Methylphenidate Hydrochloride Extended-Release Tablets
DEFINITION
Methylphenidate Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of methylphenidate hydrochloride (C14H19NO2·HCl).
IDENTIFICATION
• A. Infrared Absorption
Sample specimen:
Place a portion of powdered Tablets, equivalent to 100 mg of methylphenidate hydrochloride, in a 100-mL beaker. Add 20 mL of chloroform, stir for 5 min, and filter, collecting the filtrate. Evaporate the filtrate to about 5 mL. Add ethyl ether slowly, with stirring, until crystals form. Filter the crystals, wash with ethyl ether, and dry at 80
for 30 min.
for 30 min.
Acceptance criteria:
The IR absorption spectrum of a mineral oil dispersion of the crystals so obtained exhibits maxima only at the same wavelengths as that of a similar preparation of USP Methylphenidate Hydrochloride RS.
• B.
The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the test for Organic Impurities.
ASSAY
• Procedure
Buffer:
Dissolve 1.64 g of anhydrous sodium acetate in 900 mL of water. Adjust with acetic acid to a pH of 4.0, and dilute with water to 1000 mL.
Mobile phase:
Methanol, acetonitrile, and Buffer (4:3:3)
Internal standard solution:
0.4 mg/mL of phenylephrine hydrochloride in Mobile phase
Standard stock solution:
0.2 mg/mL of USP Methylphenidate Hydrochloride RS in Mobile phase
Standard solution:
Transfer 10.0 mL of the Standard stock solution to a glass-stoppered, 25-mL conical flask, add 5.0 mL of the Internal standard solution, and mix.
Sample stock solution:
Nominally 0.2 mg/mL of methylphenidate hydrochloride in Mobile phase. Prepare as follows: Finely powder NLT 20 Tablets. Transfer a suitable amount of the powder to a suitable volumetric flask to obtain the nominal concentration. Add 70% of the flask volume of Mobile phase, and sonicate for 15 min. Cool to room temperature, dilute with Mobile phase to volume, and mix. Pass a portion of this solution through a suitable membrane filter, discarding the first portion of the filtrate.
[Note—Avoid the use of glass filters. Polypropylene filters are suitable for use. ]
Sample solution:
Transfer 10.0 mL of the clear filtrate to a glass-stoppered, 25-mL conical flask, and add 5.0 mL of the Internal standard solution.
Chromatographic system
Mode:
LC
Detector:
UV 210 nm
Column:
4.6-mm × 25-cm; packing L10
Flow rate:
1.5 mL/min
Injection size:
50 µL
System suitability
Sample:
Standard solution
[Note—The relative retention times for phenylephrine hydrochloride and methylphenidate hydrochloride are 0.8 and 1.0, respectively. ]
Suitability requirements
Resolution:
NLT 2.0 between the analyte and internal standard peaks
Relative standard deviation:
NMT 2.0% from the peak response ratios of the analyte to the internal standard
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C14H19NO2·HCl in the portion of Tablets taken:
Result = (RU/RS) × (CS/CU) × 100
| RU | = | = peak response ratio of the analyte to the internal standard from the Sample solution |
| RS | = | = peak response ratio of the analyte to the internal standard from the Standard solution |
| CS | = | = concentration of the Standard solution (mg/mL) |
| CU | = | = nominal concentration of the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 
711
711
Test 1
Medium:
Water; 500 mL
Apparatus 2:
50 rpm
Time:
1, 2, 3.5, 5, and 7 h
Sample solution:
Use portions of the solution under test passed through a suitable filter of 0.45-µm pore size. [Note—Do not use glass fiber filters. ]
Analysis:
Determine the amount of C14H19NO2·HCl dissolved by using the procedure in the Assay, making any necessary volumetric adjustments.
Tolerances:
The percentages of the labeled amount of C14H19NO2·HCl dissolved at the times specified conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 25%–45% |
| 2 | 40%–65% |
| 3.5 | 55%–80% |
| 5 | 70%–90% |
| 7 | NLT 80% |
Test 2 (for products labeled for dosing every 24 h):
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
Medium:
Acidified water. Adjust with phosphoric acid to a pH of 3; 50 mL, at 37 ± 0.5.
.
Apparatus 7 (see Drug Release 724):
30 cycles/min; 2–3 cm amplitude. Use Sample Preparation A using a metal coil sample holder (Figure 4d). Place 1 Tablet in the holder with the Tablet orifice facing down, and cover the top of the holder with Parafilm™. 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.
724):
30 cycles/min; 2–3 cm amplitude. Use Sample Preparation A using a metal coil sample holder (Figure 4d). Place 1 Tablet in the holder with the Tablet orifice facing down, and cover the top of the holder with Parafilm™. 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.
Times:
1-h intervals for a duration of 10 h
Determine the percentages of the labeled amount of C14H19NO2·HCl dissolved by using the following method.
Dilution medium:
Mixture of acetonitrile and Medium (1:3)
Standard stock solution:
0.3 mg/mL USP Methylphenidate Hydrochloride RS in Dilution medium
Standard solutions:
Prepare at least six solutions by making serial dilutions of the Standard stock solution in Dilution medium to bracket the expected drug concentration range.
Solution A:
Dissolve 2.0 g of 1-octanesulfonic acid sodium salt in 700 mL of water, mix well, and adjust with phosphoric acid to a pH of 3.0.
Mobile phase:
Acetonitrile and Solution A (3:7)
Chromatographic system
Mode:
LC
Detector:
UV 220 nm
Column:
3.2-mm × 5-cm; 5-µm packing L1
Column temperature:
30
Flow rate:
1 mL/min
Injection size:
25 µL
System suitability
Sample:
Middle range concentration of the Standard solution
Suitability requirements
Tailing factor: NMT 2
Capacity factor: NMT 2
Relative standard deviation: NMT 2% from the peak response of the analyte; NMT 2% of the retention time of the analyte
Analysis
Samples:
Standard solutions and the solution under test
Construct a calibration curve by plotting the peak response versus the concentration of the Standard solutions. Determine the amount of C14H19NO2·HCl in each interval by linear regression analysis of the standard curve.
Tolerances:
The percentages of the labeled amount of C14H19NO2·HCl dissolved at the times specified conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 12%–32% |
| 4 | 40%–60% |
| 10 | NLT 85% |
| Average from 3 to 6 h | 9%–15%/h |
Calculate the average percentage released from 3 to 6 h:
Result = (Y 
X)/3
X)/3| Y | = | = cumulative drug released from 0 to 6 h |
| X | = | = cumulative drug released from 0 to 3 h |
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
IMPURITIES
Organic Impurities
• Procedure
Mobile phase:
Dissolve 2 g of 1-octanesulfonic acid sodium salt in 730 mL of water. Adjust with phosphoric acid to a pH of 2.7. Mix with 270 mL of acetonitrile.
Solution A:
Acidified water. Adjust with phosphoric acid to a pH of 3.
Diluent A:
Acetonitrile and Solution A (1:3)
Diluent B:
Acetonitrile and methanol (1:1)
System suitability solution:
80 µg/mL of USP Methylphenidate Hydrochloride RS, 1 µg/mL of methylphenidate hydrochloride erythro isomer from USP Methylphenidate Hydrochloride Erythro Isomer Solution RS, and 2 µg/mL of USP Methylphenidate Related Compound A RS, in Diluent A
Standard solution:
0.2 µg/mL of USP Methylphenidate Hydrochloride RS, 0.5 µg/mL of methylphenidate hydrochloride erythro isomer from USP Methylphenidate Hydrochloride Erythro Isomer Solution RS, and 1.5 µg/mL of USP Methylphenidate Related Compound A RS, in Diluent A
Sample stock solution:
Dissolve 10 Tablets in a suitable volumetric flask to obtain a nominal concentration of 1 mg/mL of methylphenidate hydrochloride containing 20% of the total flask volume of Diluent B. [Note—Alternatively, a suitable number of Tablets may be powdered and suspended in Diluent B. ] Stir for 4 h. Dilute with Solution A to volume.
Sample solution:
0.1 mg/mL of methylphenidate hydrochloride in Solution A, from the Sample stock solution. [Note—Centrifuge before chromatographic analysis. ]
Chromatographic system
Mode:
LC
Detector:
UV 210 nm
Column:
3.9-mm × 15-cm; 5-µm packing L1
Column temperature:
30
Flow rate:
1 mL/min
Injection size:
25 µL
Run time:
2 times the retention time of methylphenidate
System suitability
Sample:
System suitability solution
Suitability requirements
Tailing factor:
NMT 2.0 for the methylphenidate peak
Resolution:
NLT 6.0 between the methylphenidate and erythro isomer peaks
Relative standard deviation:
NMT 2.0% for the methylphenidate peak and NMT 4.0% each for the methylphenidate related compound A and erythro isomer peaks
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of methylphenidate related compound A or erythro isomer in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of methylphenidate related compound A or erythro isomer from the Sample solution |
| rS | = | = peak response of methylphenidate related compound A or erythro isomer from the Standard solution |
| CS | = | = concentration of USP Methylphenidate Related Compound A RS or methylphenidate hydrochloride erythro isomer, in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of methylphenidate hydrochloride in the Sample solution (mg/mL) |
Calculate the percentage of any unspecified degradation product in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak response of each impurity from the Sample solution |
| rS | = | = peak response of USP Methylphenidate Hydrochloride RS from the Standard solution |
| CS | = | = concentration of USP Methylphenidate Hydrochloride RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of methylphenidate hydrochloride in the Sample solution (mg/mL) |
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 2.5%
Impurity Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|---|---|---|
| Methylphenidate related compound Aa | 0.47 | 1.5 |
| Erythroisomerb | 0.65 | 0.5 |
| Methylphenidate hydrochloride | 1.0 | — |
| Any unspecified degradation product | — | 0.2 |
|
a
 -Phenyl-2-piperidineacetic acid.
b
Methyl (RS,SR)-2-phenyl-2-(piperidin-2-yl) acetate.
|
||
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers.
• Labeling:
The labeling states the Dissolution Test with which the product complies if other than Test 1.
• USP Reference Standards 11
11
USP Methylphenidate Hydrochloride RS 
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USP Methylphenidate Hydrochloride Erythro Isomer Solution RS
This solution contains 0.5 mg of methylphenidate hydrochloride erythro isomer per mL in methanol.
This solution contains 0.5 mg of methylphenidate hydrochloride erythro isomer per mL in methanol.
USP Methylphenidate Related Compound A RS
-Phenyl-2-piperidineacetic acid hydrochloride.
C13H17NO2·HCl 255.75
-Phenyl-2-piperidineacetic acid hydrochloride.
C13H17NO2·HCl 255.75
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Hariram Ramanathan, M.S.
Associate Scientific Liaison 1-301-816-8313 |
(SM42010) Monographs - Small Molecules 4 |
| 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 3882
Pharmacopeial Forum: Volume No. 35(6) Page 1461