Methylphenidate Hydrochloride
(meth'' il fen' i date hye'' droe klor' ide).
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C14H19NO2·HCl 269.77
2-Piperidineacetic acid, -phenyl-, methyl ester, hydrochloride, (R*,R*)-(±)-;    
Methyl -phenyl-2-piperidineacetate hydrochloride     [298-59-9].
DEFINITION
Methylphenidate Hydrochloride contains NLT 98.0% and NMT 102.0% of C14H19NO2·HCl, calculated on the dried basis.
IDENTIFICATION
•  B. Identification Tests—General, Chloride 191: Meets the requirement for the silver nitrate precipitate test for chloride
ASSAY
•  Procedure
Buffer:  2.7 g/L of monobasic potassium phosphate
Mobile phase:  Methanol and Buffer (1:2). Adjust with phosphoric acid to a pH of 4.6 ± 0.1.
System suitability solution:  0.005 mg/mL of USP Methylphenidate Related Compound A RS and 0.5 mg/mL of USP Methylphenidate Hydrochloride RS in Mobile phase
Standard solution:  0.5 mg/mL of USP Methylphenidate Hydrochloride RS in Mobile phase
Sample solution:  0.5 mg/mL of Methylphenidate Hydrochloride in Mobile phase
Chromatographic system 
Mode:  LC
Detector:  UV 209 nm
Column:  4.6-mm × 25-cm; 5-µm packing L1
Flow rate:  1.0 mL/min
Injection size:  10 µL
Run Time:  2 times the retention time of methylphenidate
System suitability 
Sample:  System suitability solution
Suitability requirements 
Tailing factor:  NMT 3.0 for the methylphenidate peak
Resolution:  NLT 2.5 between methylphenidate related compound A and methylphenidate
Relative standard deviation:  NMT 2.0% for the methylphenidate peak
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of C14H19NO2·HCl in the portion 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 Methylphenidate Hydrochloride RS in the Standard solution (mg/mL)
CU== nominal concentration of the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0, calculated on the dried basis
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.1%
•  Heavy Metals, Method II 231: NMT 10 ppm
Organic Impurities 
[Note—If ethylphenidate or bis-methylphenidate is a known process impurity, Procedure 2 is recommended. ]
•  Procedure 1
Buffer, Mobile phase, System suitability solution, Sample solution, Chromatographic system, and System suitability:  Proceed as directed in the Assay.
Analysis 
Sample:  Sample solution
Identify each impurity using the relative retention times in Impurity Table 1. Calculate the percentage of each impurity in the portion of Methylphenidate Hydrochloride taken:
Result = (rU/rT) × 100
rU== peak response for each impurity in the Sample solution
rT== sum of the responses for all impurity peaks including the methylphenidate peak in the Sample solution
Individual impurities:  See Impurity Table 1.
Total impurities:  NMT 1.0%
Impurity Table 1
Name Relative
Retention
Time
Acceptance
Criteria,
NMT (%)
Erythro(R,S) isomera 0.58 0.15
Methylphenidate related compound Ab 0.85 0.5
Methylphenidate 1.0
Any individual, unspecified impurity 0.10
a  Methyl (RS,SR)-2-phenyl-2-(piperidin-2-yl)acetate.
b  (RS,RS)2-Phenyl-2-(piperidin-2-yl)acetic acid. [Note—Also known as -phenyl-2-piperidine acetic acid. ]
•  Procedure 2
[Note—Perform this test only if ethylphenidate or bis-1,2-(-carboxymethylbenzyl) piperidine is a known process impurity. ]
Buffer A:  5.7 g of monobasic ammonium phosphate and 1.6 g of 1-octanesulfonate sodium in 1 L of water
Buffer B:  Add 4 mL of triethylamine to 1 L of Buffer A. Adjust with phosphoric acid to a pH of 2.9.
Solution A:  Acetonitrile and Buffer B (7:43)
Solution B:  Acetonitrile and Buffer A (4:1)
Standard solution:  0.5 µg/mL of USP Methylphenidate Hydrochloride RS in Solution A
System suitability solution:  0.5 mg/mL of USP Methylphenidate Hydrochloride RS; and 3 µg/mL each of USP Methylphenidate Related Compound A RS, phenylacetic acid, and USP Methylphenidate Hydrochloride Erythro Isomer Solution RS in Solution A
Sample solution:  0.5 mg/mL of Methylphenidate Hydrochloride in Solution A. [Note—Allow the solution to stand for at least 2 h. ]
Mobile phase:  See the gradient table below. (See also Chromatography 621, System Suitability).
Time
(min)
Solution A
(%)
Solution B
(%)
0 90 10
7 65 35
10 50 50
12 50 50
13 90 10
16 90 10
[Note—Equilibration of the chromatographic system at the initial conditions for a minimum of 30 min is recommended before the first injection. ]
Chromatographic system 
Mode:  LC
Detector:  UV 220 nm
Column:  3.9-mm × 15-cm; 5-µm packing L7
Column temperature:  40
Flow rate:  2.8 mL/min
Injection size:  10 µL
System suitability 
Sample:  System suitability solution. [Note—Identify the peaks using the relative retention times in Impurity Table 2. ]
Suitability requirements 
Resolution:  NLT 2.7 between methylphenidate related compound A and phenylacetic acid; NLT than 3.6 between phenylacetic acid and erythro isomer
Tailing factor:  NMT 2.0 for the methylphenidate peak
Relative standard deviation:  NMT 2.0% for the methylphenidate peak; NMT 5.0% for methylphenidate related compound A, phenylacetic acid, and methylphenidate hydrochloride erythro isomer
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of any individual impurity in the portion of Methylphenidate Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response for each impurity peak from the Sample solution
rS== peak response for the methylphenidate peak from the Standard solution
CS== concentration of USP Methylphenidate Hydrochloride RS in the Standard solution (mg/mL)
CU== concentration of Methylphenidate Hydrochloride in the Sample solution (mg/mL)
F== relative response factor (see Impurity Table 2)
Impurity acceptance criteria 
Individual impurities:  See Impurity Table 2.
Total impurities:  NMT 0.5%
Impurity Table 2
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
Methylphenidate related compound Aa 0.55 1.1 0.2
Phenylacetic acid 0.67 1.0 0.1
Erythro(R,S) isomerb 0.80 1.0 0.2
Methylphenidate 1.0
Ethylphenidatec 1.22 0.9 0.1
Bis-methylphenidated 1.80 2.6 0.1
Any individual, unspecified impurity 1.0 0.1
a  (RS,SR)2-Phenyl-2-(piperidin-2-yl)acetic acid. [Note—Also known as -phenyl-2-piperidine acetic acid. ]
b  Methyl (RS,SR)-2-phenyl-2-(piperidin-2-yl)acetate.
c  Ethyl (RR,SS)-2-phenyl-2-(piperidin-2-yl)acetate.
d  1,2-Bis(carboxymethylbenzyl)piperidine. [Note—Also known as 1,2-(-carboxymethylbenzyl)piperidine. ]
SPECIFIC TESTS
•  Loss on Drying 731: Dry a sample in a vacuum at 60 for 4 h: it loses NMT 0.5% of its weight.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in well-closed containers.
•  Labeling If a test for Organic Impurities other than Procedure 1 is used, then the labeling states the procedure with which the article complies.
•  USP Reference Standards 11
USP Methylphenidate Hydrochloride Erythro Isomer Solution RS
This solution contains 0.5 mg of methylphenidate hydrochloride erythro isomer per mL in methanol.
USP Methylphenidate Hydrochloride RS Click to View Structure
USP Methylphenidate Related Compound A RS
-Phenyl-2-piperidineacetic acid hydrochloride.
    C13H17NO2·HCl        255.75
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USP35–NF30 Page 3880
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