Oxybutynin Chloride Extended-Release Tablets
DEFINITION
Oxybutynin Chloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of oxybutynin chloride (C22H31NO3·HCl).
IDENTIFICATION
•  A. Infrared Absorption 197
Standard:  Dissolve 15 mg of USP Oxybutynin Chloride RS in 5 mL of water. Adjust with 0.1 N sodium hydroxide to a pH of between 7 and 8. Extract the solution twice with 10 mL of ether. Combine the extracts, evaporate the ether, and dry under vacuum over silica gel for at least 30 min. Redissolve the dried residue in a small amount of acetone, transfer the solution to an IR salt plate, and evaporate to cast a thin film.
Sample:  Add a quantity of finely powdered Tablets, equivalent to about 15 mg of oxybutynin chloride, to 5 mL of water per Tablet. Mix for 1 min. Adjust with 0.1 N sodium hydroxide to a pH between 7 and 8. Extract the solution twice with 10 mL of ether. Combine the extracts, evaporate the ether, and dry under vacuum over silica gel for at least 30 min. Redissolve the dried residue in a small amount of acetone, transfer the solution to an IR salt plate, and evaporate to cast a thin film.
•  B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
•  Procedure
Diluent:  Use water adjusted with phosphoric acid to a pH of 3.5.
Solution A:  Methanol and acetonitrile (1:1)
Mobile phase:  Acetonitrile, triethylamine, and water (700:3:1300). Adjust with phosphoric acid to a pH of 3.9.
Impurity stock solution:  0.11 mg/mL of USP Oxybutynin Related Compound A RS in acetonitrile
Standard stock solution:  0.37 mg/mL of USP Oxybutynin Chloride RS in acetonitrile
System suitability solution:  Transfer 10 mL of the Standard stock solution and 1 mL of the Impurity stock solution to a 100-mL volumetric flask, and dilute with Diluent to volume.
Standard solution:  0.1 mg/mL in Diluent from the Standard stock solution
Sample solution 
For Tablets that contain 5 mg of oxybutynin chloride:  Place 10 Tablets in a 500-mL volumetric flask, add 150 mL of Solution A, and stir for at least 4 h or until dissolved. Dilute with Diluent to volume. Mix thoroughly, centrifuge, and use the clear supernatant.
For Tablets that contain 10 mg or more of oxybutynin chloride:  Place 10 Tablets in a 1000-mL volumetric flask, add 300 mL of Solution A, and stir for at least 4 h or until dissolved. Dilute with Diluent to volume. If necessary, make a further dilution with Diluent to obtain a solution having a final concentration equivalent to 0.1 mg/mL of oxybutynin chloride. Mix thoroughly, centrifuge, and use the clear supernatant.
Chromatographic system 
Mode:  LC
Detector:  UV 220 nm
Column:  4.6-mm × 15-cm; packing L11
Flow rate:  1.5 mL/min
Injection size:  50 µL
System suitability 
Sample:  System suitability solution
[Note—The relative retention times for oxybutynin and oxybutynin related compound A are about 1.0 and 1.6, respectively. ]
Suitability requirements 
Resolution:  NLT 1.5 between oxybutynin and oxybutynin related compound A
Tailing factor:  Greater than 0.75 and NMT 2.5 for each peak
Relative standard deviation:  NMT 3% for each compound for six replicate injections
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of the labeled amount of oxybutynin chloride (C22H31NO3·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 Oxybutynin Chloride RS in the Standard solution (mg/mL)
CU== nominal concentration of oxybutynin chloride in the Sample solution (mg/mL)
Acceptance criteria:  90.0%–110.0%
PERFORMANCE TESTS
Change to read:
•  Dissolution 711
Test 1 
Medium:  Simulated gastric fluid without enzyme; 50 mL
Apparatus 7:  See Drug Release 724, 30 cycles/min; 2- to 3-cm amplitude, at 37.0 ± 0.5
Times:  4, 10, and 24 h
Solution A:  4.83 g/L of monobasic sodium phosphate in water. Add 2.3 mL/L of triethylamine, and adjust with phosphoric acid to a pH of 2.2 ± 0.2.
Mobile phase:  Acetonitrile and Solution A (7:13)
Solution B:  To 1 L of water add phosphoric acid dropwise to a pH of 3.5, and mix well.
Standard stock solutions:  250, 300, and 350 µg/mL each of USP Oxybutynin RS in acetonitrile
Standard solutions:  Prepare a series of dilutions of the Standard stock solutions in Solution B having final concentrations similar to those expected in the Sample solution.
System suitability solution:  Use a medium range Standard solution of USP Oxybutynin Chloride RS.
Sample solution:  Use portions of the solution under test. If the solution is cloudy, centrifuge at 2000 rpm for 10 min, and use the supernatant.
Chromatographic system 
Mode:  LC
Detector:  UV 230 nm
Column:  4.6-mm × 5-cm; packing L11
Column temperature:  35
Flow rate:  1.5 mL/min
Injection size:  50 µL
System suitability 
Sample:  System suitability solution
Suitability requirements 
Tailing factor:  Greater than 0.5 and less than 2.5
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solutions and Sample solution
Construct a calibration curve by plotting the peak response versus concentration of the Standard solutions. A weighing factor, 1/x, is applied to the regression line of the calibration curve to enhance the accuracy of the low standard concentrations. Determine the percentage of oxybutynin chloride (C22H31NO3·HCl) dissolved in each interval from a linear regression analysis of the calibration curve.
Tolerances:  See Tables 1 and 2.
Table 1. For Tablets labeled to contain 5 or 10 mg of oxybutynin chloride
Time
(h)
Amount
Dissolved
4 NMT 20%
10 34.5%–59.5%
24 NLT 80%
Table 2. For Tablets labeled to contain 15 mg of oxybutynin chloride
Time
(h)
Amount
Dissolved
4 NMT 20%
10 34.5%–59.5%
24 NLT 75%
The percentages of the labeled amount of oxybutynin chloride (C22H31NO3·HCl) dissolved at the times specified conform to Acceptance Table 2 in Dissolution 711.
Test 2:  If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2.
Acid stage medium:  Simulated gastric fluid, without enzymes, pH 1.2 ± 0.05; 250 mL (first row)
Buffer stage medium:  Simulated intestinal fluid, without enzymes, pH 6.8 ± 0.1; 250 mL (rows 2–4)
Apparatus 3:  25 dips/min; 20-mesh polypropylene screen on top and bottom; 30 s drip time
Times:  2 h in the Acid stage medium(RB 1-May-2011) (first row); 4, 8, and 16 h (corresponding to 2, 6, and 14 h after changing the medium)(RB 1-May-2011) in the Buffer stage medium(RB 1-May-2011) (rows 2–4)
Solution A:  Transfer 1 mL of triethylamine to 1000 mL of water. Adjust with phosphoric acid to a pH of 3.50 ± 0.05.
Mobile phase:  Acetonitrile and Solution A (4:1)
Standard stock solution:  0.2 mg/mL of USP Oxybutynin Chloride RS in Acid stage medium
Working standard solution:  Transfer 5.0 mL of the Standard stock solution for Tablets labeled to contain 5 mg, or transfer 10 mL for Tablets labeled to contain 10 mg, to a 100-mL volumetric flask. Dilute with Buffer stage medium to volume.
Sample solution:  Centrifuge a portion of the solution under test at approximately 3000 rpm for 10 min. Use the supernatant.
Chromatographic system 
Mode:  LC
Detector:  UV 203 nm
Column:  4.6-mm × 25-cm; packing L7
Flow rate:  1.5 mL/min
Injection size:  25 µL
System suitability 
Sample:  Working standard solution
Suitability requirements 
Tailing factor:  NMT 2.0
Relative standard deviation:  NMT 3.0%
Analysis 
Samples:  Working standard solution and Sample solution
Calculate the percentage of oxybutynin chloride (C22H31NO3·HCl) dissolved at each time point (CT2, CT4, CT8, CT16):
Ci = (rU/rS) × (CS/L) × V × 100(RB 1-May-2011)
rU== peak response from the Sample solution
rS== peak response from the Working standard solution
CS== concentration of the Working standard solution (mg/mL)
L== label claim (mg/Tablet)
V== volume of Medium, 250 mL
CT2== percentage dissolved at 2 h, C2
CT4== percentage dissolved at 4 h, C2 + C4
CT8== percentage dissolved at 8 h, C2 + C4 + C8
CT16== percentage dissolved at 16 h, C2 + C4 + C8 + C16
Tolerances:  See Tables 3 and 4.
Table 3. For Tablets labeled to contain 5 or 10 mg
Time
(h)
Amount
Dissolved
2 0%–10%
4 10%–30%
8 40%–65%
16 NLT 80%
Table 4. For Tablets labeled to contain 15 mg
Time
(h)
Amount
Dissolved
2 0%–10%
4 10%–30%
8 35%–65%
16 NLT 75%
The percentages of the labeled amount of oxybutynin chloride (C22H31NO3·HCl) dissolved at the times specified conform to Acceptance Table 2 in Dissolution 711.
Test 3:  If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3.
Medium:  Simulated gastric fluid without enzyme; 50 mL
Apparatus 7:  See Drug Release 724. Use acrylic rods. 30 dips/min, 37.0 ± 0.5, 10 s drip time. Dip time interval: row 1, 1 h; row 2, 3 h; row 3, 6 h; row 4, 5 h; row 5, 9 h.
Times:  4, 10, and 24 h
pH 2.3 phosphate buffer:  3.4 mg/mL of monobasic potassium phosphate in water. Adjust with phosphoric acid or 2 N potassium hydroxide to a pH of 2.30 ± 0.05.
Standard solution:  (L/200) mg/mL of USP Oxybutynin Chloride RS in Medium, where L is the Tablet label claim, in mg
Sample solution:  Pass a portion of the solution under test through a suitable nylon filter of 0.45-µm pore size, discarding the first few mL.
Mobile phase:  pH 2.3 phosphate buffer and acetonitrile (7:3)
Chromatographic system 
Mode:  LC
Detector:  UV 220 nm
Column:  4.6-mm × 15-cm; packing L10
Flow rate:  1.0 mL/min
Injection size:  10 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Tailing factor:  NMT 2.0
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the amount, in mg, of oxybutynin chloride (C22H31NO3·HCl) dissolved at each time interval:
Result = (rU/rS) × (CS/L) × V
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of the Standard solution (mg/mL)
L== label claim (mg/Tablet)
V== volume of Medium, 50 mL
Calculate the percentage of oxybutynin dissolved:
Result = S(amount dissolved at current time interval + amount dissolved at previous time intervals) × 100/L
Tolerances:  See Table 5.
Table 5
Time
(h)
Amount
Dissolved
4 NMT 25%
10 40%–65%
24 NLT 75%
The percentages of the labeled amount of oxybutynin chloride (C22H31NO3·HCl) dissolved at the times specified conform to Acceptance Table 2 in Dissolution 711.
Test 4:  If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 4.
Acid stage medium:  0.1 N hydrochloric acid; 900 mL
Buffer stage medium:  pH 6.0 sodium phosphate buffer with 0.2% of sodium lauryl sulfate; 900 mL
Apparatus 2:  50 rpm, with sinkers. [Note—A suitable sinker is available as catalog number CAPWHT-2S from www.QLA-LLC.com. ]
Times:  2 h in the Acid stage medium; 4, 6, and 14 h (corresponding to 2, 4, 12 h after changing the medium) in the Buffer stage medium
Standard solution:  (L/1000) mg/mL of USP Oxybutynin Chloride RS in Buffer stage medium, where L is the Tablet label claim, in mg
Sample solution:  Pass a portion of the solution under test through a suitable PVDF filter of 0.45-µm pore size.
pH 3.5 phosphate buffer:  6.94 mg/mL of monobasic potassium phosphate in water. Adjust with diluted phosphoric acid to a pH of 3.50 ± 0.05.
Mobile phase:  pH 3.5 phosphate buffer and acetonitrile (1:1)
Chromatographic system 
Mode:  LC
Detector:  UV 210 nm
Column:  4.6-mm × 15-cm; packing L7
Flow rate:  1.0 mL/min
Injection size:  20 µL
System suitability 
Sample:  Standard solution
Suitability requirements 
Column efficiency:  NLT 2000 theoretical plates
Tailing factor:  NMT 2.0
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Calculate the concentration (mg/mL) of oxybutynin chloride (C22H31NO3·HCl) (Ci) at each time point:
Ci = (rU/rS) × CS
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of the Standard solution (mg/mL)
Calculate the cumulative percentage of oxybutynin chloride (C22H31NO3·HCl) dissolved (Qi) at each time point (i):
At i = 1
Q1 = (C1 × V/L) × 100
At i = 2 to n
Click to View Image
i== 1, 2, ..., n
j== 2, 3, ..., n1
VS== sampling volume (mL)
Ci== concentration of oxybutynin chloride in the Sample solution at time point i (mg/mL)
Cj== concentration of oxybutynin chloride in the Sample solution at time point 2 through n1 (mg/mL)
L== label claim (mg/Tablet)
Tolerances:  See Table 6.
Table 6
Time
(h)
Amount
Dissolved
2 NMT 10%
4 10%–40%
6 40%–75%
14 NLT 85%
The percentages of the labeled amount of oxybutynin chloride (C22H31NO3·HCl) dissolved at the times specified conform to Acceptance Table 2 in Dissolution 711.
•  Uniformity of Dosage Units 905: Meet the requirements
IMPURITIES
•  Organic Impurities
Diluent, Solution A, Mobile phase, Impurity stock solution, System suitability solution, Sample solution, Chromatographic system, and System suitability:  Proceed as directed in the Assay.
Impurity standard solution:  1 µg/mL of USP Oxybutynin Related Compound A RS in Diluent from the Impurity stock solution
Analysis 
Samples:  Impurity standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response for each impurity from the Sample solution
rS== peak response from the Impurity standard solution
CS== concentration of USP Oxybutynin Related Compound A RS in the Standard solution (mg/mL)
CU== concentration of the Sample solution (mg/mL)
[Note—Disregard any peak less than 0.1%. ]
Acceptance criteria 
Individual impurities:  NMT 1% of oxybutynin related compound A is found.
Total impurities:  NMT 2%
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight containers. Store at controlled room temperature.
•  Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.
•  USP Reference Standards 11
USP Oxybutynin Chloride RS Click to View Structure
USP Oxybutynin Related Compound A RS Click to View Structure
Phenylcyclohexylglycolic acid.
    C14H18O3        234.30
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Elena Gonikberg, Ph.D.
Principal Scientific Liaison
1-301-816-8251
(SM32010) Monographs - Small Molecules 3
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 4167
Pharmacopeial Forum: Volume No. 33(4) Page 671