Accessed from 167.205.22.

104 by merck1 on Tue Oct 28 01:57:14 EDT 2014

USP 37

Official Monographs / Metformin 3729

Identification
A: Infrared Absorption 197K.
B: To 0.5 mL of a solution (1 in 2000) add 1 mL of FolinCiocalteu phenol TS, then add 5 mL of sodium carbonate
solution (1 in 10), mix, and allow to stand for 5 minutes: an
intense blue color appears (presence of a phenol).
C: To 4 mL of a solution (1 in 2000) add 5 mL of pH 9.6
alkaline borate buffer (see Buffer Solutions in the section Reagents, Indicators, and Solutions), then add about 5 mg of naphthoquinone-4-sodium sulfonate, mix until dissolved,
and allow to stand for 5 minutes. Add 0.2 mL of benzalkonium chloride solution (1 in 100), mix, add 5 mL of toluene,
and shake: the toluene layer turns purple immediately (distinction from phenylephrine).
Melting range 741: between 171 and 175.
Specific rotation 781S: between 31.5 and 33.5 (=
405 nm).
Test solution: 100 mg per mL, in 0.5 N hydrochloric acid.
pH 791: between 3.2 and 3.5, in a solution (1 in 20).
Loss on drying 731Dry it at 105 for 2 hours: it loses
not more than 1.0% of its weight.
Residue on ignition 281: not more than 0.1%.
Heavy metals, Method I 231: 0.002%.
AssayDissolve about 600 mg of Metaraminol Bitartrate,
accurately weighed, in 20 mL of glacial acetic acid, warming
slightly to effect solution. Cool the solution to room temperature, add 2 drops of crystal violet TS, and titrate with 0.1 N
perchloric acid VS to an emerald-green color. Perform a
blank determination, and make any necessary correction.
Each mL of 0.1 N perchloric acid is equivalent to 31.73 mg
of C9H13NO2 C4H6O6.

Mobile phasePrepare a suitable degassed and filtered

mixture of methanol and 0.0032 M Hexanesulfonate buffer
(7:3). Make adjustments if necessary (see System Suitability
under Chromatography 621).
Standard preparationDissolve an accurately weighed
quantity of USP Metaraminol Bitartrate RS in water to obtain
a solution having a known concentration of about 0.2 mg of
metaraminol per mL.
Assay preparationTransfer an accurately measured volume of Injection, equivalent to about 20 mg of metaraminol, to a 100-mL volumetric flask, dilute with water to volume, and mix.
System suitability preparationPrepare a solution of propylparaben in alcohol containing 0.4 mg per mL. Mix 1 volume of this solution with 99 volumes of the Standard preparation.
Chromatographic system (see Chromatography 621)The
liquid chromatograph is equipped with a 264-nm detector
and a 4-mm 25-cm column that contains packing L7. The
flow rate is about 1 mL per minute. Chromatograph the System suitability preparation and the Standard preparation, and
record the peak responses as directed for Procedure: the column efficiency is not less than 2600 theoretical plates, the
resolution, R, between the metaraminol bitartrate and propylparaben peaks is not less than 3.0 with propylparaben
eluting first, and the relative standard deviation for replicate
injections is not more than 2.0%.
ProcedureSeparately inject equal volumes (about 10 L)
of the Standard preparation and the Assay preparation into
the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of metaraminol (C9H13NO2) in each mL of the
Injection taken by the formula:
100(C / V)(rU / rS)

Metaraminol Bitartrate Injection is a sterile solution of Metaraminol Bitartrate in Water for Injection. It contains, in each mL, an amount of
metaraminol bitartrate equivalent to not less than
9.0 mg and not more than 11.0 mg of metaraminol (C9H13NO2).
Packaging and storagePreserve in single-dose or in
multiple-dose containers, preferably of Type I glass, protected from light.
USP Reference standards 11
USP Endotoxin RS
USP Metaraminol Bitartrate RS
Identification
A: Evaporate a 1-mL portion to dryness: the residue so
obtained meets the requirements for Identification test A
under Metaraminol Bitartrate.
B: It meets the requirements for Identification tests B and
C under Metaraminol Bitartrate.
Bacterial endotoxins 85It contains not more than 3.5
USP Endotoxin Units per mg of metaraminol.
pH 791: between 3.2 and 4.5.
Particulate matter 788: meets the requirements for
small-volume injections.
Other requirementsIt meets the requirements under Injections 1.
Assay
0.0032 M Hexanesulfonate bufferMix 600 mg of sodium
1-hexanesulfonate with water to obtain 1000 mL of solution,
adjust with phosphoric acid to a pH of 3.0 0.05, and
filter.

in which C is the concentration, in mg per mL, of metaraminol represented by the USP Metaraminol Bitartrate RS in the
Standard preparation; V is the volume, in mL, of Injection
taken; and rU and rS are the peak responses obtained from
the Assay preparation and the Standard preparation, respectively.

Metformin Hydrochloride

C4H11N5 HCl
165.62
Imidodicarbonimidic diamide, N,N-dimethyl-,
monohydrochloride;
1,1-Dimethylbiguanide monohydrochloride [1115-70-4].
DEFINITION
Metformin Hydrochloride contains NLT 98.5% and NMT
101.0% of metformin hydrochloride (C4H11N5 HCl), calculated on the dried basis.
IDENTIFICATION
A. INFRARED ABSORPTION 197K
B. IDENTIFICATION TESTSGENERAL, Chloride 191: Meets
the requirements
ASSAY
PROCEDURE
Sample: 60 mg of Metformin Hydrochloride
Analysis
[NOTETo avoid overheating of the reaction medium,
mix thoroughly throughout the titration, and stop the

Official from August 1, 2014

Copyright (c) 2014 The United States Pharmacopeial Convention. All rights reserved.

USP Monographs

Metaraminol Bitartrate Injection

.

Accessed from 167.205.22.104 by merck1 on Tue Oct 28 01:57:14 EDT 2014

3730 Metformin / Official Monographs

USP Monographs

titration immediately after the endpoint has been

reached.]
Dissolve the Sample in 4 mL of anhydrous formic acid,
and add 50 mL of acetic anhydride. Titrate with 0.1 N
perchloric acid VS, determining the endpoint potentiometrically. Perform a blank determination, and make
any necessary correction (see Titrimetry 541). Each
mL of 0.1 N perchloric acid is equivalent to 8.28 mg
of metformin hydrochloride (C4H11N5 HCl).
Acceptance criteria: 98.5%101.0% on the dried basis
IMPURITIES
RESIDUE ON IGNITION 281: NMT 0.1%
HEAVY METALS, Method I 231: NMT 10 ppm
ORGANIC IMPURITIES
Mobile phase: 17 g/L of monobasic ammonium phosphate in water, adjusted with phosphoric acid to a pH
of 3.0
System suitability stock solution: 0.25 mg/mL of
metformin hydrochloride and 0.1 mg/mL of melamine
in water
System suitability solution: Transfer 1.0 mL of the System suitability stock solution to a 50-mL volumetric flask,
and dilute with Mobile phase to volume.
Standard stock solution: 0.2 mg/mL of USP Metformin
Related Compound A RS in water
Standard solution: 0.001 mg/mL of USP Metformin Related Compound A RS in Mobile phase from the Standard stock solution
Sample solution: 5 mg/mL of Metformin Hydrochloride
in Mobile phase
Diluted sample solution: 0.005 mg/mL of Metformin
Hydrochloride in Mobile phase from the Sample solution
Chromatographic system
(See Chromatography 621, System Suitability.)
Mode: LC
Detector: UV 218 nm
Column: 4.6-mm 25-cm; packing L9
Flow rate: 1.01.7 mL/min
Run time: NLT twice the retention time of metformin
Injection volume: 20 L
System suitability
Sample: System suitability solution
Suitability requirements
Resolution: NLT 10 between melamine and
metformin
Analysis
Samples: Standard solution, Sample solution, and Diluted sample solution
Calculate the percentage of metformin related compound A in the portion of Metformin Hydrochloride
taken:
Result = (rU/rS) (CS/CU) 100
rU

= peak response of metformin related

compound A from the Sample solution
rS
= peak response of metformin related
compound A from the Standard solution
CS
= concentration of USP Metformin Related
Compound A RS in the Standard solution
(mg/mL)
CU
= concentration of Metformin Hydrochloride in
the Sample solution (mg/mL)
Calculate the percentage of any other impurity in the
portion of Metformin Hydrochloride taken:
Result = (rU/rS) D 100
rU
rS
D

= peak response of an individual impurity from

the Sample solution
= peak response of metformin from the Diluted
sample solution
= dilution factor for the preparation of the
Diluted sample solution, 0.001

USP 37
Acceptance criteria
Individual impurities: NMT 0.02% for metformin related compound A; NMT 0.1% for any other impurity
Total impurities: NMT 0.5%
SPECIFIC TESTS
LOSS ON DRYING 731
Analysis: Dry a sample at 105 for 5 h.
Acceptance criteria: NMT 0.5%
ADDITIONAL REQUIREMENTS
PACKAGING AND STORAGE: Preserve in well-closed containers. Store at room temperature.
USP REFERENCE STANDARDS 11
USP Metformin Hydrochloride RS
USP Metformin Related Compound A RS
1-Cyanoguanidine.
C2H4N4
84.08

Metformin Hydrochloride Tablets

DEFINITION
Metformin Hydrochloride Tablets contain NLT 95.0% and
NMT 105.0% of the labeled amount of metformin hydrochloride (C4H11N5 HCl).
IDENTIFICATION
A. INFRARED ABSORPTION 197K
Sample: Transfer an amount of powdered Tablets,
equivalent to 20 mg of metformin hydrochloride, to a
suitable flask. Add 20 mL of dehydrated alcohol, and
shake. Filter, evaporate the filtrate on a water bath to
dryness, and dry the residue at 105 for 2 h.
Acceptance criteria: Meet the requirements
B.
Solution A: Dissolve 1 g of 1-naphthol in a solution
containing 6 g of sodium hydroxide and 16 g of anhydrous sodium carbonate in 100 mL of water.
Sample solution: Triturate an amount of powdered
Tablets, equivalent of 50 mg of metformin hydrochloride, with 10 mL of water, filter, and use the filtrate.
Analysis: To 5 mL of the Sample solution add 1.5 mL of
5 N sodium hydroxide solution and 1 mL of Solution A.
Add 0.5 mL of sodium hypochlorite TS, dropwise, and
with shaking.
Acceptance criteria: An orange-red color is produced
that darkens on standing.
C. IDENTIFICATION TESTSGENERAL, Chloride 191
Sample solution: Prepare as directed for the Sample solution in Identification test B.
Acceptance criteria: Meet the requirements
ASSAY
PROCEDURE
Standard solution: 10 g/mL of USP Metformin Hydrochloride RS in water
Sample solution: Weigh and finely powder NLT 20
Tablets. Transfer the amount of powder, equivalent to
100 mg of metformin hydrochloride, to a 100-mL volumetric flask. Add 70 mL of water, shake by mechanical
means for 15 min, dilute with water to volume, and
filter, discarding the first 20 mL of the filtrate. Dilute
10.0 mL of the filtrate with water to 100.0 mL, and dilute 10.0 mL of the resulting solution with water to
100.0 mL. The nominal concentration of this solution is
10 g/mL.
Instrumental conditions
(See Spectrophotometry and Light-Scattering 851.)
Mode: UV
Analytical wavelength: Wavelength of maximum absorbance at about 232 nm

Official from August 1, 2014

Copyright (c) 2014 The United States Pharmacopeial Convention. All rights reserved.