Interim Revision Announcement

Official March 1, 2013 Tramadol 1

. rU = peak response of tramadol from the Sample
solution
Tramadol Hydrochloride
rS = peak response of tramadol from the Standard
solution
CS = concentration of USP Tramadol Hydrochloride
RS in the Standard solution (mg/mL)
CU = concentration of Tramadol Hydrochloride in
the Sample solution (mg/mL)
Acceptance criteria: 98.0%102.0% on the anhydrous
basis
IMPURITIES
C16H25NO2 HCl 299.84
RESIDUE ON IGNITION 281: NMT 0.1%
()-cis-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)
HEAVY METALS, Method I 231: 20 ppm
cyclohexanol hydrochloride;
CONTENT OF CHLORIDE
()-cis-2-[(Dimethylamino)methyl]-1-(m-methoxyphenyl)
Sample solution: 150 mg of Tramadol Hydrochloride
cyclohexanol hydrochloride [36282-47-0].
in 40 mL of water
Analysis: To the Sample solution add, with stirring,
DEFINITION
7.5 mL of 4 N nitric acid and 15.0 mL of 0.1 N silver
Tramadol Hydrochloride contains NLT 98.0% and NMT
nitrate, and titrate with 0.1 N ammonium thiocyanate
102.0% of tramadol hydrochloride (C16H25NO2 HCl), cal-
VS, determining the endpoint potentiometrically, and
culated on the anhydrous basis.
using a silverglass electrode system. Each mL of 0.1 N
IDENTIFICATION ammonium thiocyanate is equivalent to 3.545 mg of
A. INFRARED ABSORPTION 197K chloride.
B. IDENTIFICATION TESTSGENERAL, Chloride 191: An Acceptance criteria: 11.6%12.1% of chloride is
aqueous solution (1 in 100) meets the requirements. found.
Add the following: Change to read:

. C. The retention time of the major peak of the Sample LIMIT OF TRAMADOL RELATED COMPOUND B

.(2-[(Dimethy-
solution corresponds to that of the Standard solution, as lamino)methyl]cyclohexanone hydrochloride)

(IRA 1-Mar-2013)
obtained in the Assay.

(IRA 1-Mar-2013) Standard solution: 0.1 mg/mL of USP Tramadol Re-

lated Compound B RS in methanol
ASSAY
Sample solution: 50 mg/mL of Tramadol Hydrochlo-
ride in methanol
Adsorbent: 0.25-mm layer of chromatographic silica
Change to read:
gel mixture
Developing solvent system: Toluene, isopropyl alco-
PROCEDURE
hol, and 25% ammonia water (80:19:1)
Solution A: Dissolve

.2

(ERR 1-Jan-2012) mL of trifluoroace-

Sodium nitrite solution: 50 mg/mL of sodium nitrite
tic acid in 1000 mL of water.
in water
Mobile phase: Acetonitrile and Solution A (30:70)
Analysis:

.Place the plate in a chromatographic cham-

System suitability solution: 0.05 mg/mL each of USP
ber saturated with ammonia vapor from stronger am-
Tramadol Hydrochloride RS and USP Tramadol Hydro-
monia water, and allow to stand for NLT 20 min.

(IRA 1-
chloride Related Compound A RS in Mobile phase
Mar-2013) Separately apply about 10 L each of the Sam-
Standard solution: 1.5 mg/mL of USP Tramadol Hy-
ple solution and the Standard solution to the plate, and
drochloride RS in Mobile phase
develop the plate until the solvent front is

.NLT

(IRA 1-
Sample solution: 1.5 mg/mL of Tramadol Hydrochlo-
Mar-2013) 10 cm above the line of application. Remove
ride in Mobile phase
the plate, spray with Dragendorffs TS, and air-dry for
Chromatographic system
5 min. Spray the dried plate with Sodium nitrite solution
(See Chromatography 621, System Suitability.)
until the spot from tramadol related compound B in
Mode: LC
the Standard solution is visible. Any secondary spot
Detector: UV 270 nm
from the Sample solution corresponding to tramadol re-
Column: 4.6-mm 25-cm; 5-m packing L1
lated compound B is not more intense than a corre-
Flow rate: 1 mL/min
sponding spot from the Standard solution.
Injection volume: 20 L
Acceptance criteria: NMT 0.2%
System suitability
ORGANIC IMPURITIES
Sample: System suitability solution
Mobile phase, System suitability solution, Sample so-
[NOTEThe relative retention times for tramadol re-
lution, Chromatographic system, and System suita-
lated compound A and tramadol are about 0.9 and
bility: Proceed as directed in the Assay.
1.0, respectively.]
Analysis
Suitability requirements
Sample: Sample solution
Resolution: NLT 2.0 between tramadol related com-
Calculate the percentage of each impurity in the por-
pound A and tramadol
tion of Tramadol Hydrochloride taken:
Relative standard deviation: NMT 2.0%
Analysis
Result = (rU/rT) 100
Samples: Standard solution and Sample solution
Calculate the percentage of tramadol hydrochloride
rU = peak response of each impurity from the
(C16H25NO2 HCl) in the portion of Tramadol Hydro-
Sample solution
chloride taken:
rT = sum of all the peak responses from the Sample
solution
Result = (rU/rS) (CS/CU) 100
2013 The United States Pharmacopeial Convention All Rights Reserved.
Interim Revision Announcement
2 Tramadol Official March 1, 2013
Acceptance criteria
Change to read:
Tramadol related compound A: NMT 0.2%
Individual impurities: NMT 0.1%
USP REFERENCE STANDARDS 11
Total impurities: NMT 0.4%
USP Tramadol Hydrochloride RS
USP Tramadol Related Compound A RS
SPECIFIC TESTS

.(RS,SR)-1-(3-Methoxyphenyl)-2-(dimethylami-
WATER DETERMINATION, Method Ia 921: NMT 0.5%
nomethyl)cyclohexanol hydrochloride.
ACIDITY
C16H25NO2 HCl 299.84

(IRA 1-Mar-2013)
Sample solution: 500 mg of Tramadol Hydrochloride
USP Tramadol Related Compound B RS
in 10 mL of water

.(2-[(Dimethylamino)methyl]cyclohexanone
Analysis: To the Sample solution add 0.2 mL of methyl
hydrochloride).
red TS and 0.2 mL of 0.01 N hydrochloric acid VS, and
C9H17NO HCl 191.70

(IRA 1-Mar-2013)
titrate with 0.01 N sodium hydroxide VS.
Acceptance criteria: NMT 0.4 mL of 0.01 N sodium
hydroxide VS is required to produce a yellow color.
ADDITIONAL REQUIREMENTS
PACKAGING AND STORAGE: Preserve in tight containers,
and store at controlled room temperature.
2013 The United States Pharmacopeial Convention All Rights Reserved.