Felodipine Extended-Release Tablets
DEFINITION
Felodipine Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of felodipine (C18H19Cl2NO4).
IDENTIFICATION
•  The retention time of the major peak from the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
•  Procedure
Solution A:  6.9 mg/mL of monobasic sodium phosphate in water. Adjust with 1 M phosphoric acid to a pH of 3.0 ± 0.05.
Mobile phase:  Acetonitrile, methanol, and Solution A (2:1:2)
Standard stock solution:  2 mg/mL of USP Felodipine RS in methanol
Standard solution:  0.02 mg/mL from the Standard stock solution in Mobile phase
Sample solution:  Dissolve a quantity equivalent to 10 mg of felodipine from powdered Tablets (NLT 10 Tablets), in 40 mL of acetonitrile and 20 mL of methanol in a 100-mL volumetric flask, and sonicate for 5 min. Add about 30 mL of Solution A, and shake by mechanical means for 30 min. Allow the solution to cool to room temperature, and dilute with Solution A to volume. Centrifuge a portion of the solution at high speed for 15 min. Transfer 10 mL of the supernatant to a 50-mL volumetric flask, and dilute with Mobile phase to volume. Pass a portion of this solution through a filter having a 0.5-µm or finer porosity, discarding the first 4 mL of the filtrate.
Chromatographic system 
Mode:  LC
Detector:  UV 362 nm
Column:  4.6-mm × 15-cm; packing L1
Flow rate:  1 mL/min
Injection size:  40 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Column efficiency:  NLT 1500 theoretical plates
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of C18H19Cl2NO4 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 Felodipine RS in the Standard solution (mg/mL)
CU== nominal concentration of felodipine in the Sample solution (mg/mL)
Acceptance criteria:  90.0%–110.0%
PERFORMANCE TESTS
•  Dissolution 711
Test 1 
Medium:  pH 6.5 phosphate buffer with 1% sodium lauryl sulfate (Transfer 206 mL of 1 M monobasic sodium phosphate monohydrate, 196 mL of 0.5 M anhydrous dibasic sodium phosphate, and 50.0 g of sodium lauryl sulfate to a 5000-mL volumetric flask. Add about 4000 mL of water, and mix well. If necessary, adjust with 1 N sodium hydroxide to a pH of 6.5. Dilute with water to volume.); 500 mL
Apparatus 2:  50 rpm
Times:  2, 6, and 10 h
Buffer solution:  6.9 mg/mL of monobasic sodium phosphate. Adjust with 1 M phosphoric acid to a pH of 3.0 ± 0.05.
Mobile phase:  Acetonitrile, methanol, and Buffer solution (2.5:1:2)
Standard stock solution:  0.25 mg/mL of USP Felodipine RS in alcohol
Standard solution:  (0.6 L/500) mg/mL of USP Felodipine RS from the Standard stock solution in Medium, where L is the label claim in mg/Tablet. [Note—L equals Label claim ]
Sample solution:  Place each Tablet in a specially made quadrangular basket of stainless steel wire gauze, soldered in one of its upper, narrow sides to the end of a steel rod (see Figure 1). Place the tablet cover in the horizontal diagonal of the basket. Put the rod assembly up through the cover of the dissolution vessel, and fix it by means of two teflon nuts, 3.2 cm from the center of the vessel, or by any other appropriate means. Adjust the lower edge of the bottom of the basket to about 1 cm above the top of the paddle blade (see Figure 2). Orient the large side of the basket tangentially to the flow stream with the Tablet standing on its edge. Pass a 10-mL portion of the solution under test, obtained at each time interval, through a suitable filter.
Click to View Image
Figure 1. Stationary tablet basket.
Click to View Image
Figure 2. Drug release stationary tablet basket configuration diagram.
Chromatographic system:  Proceed as directed in the Assay.
Analysis 
Injection size:  100 µL
Samples:  Standard solution and Sample solution
Calculate the percentage of C18H19Cl2NO4 dissolved in the Medium:
Result = (rU/rS) × CS × D × V × 100/L
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of USP Felodipine RS in the Standard solution (mg/mL)
D== dilution factor of the Sample solution
V== volume of the Medium (mL), 500
L== Tablet label claim (mg)
Tolerances:  The percentages of the labeled amount of C18H19Cl2NO4 dissolved at the times specified conform to Acceptance Table 2.
Time
(h)
Amount
Dissolved
2 10%–30%
6 42%–68%
10 NLT 75%
Test 2:  If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
Medium:  1% (w/v) polysorbate 80; 500 mL
Apparatus 1:  100 rpm
Times:  1, 4, and 8 h
Buffer solution:  Dissolve 6.9 g of monobasic sodium phosphate in 400 mL of water, add 8.0 mL of 1 M phosphoric acid, and dilute with water to 1000.0 mL.
Mobile phase:  Acetonitrile, methanol, and Buffer solution (2:1:2)
Standard stock solution:  0.2 mg/mL of USP Felodipine RS in methanol. Sonicate for 2 min, cool, and dilute with methanol to final concentration.
Standard solution:  Transfer the appropriate volume of Standard stock solution into a suitable volumetric flask according to the following table. Dilute with Medium to volume.
Tablet Label Claim
(mg)
Volume
Transferred
(mL)
Volumetric Flask
(mL)
10 10 100
5 5 100
2.5 2.5 100
Sample solution:  Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Replace the withdrawn amount with Medium.
Chromatographic system 
Mode:  LC
Detector:  UV 254 nm
Column:  4.6-mm × 15-cm; packing L1
Flow rate:  1 mL/min
Injection size:  20 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Capacity factor (k'):  NLT 5
Column efficiency:  NLT 1500 theoretical plates
Tailing factor:  NMT 1.5
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the quantity, in mg, of C18H19Cl2NO4 dissolved:
CU = (rU/rS) × CS
CU== concentration of felodipine in the sample at each time point
rU== peak response from the Sample solution
rS== peak response from the Standard solution
=
CS== concentration of felodipine in the Standard solution (mg/mL)
Calculate the percentage of C18H19Cl2NO4 dissolved, with volume correction:
Click to View Image
CN== concentration of felodipine in the Sample solution at each time point (mg/mL)
VM== volume of Medium (mL), 500
VU== volume of sample withdrawn at each time point (mL)
n== the time point (at 4 h, n + 1)
Click to View Image
== summation of the concentration of the Sample solution from the first to the (n 1)th time point (only applicable for n = 2)
L== Tablet label claim (mg)
Tolerances:  The percentages of the labeled amount of felodipine dissolved at the times specified conform to Acceptance Table 2.
Time
(h)
Amount
Dissolved
1 5%–30%
4 45%–70%
8 NLT 80%
Test 3:  If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3.
Medium:  pH 6.5 phosphate buffer with 1% sodium lauryl sulfate (5.7 g/L of monobasic sodium phosphate monohydrate, 2.8 g/L of dibasic sodium phosphate, and 10 g/L of sodium lauryl sulfate in water, adjusted, if necessary, with diluted sodium hydroxide to a pH of 6.5 ± 0.05); 500 mL
Apparatus 2:  50 rpm
Times:  2, 6, and 10 h
Buffer solution:  6.9 g/L of monobasic sodium phosphate monohydrate in water. Adjust with phosphoric acid to a pH of 3.0 ± 0.05.
Mobile phase:  Buffer solution, acetonitrile, and methanol (30:45:25)
Standard stock solution:  0.5 mg/mL of USP Felodipine RS in methanol
Standard solution:  Transfer 2.0 mL of the Standard stock solution to a 100-mL volumetric flask, and dilute to volume with Medium. This solution is stable for 5 days at room temperature.
Sample solution:  Place each Tablet in a specially made quadrangular basket of stainless steel wire gauze, soldered in one of its upper, narrow sides to the end of a steel rod (see Figure 1, under Test 1). Place the tablet cover in the horizontal diagonal of the basket. Put the rod assembly up through the cover of the dissolution vessel, and fix it by means of two teflon nuts 3.2 cm from the center of the vessel, or by any other appropriate means. Adjust the lower edge of the bottom of the basket to approximately 1 cm above the top of the paddle blade (see Figure 2, under Test 1). Orient the large side of the basket tangentially to the flow stream with the Tablet standing on its edge. Pass a portion of the solution under test, obtained at each time interval, through a suitable filter, discarding the first few mL.
Chromatographic system  
Mode:  LC
Detector:  UV 362 nm
Column:  4.6-mm × 15-cm; 5-µm packing L1
Flow rate:  2.0 mL/min
Injection size:  40 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Column efficiency:  NLT 1500 theoretical plates
Relative standard deviation:  NMT 2.0%
Calculate the percentage of felodipine dissolved:
Result = (rU/rS) × (CS/L) × V × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of the Standard solution (mg/mL)
V== volume of Medium (mL), 500
Tolerances:  The percentages of the labeled amount of felodipine dissolved at the times specified conform to Acceptance Table 2.
Time
(h)
Amount
Dissolved
2 10%–30%
6 50%–80%
10 NLT 80%
•  Uniformity of Dosage Units 905: Meet the requirements
Procedure for content uniformity 
Solution A:  6.9 mg/mL of monobasic sodium phosphate. Adjust with 1 M phosphoric acid to a pH of 3.0 ± 0.05.
Mobile phase:  Acetonitrile, methanol, and Solution A (2:1:2)
Standard stock solution:  2 mg/mL of USP Felodipine RS in methanol
Standard solution:  20 µg/mL from the Standard stock solution in Mobile phase
Sample solution:  20 µg/mL of felodipine, prepared by combining one Tablet taken in a 100 -mL volumetric flask and, 40 mL of acetonitrile, and sonicating for 20 min with occasional swirling. Add 20 mL of methanol, and shake by mechanical means for 30 min. Allow to cool to room temperature, and dilute with Solution A to volume. Centrifuge a portion of the solution at high speed for 15 min. Dilute a portion of the supernatant with Mobile phase to obtain a final concentration. Pass this solution through a filter of 0.5-µm or finer pore size.
Chromatographic system 
Mode:  LC
Detector:  UV 362 nm
Column:  4.6-mm × 15-cm; packing L1
Flow rate:  1 mL/min
Injection size:  40 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Column efficiency:  NLT 1500 theoretical plates
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of C18H19Cl2NO4 in the Tablet 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 Felodipine RS in the Standard solution (µg/mL)
CU== nominal concentration of felodipine in the Sample solution (µg/mL)
IMPURITIES
Organic Impurities 
•  Procedure
Solution A:  6.9 mg/mL of monobasic sodium phosphate. Adjust with 1 M phosphoric acid to a pH of 3.0 ± 0.05
Mobile phase:  Acetonitrile, methanol, and Solution A (2:1:2)
Standard stock solution A:  0.2 mg/mL of USP Felodipine Related Compound A RS in methanol
Standard solution A:  0.02 mg/mL of USP Felodipine Related Compound A RS from the Standard stock solution A in Mobile phase
Standard solution B:  2 mg/mL of USP Felodipine RS in methanol
System suitability solution:  Combine 15.0 mL of Standard solution A and 5.0 mL of Standard solution B, and dilute with Mobile phase to 100.0 mL.
Standard solution:  Dilute 10.0 mL of Standard solution A with Mobile phase to 100.0 mL.
Sample solution:  Dissolve a quantity equivalent to 10 mg of felodipine from powdered Tablets (NLT 10 Tablets) in a 100-mL volumetric flask. Add 40 mL of acetonitrile and 20 mL of methanol, and sonicate for 5 min. Add about 30 mL of Solution A, and shake by mechanical means for 30 min. Allow the solution to cool to room temperature, and dilute with Solution A to volume. Centrifuge a portion of the solution at high speed for 15 min, and pass a portion of the supernatant through a filter of 0.5-µm or finer pore size, discarding the first 4 mL of the filtrate.
Chromatographic system  
Mode:  LC
Detector:  UV 254 nm
Column:  4.6-mm × 15-cm; packing L1
Flow rate:  1 mL/min
Injection size:  40 µL
System suitability 
Sample:  System suitability solution
[Note—The relative retention times for felodipine related compound A and felodipine are about 0.75 and 1.0, respectively. ]
Suitability requirements 
Resolution:  NLT 1.5 between felodipine and felodipine related compound A
Column efficiency:  NLT 1500 theoretical plates
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of felodipine related compound A in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of felodipine related compound A from the Sample solution
rS== peak response of felodipine related compound A from the Standard solution
CS== concentration of USP Felodipine Related Compound A RS in the Standard solution (mg/mL)
CU== nominal concentration of felodipine in the Sample solution (mg/mL)
Acceptance criteria:  NMT 2.0%
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers.
•  Labeling: When more than one test for Dissolution is given, the Labeling section states the test for Dissolution used only if Test 1 is not used.
•  USP Reference Standards 11
USP Felodipine RS Click to View Structure
USP Felodipine Related Compound A RS Click to View Structure
Ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylate.
    C18H17Cl2NO4        382.24
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