2.
Standard solution—
Transfer 5.0mLof each Reference solutionto a container,add 5.0mLof Mobile phase,and mix.Each mLof this solution contains about 2µg of USP Nifedipine Nitrophenylpyridine Analog RSand 0.5µg of USP Nifedipine Nitrosophenylpyridine Analog RS.
Test solution—
Use a portion of the Assay preparation.
Chromatographic system (see Chromatography á621ñ)—
Prepare as directed in the Assay.Chromatograph the System suitability solution,and record the peak responses as directed for Procedure:the resolution,R,between nitrophenylpyridine analog and nitrosophenylpyridine analog is not less than 1.5;the resolution,R,between nitrosophenylpyridine analog and nifedipine is not less than 1.0;and for each analog,the relative standard deviation for replicate injections is not more than 10%.
Procedure—
Separately inject equal volumes (about 25µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the percentage of each related compound in the portion of Tablets taken by the formula:
417(C/W)(ri/rS),
in which Cis the concentration,in µg per mL,of the appropriate analog USP Reference Standard in the Standard solution;Wis the weight,in mg,of nifedipine in the Tablets taken to prepare the Test solution;and riand rSare the peak responses of the corresponding related compound obtained from the Test solutionand the Standard solution,respectively:not more than 2.0%of nifedipine nitrophenylpyridine analog and not more than 0.5%of nifedipine nitrosophenylpyridine analog,both relative to the nifedipine content,are found.
Assay—
[NOTE—Conduct the Assaypromptly after preparation of the Standard preparationand the Assay preparation.]
Assay preparation—
Select a number of Tablets,equivalent to about 420mg of nifedipine.Finely powder the Tablets,and transfer the powder to a 250-mLvolumetric flask containing 130mLof water;or transfer the intact Tablets to a 400-mL,high-speed blender cup containing 130mLof water,homogenize until a uniform suspension is achieved (about 2minutes),and transfer the suspension with the aid of a mixture of acetonitrile and methanol (1:1)to a 250-mLvolumetric flask.Add a mixture of acetonitrile and methanol (1:1)to volume,and stir for 30minutes.Centrifuge the resulting suspension to obtain a clear supernatant stock solution.Transfer 3.0mLof the stock solution to a 50-mLvolumetric flask,dilute with Mobile phaseto volume,mix,and filter to obtain a solution having a concentration of about 0.1mg of nifedipine per mL.[NOTE—Reserve a portion of this Assay preparationfor use as the Test solutionin the test for Related compounds.]
Chromatographic system (see Chromatography á621ñ)—
The liquid chromatograph is equipped with a 265-nm detector,a 4.6-mm ×25-cm analytical column that contains packing L1,and a 2.1-mm ×3-cm guard column that contains packing L1.The flow rate is about 1mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the column efficiency is not less than 4000theoretical plates;the tailing factor is not more than 1.5;and the relative standard deviation for replicate injections is not more than 1.0%.
Procedure—
Separately inject equal volumes (about 25µL)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 nifedipine (C17H18N2O6)in the Tablets taken by the formula:
4167C(rU/rS),
in which Cis the concentration,in mg per mL,of USP Nifedipine 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 1377
Pharmacopeial Forum:Volume No.30(4)Page 1269
Phone Number:1-301-816-8305