3660 Levetiracetam / Official Monographs USP 35

Mr1 = molecular weight of levetiracetam related Mode: LC

compound B free base, 102.1 Detector: UV 215 nm
Mr2 = molecular weight of levetiracetam related Column: 4.6-mm 25-cm; 10-m packing L51
compound B, 138.6 Flow rate: 1.0 mL/min
Acceptance criteria: NMT 0.10% Injection size: 20 L
[NOTEThe amount of levetiracetam related compound B System suitability
measured is to be included in the total impurities in the Sample: System suitability solution
test for Organic Impurities, Procedure 2.] [NOTEThe relative retention times for levetiracetam R-
PROCEDURE 2 enantiomer and levetiracetam S-enantiomer are 0.55 and
Buffer, Solution A, Solution B, Mobile phase, System 1.0, respectively.]
suitability solution, and Chromatographic system: Suitability requirements
Proceed as directed in the Assay. Resolution: NLT 4.0 between the R- and S-enantiomers
Standard solution: 0.005 mg/mL of USP Levetiracetam RS [NOTEIf a loss of resolution (less than 4.0) is observed, it
in Solution A is recommended that the column temperature be
Sample solution: 5 mg/mL of Levetiracetam in Solution A maintained at 25 to stabilize the system.]
Analysis Analysis
Samples: Standard solution and Sample solution Samples: Standard solution and Sample solution
Calculate the percentage of each impurity in the portion Calculate the percentage of levetiracetam R-enantiomer in
of Levetiracetam taken: the portion of Levetiracetam taken:
Result = (rU/rS) (CS/CU) (1/F) 100 Result = (rU/rS) (CS/CU) 100
rU = peak response of each impurity from the Sample rU = peak response of levetiracetam R-enantiomer
solution from the Sample solution
rS = peak response of levetiracetam from the rS = peak response of levetiracetam from the Standard
Standard solution solution
CS = concentration of USP Levetiracetam RS in the CS = concentration of USP Levetiracetam RS in the
Standard solution (mg/mL) Standard solution (mg/mL)
CU = concentration of Levetiracetam in the Sample CU = concentration of Levetiracetam in the Sample
solution (mg/mL) solution (mg/mL)
F = relative response factor (see Impurity Table 1) Acceptance criteria: NMT 0.8%
[NOTEDisregard any peak with a relative retention time
ADDITIONAL REQUIREMENTS
of 0.19 or less.]
PACKAGING AND STORAGE: Preserve in well-closed containers,
Acceptance criteria
and store at room temperature.
Individual impurities: See Impurity Table 1.
USP REFERENCE STANDARDS 11
Total impurities: NMT 0.4%
USP Levetiracetam RS
USP Levetiracetam Racemic Mixture RS
Impurity Table 1
A 1:1 mixture of levetiracetam S-enatiomer-(2S)-2-(2-
Relative Relative Acceptance oxopyrrolidin-1-yl)butanamide and levetiracetam R-
Retention Response Criteria, enantiomer (2R)-2-(2-oxopyrrolidin-1-yl)butanamide.
Name Time Factor NMT (%) USP Levetiracetam Related Compound A RS
(S)-N-(1-Amino-1-oxobutan-2-yl)-4-chlorobutanamide.
Pyridin-2-ol
a
0.37 1.0 0.025
C8H14ClNO3 207.65
Levetiracetam acid
b
0.62 1.2 0.3
USP Levetiracetam Related Compound B RS
Levetiracetam 1.00
(S)-2-Aminobutanamide hydrochloride.
Levetiracetam related
C4H10N2O HCl 138.6
compound A
c
1.25 0.35 0.05
Any individual
unspecified impurity 1.0 0.05
.
a
Not included in the Total impurities limit.
b
(S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid. Included in the Total impurities Levetiracetam Tablets
limit.
c
(S)-N-(1-Amino-1-oxobutan-2-yl)-4-chlorobutanamide. Included in the
DEFINITION
Total impurities limit only if levetiracetam related compound B is a known
Levetiracetam Tablets contain NLT 90.0% and NMT 110.0% of
process impurity.
the labeled amount of levetiracetam (C8H14N2O2).
SPECIFIC TESTS
IDENTIFICATION
WATER DETERMINATION, Method Ia 921: NMT 0.5%
A. INFRARED ABSORPTION 197K
LIMIT OF LEVETIRACETAM R-ENANTIOMER
B. The retention time of the major peak of the Sample solu-
Mobile phase: n-Hexane and dehydrated alcohol (4:1)
tion corresponds to that of the Standard solution, as obtained
System suitability solution: 0.1 mg/mL of USP
in the Assay.
Levetiracetam Racemic Mixture RS in Mobile phase
Standard solution: 0.05 mg/mL of USP Levetiracetam RS in
ASSAY
Mobile phase
PROCEDURE
Sample solution: 10 mg/mL of Levetiracetam in Mobile
Buffer: 1.4 g/L of monobasic potassium phosphate and 0.6
phase
g/L of sodium 1-heptanesulfonate, adjusted with phosphoric
Chromatographic system
acid to a pH of 2.8
(See Chromatography 621, System Suitability.)
Mobile phase: Acetonitrile and Buffer (8:92)
Diluent: Acetonitrile and water (20:80)
Standard solution: 0.35 mg/mL of USP Levetiracetam RS in
Diluent. Sonication may be used to aid dissolution.
Sample solution: Nominally 0.4 mg/mL of levetiracetam
from NLT 20 Tablets, finely crushed, in Diluent. Sonication
may be used to aid dissolution.
Official from May 1, 2012
Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 128.83.63.20 by nEwp0rt1 on Fri Nov 25 03:25:11 EST 2011
USP 35 Official Monographs / Levetiracetam 3661
Chromatographic system CS = concentration of USP Levetiracetam RS in the
(See Chromatography 621, System Suitability.) Standard solution (mg/mL)
Mode: LC L = label claim (mg/Tablet)
Detector: UV 220 nm V = volume of Medium, 900 mL
Column: 4.6-mm 25-cm; 4-m packing L1 Tolerances: NLT 70% (Q) of the labeled amount of
Flow rate: 2 mL/min levetiracetam (C8H14N2O2) in 15 min for Tablets labeled to
Injection size: 10 L contain 250, or 500, or 750 mg; NLT 80% (Q) of the
System suitability labeled amount of levetiracetam (C8H14N2O2) in 30 min for
Sample: Standard solution Tablets labeled to contain 1000 mg
Suitability requirements

Test 2: If the product complies with this test, the labeling

Tailing factor: NMT 2.0 indicates that the product meets USP Dissolution Test 2.
Relative standard deviation: NMT 2.0% Medium: Water; 900 mL, deaerate, if necessary
Analysis Apparatus 2: 50 rpm
Samples: Standard solution and Sample solution Time: 15 min
Calculate the percentage of levetiracetam (C8H14N2O2) in the Buffer: 1.36 g/L of monobasic potassium phosphate,
portion of Tablets taken: adjusted with 10% potassium hydroxide to a pH of 5.0
Mobile phase: Acetonitrile and Buffer (10:90)
Result = (rU/rS) (CS/CU) 100 Standard solution: 54 g/mL of USP Levetiracetam RS in
Medium
rU = peak response from the Sample solution
Sample solution: Pass a portion of the solution under test
rS = peak response from the Standard solution
through a suitable filter. Dilute an aliquot with Medium to
CS = concentration of USP Levetiracetam RS in the
obtain a concentration similar to that of the Standard
Standard solution (mg/mL)
solution.
CU = nominal concentration of levetiracetam in the
Chromatographic system
Sample solution (mg/mL)
(See Chromatography 621, System Suitability.)
Acceptance criteria: 90.0%110.0%
Mode: LC
Detector: UV 210 nm
PERFORMANCE TESTS
Column: 4.6-mm 15-cm; 5-m packing L1
Column temperature: 30
Flow rate: 1.5 mL/min Change to read:
Injection size: 20 L
System suitability
Dissolution 711
Sample: Standard solution
Test 1

(RB 1-May-2011)
Suitability requirements
Medium: Water; 900 mL
Tailing factor: NMT 1.5
Apparatus 2: 50 rpm
Relative standard deviation: NMT 1.0%
Time: See Table 1.
Analysis
Samples: Standard solution and Sample solution
Table 1
Determine the percentage of levetiracetam (C8H14N2O2)
Tablet Strength Time dissolved:
(mg/Tablet) (min)
Result = (rU/rS) (CS/L) D V 100
250 15
500 15
rU = peak response from the Sample solution
750 15
rS = peak response from the Standard solution
1000 30 CS = concentration of USP Levetiracetam RS in the
Standard solution (mg/mL)
Buffer: 6.8 g/L of monobasic potassium phosphate,
L = label claim (mg/Tablet)
adjusted with dilute potassium hydroxide to a pH of 5.6
D = dilution factor of the Sample solution
Mobile phase: Acetonitrile and Buffer (15:85)
V = volume of Medium, 900 mL
Standard solution: (L/1000) mg/mL in Medium, where L is
Tolerances: NLT 80% (Q) of the labeled amount of
the Tablet label claim, in mg
levetiracetam (C8H14N2O2) is dissolved.
Sample solution: Pass a portion of the solution under test
Test 3: If the product complies with this test, the labeling
though a suitable filter of 0.45-m pore size.
indicates that the product meets USP Dissolution Test 3.
Chromatographic system
Medium: Water; 900 mL
(See Chromatography 621, System Suitability.)
Apparatus 2: 50 rpm
Mode: LC
Time: 30 min
Detector: UV 220 nm
Buffer, Mobile phase, Standard solution, Sample solution,
Column: 4.6-mm 15-cm; 5-m packing L1
Chromatographic system, System suitability, and
Flow rate: 1.2 mL/min
Analysis: Proceed as directed for Test 1.
Injection size: 10 L
Tolerances: NLT 80% (Q) of the labeled amount of
System suitability
levetiracetam (C8H14N2O2) is dissolved.

(RB 1-May-2011)
Sample: Standard solution
UNIFORMITY OF DOSAGE UNITS 905: Meet the requirements
Suitability requirements
Tailing factor: NMT 2.0 IMPURITIES
Relative standard deviation: NMT 2.0% ORGANIC IMPURITIES
Analysis Buffer: 6.8 g/L of monobasic potassium phosphate and 0.85
Samples: Standard solution and Sample solution g/L of sodium 1-heptanesulfonate, adjusted with phosphoric
Determine the percentage of levetiracetam ( C8H14N2O2) acid to a pH of 2.8
dissolved: Mobile phase: Acetonitrile and Buffer (5:95)
System suitability solution: 3.6 g/mL of USP
Result = (rU/rS) (CS/L) V 100
Levetiracetam RS and 3.6 g/mL of USP Levetiracetam
Related Compound B RS in Mobile phase
rU = peak response from the Sample solution
Standard solution: 3.6 g/mL of USP Levetiracetam RS in
rS = peak response from the Standard solution
Mobile phase
Official from May 1, 2012
Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 128.83.63.20 by nEwp0rt1 on Fri Nov 25 03:25:11 EST 2011
3662 Levetiracetam / Official Monographs USP 35
Sample solution: Equivalent to 1.2 mg/mL of levetiracetam .
from NLT 20 Tablets, finely crushed, in Mobile phase.
Levmetamfetamine
[NOTESonicate if necessary, and centrifuge the solution
before passing through a suitable filter.]
Chromatographic system
(See Chromatography 621, System Suitability.)
Mode: LC
C10H15N 149.24
Detector: UV 200 nm
Benzeneethanamine, N, -dimethyl-, (R)-.
Column: 4.6-mm 25-cm; 4-m packing L1
()-(R)-N, -Dimethylphenethylamine [33817-09-3].
Flow rate: 1 mL/min
Injection size: 10 L
Levmetamfetamine contains not less than 98.0
System suitability
percent and not more than 100.5 percent of Samples: System suitability solution and Standard solution
Suitability requirements C
10
H
15
N.
Resolution: NLT 2.0 between levetiracetam related
Packaging and storagePreserve in tight, light-resistant compound B and levetiracetam, System suitability solution
containers. Tailing factor: NMT 2.0, Standard solution
Relative standard deviation: NMT 10.0%, Standard
USP Reference standards 11
solution
USP Levmetamfetamine RS
Analysis
USP Methamphetamine Hydrochloride RS
Samples: Standard solution and Sample solution
Calculate the percentage of each impurity in the portion of Identification
Tablets taken:
A: Infrared Absorption 197F.
B: The retention time of the major peak in the chromato-
Result = (rU/rS) (CS/CU) (1/F) 100
gram of the Test solution corresponds to that in the chromato-
gram of the System suitability solution, as obtained in the test
rU = peak response of each impurity from the Sample
for Limit of methamphetamine.
solution
Specific rotation 781S: between 18.5 and 21.5. rS = peak response of levetiracetam from the Standard
solution Test solution: 16 mg per mL, in 1.2 N hydrochloric acid.
CS = concentration of USP Levetiracetam RS in the
Limit of methamphetamine
Standard solution (mg/mL)
Mobile phasePrepare a filtered and degassed mixture of
CU = nominal concentration of levetiracetam in the
hexane, isopropyl alcohol, and acetonitrile (98:1.5:0.5). Make
Sample solution (mg/mL)
adjustments if necessary (see System Suitability under Chroma-
F = relative response factor (see Table 2)
tography 621).
Acceptance criteria: See Table 2.
Resolution solutionMix suitable quantities of a solution of
USP Methamphetamine Hydrochloride RS in chloroform and
Table 2
USP Levmetamfetamine RS in chloroform to obtain a solution
Relative Relative Acceptance containing about 0.025 mg per mL and 2.5 mg per mL of
Retention Response Criteria, methamphetamine hydrochloride and levmetamfetamine, re-
Name Time Factor NMT (%) spectively. Transfer 2.0 mL of this solution to a suitable con-
tainer, add 10 mg of 2-naphthyl chloroformate and 2.0 mL of
Levetiracetam related

chloroform, mix with a vortex mixer, and allow to stand for 5
compound B
a,b
0.54
minutes. To this solution, add 2 mL of 1 N sodium hydroxide,
Levetiracetam 1.0
mix with a vortex mixer, allow to stand for 5 minutes, and
Levetiracetam related
discard the aqueous layer. Wash the organic layer twice with 2
compound A
a,c
1.7
mL of 1 N sodium hydroxide, discarding the aqueous layer. To
Levetiracetam acid
d
2.1 0.79 0.3
the organic layer add 2 mL of 1 N hydrochloric acid, mix with a
Any individual
vortex mixer, and discard the aqueous layer. Wash the organic
unspecified impurity 1.0 0.1
layer twice with 2 mL of 1 N hydrochloric acid, discarding the
Total impurities 0.6 aqueous layer. To the organic layer add 2 mL of water, mix
with a vortex mixer, and discard the aqueous layer. Wash the a
These impurities are listed for information only; they are process
organic layer twice with 2 mL of water, discarding the aqueous
impurities, which are controlled in the drug substance.
layer. To the organic layer add about 1.0 g of anhydrous so- b
(S)-2-Aminobutanamide.
dium sulfate, and mix with a vortex mixer. Transfer 1.0 mL of c
(S)-N-(1-Amino-1-oxobutan-2-yl)-4-chlorobutanamide.
this solution to a 10-mL volumetric flask, dilute with Mobile d
(S)-2-(2-Oxopyrrolidine-1-yl)butanoic acid.
phase to volume, mix, and filter.
ADDITIONAL REQUIREMENTS
Test solutionTransfer about 62.5 mg of Levmetamfetamine,
PACKAGING AND STORAGE: Preserve in tight containers. Store
accurately weighed, to a 25-mL volumetric flask, dissolve in and
at controlled room temperature.
dilute with chloroform to volume, and mix. Transfer 2.0 mL of
this solution to a suitable container, and proceed as directed in
Resolution solution beginning with add 10 mg of 2-naphthyl Add the following:
chloroformate and 2 mL of chloroform.

LABELING: When more than one Dissolution test is given, Chromatographic system (see Chromatography 621)The
the labeling states the Dissolution test used only if Test 1 is liquid chromatograph is equipped with a 274-nm detector and
not used.

(RB 1-May-2011) a 4.6-mm 25-cm column that contains packing L36. The flow
USP REFERENCE STANDARDS 11 rate is about 1.5 mL per minute. Chromatograph the Resolution
USP Levetiracetam RS solution, and record the peak responses as directed for Proce-
USP Levetiracetam Related Compound B RS dure: the relative retention times are about 0.9 for
(S)-2-Aminobutanamide. methamphetamine and 1.0 for levmetamfetamine; and the res-
C4H10N2O 102.13 olution, R, between methamphetamine and levmetamfetamine
is not less than 1.4. Chromatograph the Test solution, and re-
cord the peak responses as directed for Procedure: the relative
Official from May 1, 2012
Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 128.83.63.20 by nEwp0rt1 on Fri Nov 25 03:25:11 EST 2011