2024 Metformin Hydrochloride ll-251

PhEur _
Phenones
Absorbance of a 0.2% w/v solution at 310 nm, not more than DEFINITION
0.2, calculated with reference to the dried substance,
1,1-Dimethylbiguanide hydrochloride.
Appendix II B.
Content
Related substances
98.5 per cent to 101.0 per cent (dried substance).
Carry out in subdued light the method for thin-layer
chromatography, Appendix III A, using the following solutions CHARACTERS
in methanol. Appearance
(1) 1.0% w/v of the substance being examined. White or almost white crystals.
(2) 0.050% w/v of the substance being examined. Solubility
Freely soluble in water, slightly soluble in ethanol
(3) 0.0050% w/v of the substance being examined.
(96 per cent), practically insoluble in acetone and in
(4) 0.050% w/v of metaraminol tartrate BPCRS.
methylene chloride.
CHROMATOGRAPIDC CONDITIONS
IDENTIFICATION
(a) Use a silica gel precoated plate (Merck silica gel 60 plates First identification: B, E.
are suitable).
Second identification: A, C, D, E.
(b) Use the mobile phase as descnbed below.
A. Melting point (2.2.14): 222°C to 226 DC.
(c) Apply 10 !1L of each solution.
B. Infrared absorption spectrophotometry (2.2.24).
(d) Develop the plate to 15 em.
Comparison metformin hydrochloride CRS.
(e) After removal of the plate, dry in air and spray with a
C. Thin-layer chromatography (2.2.27).
solution prepared in the following manner. Mix 25 mL of a
0.45% w/v solution of sulfanilic acid in 1M hydrochloric acid Testsolution Dissolve 20 mg of the substance to be
with 1.5 mL of a 5% w/v solution of sodium nitrite, allow to examined in waterR and dilute to 5 mL with the same
stand for 5 minutes and mix cautiously with 25 mL of solvent.
2M sodium carbonate. Reference solution Dissolve 20 mg of metformin
MOBILE PHASE
hydrochloride CRS in waterR and dilute to 5 mL with the
same solvent.
10 volumes of 13.5M ammonia, 80 volumes of chloroform and
80 volumes of methanol. Plate TLC silica gel G plate R.
Mobile phase glacial acetic acidR, butanol R, water R
LIMITS
(10:40:50 VIV/V); use the upper layer.
Any secondary spot in the chromatogram obtained with
Application 5!1L.
solution (1) is not more intense than the spot in the
chromatogram obtained with solution (3) (0.5%). Development Over 3/4 of the plate.
Loss on drying Drying At 100-105 °C for 15 min.
When dried to constant weight at 105°, loses not more than Detection Spray with a mixture of equal volumes of a
0.5% of its weight. Use 1 g. 100 gIL solution of sodium nitroprusside R, a 100 gIL solution
of potassium ferricyanide R and a 100 gIL solution of sodium
Sulfated ash
hydroxide R, prepared 20 min before use.
Not more than 0.1 %, Appendix IX A.
Results The principal spot in the chromatogram obtained
ASSAY with the test solution is similar in position, colour and size to
Carry out Method I for non-aqueous titration, the principal spot in the chromatogram obtained with the
Appendix VIII A, using 0.6 g and crystal violet solution as reference solution.
indicator. Each mL of O.lM perchloric acid VS is equivalent to
D. Dissolve about 5 mg in water R and dilute to 100 mL
31.73 mg of C9H13N02,C~606'
with the same solvent. To 2 mL of the solution add 0.25 mL
of strong sodium hydroxide solution Rand 0.10 mL of
a-naphthol solution R. Mix and allow to stand in iced water
Metformin Hydrochloride for 15 min. Add 0.5 mL of sodium hypobromite solution Rand
mix. A pink colour develops.
(Ph. Eur. monograph 0931) E. It gives reaction (a) of chlorides (2.3.1).
NH NH TESTS
H N~N~N~CH3 , HCI Solution S
2 H I Dissolve 2.0 g in waterR and dilute to 20 mL with the same
CH3
solvent.
165.6 1115-70-4 Appearance of solution
Solution S is clear (2.2.1) and colourless (2.2.2, Method lI).
Action and use Heat the solution to 50°C and cool to room temperature.
Biguanide; treatment of diabetes mellitus.
ImpurityF
Preparations Liquid chromatography (2.2.29).
Metformin Oral Solution Derivatisation solution Prepare the solution immediately before
Metformin Tablets use. Dilute 1 mL ofjluorodinitrobenzene R in 100.0 mL of
Metformin Prolonged-release Tablets acetonitrile R.
Metformin and Sitagliptin Prolonged-release Tablets Blank solution To 5.0 mL of acetonitrile R add 100 !1L of
Metformin and Sitagliptin Tablets triethylamine R1 and 1.0 mL of the derivatisation solution.
ll-252 Metfonnin Hydrochloride 2024

Shake well and heat at 60 "C for 30 min. After cooling, Column:
dilute to 10.0 mL with acetonitrile R. =
- size: 1= 0.25 m, 0 4.6 mrn;
Test solution Prepare the solution immediately before use. - stationary phase: strong cation-exchange silica gelfor
Suspend 10.0 mg of the substance to be examined in 5.0 mL chromatography R (10 um).
of acetonitrile R and sonicate for 5 min. Add 100 !JL of Mobile phase 17 gIL solution of ammonium dihydrogen
triethylamine R1 and 1.0 mL of the derivatisation solution. phosphate R adjusted to pH 3.0 with phosphoric acidR.
Shake well and heat at 60°C for 30 min. After cooling, Flow rate 1.0 mlJmin.
dilute to 10.0 mL with acetonitrile R. Filter or centrifuge at Detection Spectrophotometer at 218 nm.
800 g for 5 min before use.
Injection 20!JL.
Reference solution Dilute 1.0 mL of metformin
impurityF CRS in 100.0 mL of acetonitrile R. Dilute 2.5 mL Run time Twice the retention time of metformin,
of the solution to 100.0 mL with acetonitrile R. To 1.0 mL of Identification of impurities Use the chtomatogram obtained
this solution add successively 5.0 mL of acetonitrile R, 100 !JL with reference solution (a) to identify the peak due to
of triethylamine R1 and 1.0 mL of the derivatisation solution. impurity A; use the chtomatogram obtained with reference
Shake well and heat at 60°C for 30 min. After cooling, solution (c) to identify the peak due to impurity D.
dilute to 10.0 mL with acetonitrile R. Relative retention With reference to metformin (retention
Column: =
time about 14 min): impurity A about 0.3;=
=
- size: 1= 0,125 m, 0 3 mrn; impurity D = about 004.
- stationary phase: spherical end-capped oetadecylsilyl silica gel System suitability Reference solution (c):
for chromatography R1 (5 urn); - resolution: minimum 10 between the peaks due to
- temperature: 30 "C. impurity D and metformin.
Mobile phase: Limits:
- mobile phase A: phosphoric acidR, water for - impurity A: not more than the area of the corresponding
chromatography R (0.1:99.9 V/V); peak in the chtomatogram obtained with reference
- mobile phase B: acetonitrile R; solution (a) (0.02 per cent);
- unspecified impurities: for each impurity, not more than
Time Mobile phase A Mobile phase B 0.5 times the area of the principal peak in the
(min) (per cent VIJ1 (per cent VIP) chtomatogram obtained with reference solution (b)
0-10 60 -+ 45 40 -+ 55 (0.05 per cent);
10 - 11 45 -+ 25 55 -+ 75 - total: maximum 0.2 per cent;
11 - 15 25 75 - disregard limit: 0.3 times the area of the principal peak in
the chtomatogram obtained with reference solution (b)
Flow rate 0.7 mlJmin. (0.03 per cent); do not disregard the peak due to
Detection Spectrophotometer at 380 nm. impurity A.
Injection 5!JL. Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in
Identification of impurities Use the chtomatograms obtained
an oven at 105°C for 5 h.
with the blank solution and the reference solution to identify
the peak due to the impurity F derivative. Sulfated ash (2.4.14)
=
Retention time Impurity F derivative about 4 min. Maximum 0.1 per cent, determined on 1.0 g.
System suitability Reference solution: ASSAY
- resolution: minimum 3.0 between the peak due to the Dissolve 0.100 gin 4 mL of anhydrous formic acid R.
impurity F derivative and the nearby eluting peaks due to Add 80 mL of acetonitrile R. Carry out the titration
the derivatisation reagent. immediately. Titrate with 0.1 M perch/oric acid, determining
Limit: the end-point potentiometrically (2.2.20).
- impurity F: not more than the area of the corresponding 1 mL of 0.1 M perchloric acid is equivalent to 16.56 mg of
peak in the chtomatogram obtained with the reference C 4H 12ClNS '
solution (0.05 per cent). IMPURITIES
Related substances Specified impurities A, F.
Liquid chromatography (2.2.29). Other detectable impurities (thefollowing substances would, if
Test solution Dissolve 50.0 mg of the substance to be present at a sufficient level, be detected by one or other of the tests
examined in the mobile phase and dilute to 10.0 mL with in the monograph. They are limited by the general acceptance
the mobile phase. criterion for other/unspecified impurities and/or by the general
Reference solution (a) Dissolve 20.0 mg of metformin monograph Substances for pharmaceutical use (2034). It is
impurity A CRS in water R and dilute to 100.0 mL with the therefore not necessary to identify these impurities for
same solvent. Dilute 1.0 mL of the solution to 200.0 mL demonstration of compliance. See also 5.10. Control of impurities
with the mobile phase. in substances for pharmaceutical use) B, C, D, E.
Reference solution (b) Dilute 1.0 mL of the test solution to
50.0 mL with the mobile phase. Dilute 1.0 mL of this
solution to 20.0 mL with the mobile phase.
Reference solution (c) Dissolve 10 mg of melamine R
(impurity D) in about 90 mL of water R. Add 5 mL of the
A. cyanoguanidine,
test solution and dilute to 100 mL with waterR. Dilute 1 mL
of this solution to 50 mL with the mobile phase.
 2024 Methacrylate Copolymers ll-253

TESTS
Solution S
Dissolve 12.5 g in a mixture of 35.0 g of acetone R and
52.5 g of 2-propanol R.
Viscosity (2.2.10)
B. (4,6-diamino-1,3,5-triazin-2-yl)guanidine, 3 mf'a-s to 6 ml'a-s, determined on solution S.
Apparatus Rotating viscometer.
Dimensions:
- spindle: diameter = 25.15 mm, height = 90.74 mm, shaft
=
diameter 4 mm;
=
- cylinder. diameter 27.62 mm, height 0.135 m. =
Rotating speed 30 r/min.
C. N 2,N2-dimethyl-1,3,5-triazine-2,4,6-triamine (N,N- Volume of solution 16 mL of solution S.
dimethyhnelamine), Temperature 20 -c.
Absorbance (2.2.25)
Maximum 0.30 at 420 nm, determined on solution S.
Appearance of a film
Spread 1.0 mL of solution S evenly on a glass plate. Upon
drying a clear film is formed.
D. 1,3,5-triazine-2,4,6-triamine (melamine), Monomers
Maximum 0.1 per cent for each monomer (butyl
methacrylate, methyl methacrylate and 2-(dimethylarnino)
ethyl methacrylate), determined by procedures A and B.
A. Butyl methacrylate and methyl methacrylate. Liquid
chromatography (2.2.29).
E. 1-methylbiguanide,
Solventmixture acetonitrile R1, phosphate buffer solution
pH 2.0 R (40:60 VIV).
Testsolution Dissolve 1.00 g of the substance to be
examined in the solvent mixture and dilute to 50.0 mL with
F. N-methyhnethanamine (dimethylamine). the solvent mixture.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ PhEur Reference solution Dissolve 20.0 mg of butyl methacrylate CRS
(impurity A) and 10.0 mg of methylmethacrylate CRS
(impurity B) in 3.0 mL of butanol R and dilute to 10.0 mL
with the solvent mixture. Dilute 1.0 mL of the solution to
250.0 mL with the solvent mixture.
Basic Butylated Methacrylate
Column:
Copolymer = =
- size: l 0.125 m, 0 4.6 mm;
(ph. Bur. monograph 1975) - stationary phase: end-capped octadecylsilyl silica gelfor
chromatography R (7 urn).
Action and use
Mobile phase phosphate buffer solution pH 2. 0 R, methanol R2
Excipient.
(45:55 VIV).
Ph Eur _
Flow rate 2.0 mlJmin.
DEFINITION Detection Spectrophotometer at 205 nm.
Copolymer of 2-(dimethylamino)ethyl methacrylate, butyl Injection 50~.
methacrylate and methyl methacrylate having a mean relative System suitability Reference solution:
molecular mass of about 47 000. The ratio of - resolution: minimum 5 between the peaks due to
2-(dimethylamino)ethyl methacrylate groups to butyl impurities A and B.
methacrylate and methyl methacrylate groups is about 2:1:1. Calculate the percentage contents of impurities A and B
Content of (dimethylamino) ethylgroups 20.8 per cent to using the following expression:
25.5 per cent (dried substance).
CHARACTERS 6 C AT
100x 10- x50x - x A-
Appearance M R
Colourless or yellowish granules or white or ahnost white
C concentration of the monomer in the reference solution, in
powder, slightly hygroscopic. micrograms per millilitre;
Solubility M mass of substance to be examined in the test solution, in grams;
AT area of the peak due to the monomer in the chromatogram
Practically insoluble in water, freely soluble in methylene obtained with the test solution;
chloride. It dissolves slowly in ethanol (96 per cent). AR area of the peak due to the monomer in the chromatogram
obtained with the reference solution.
IDENTIFICATION
A. Infrared absorption spectrophotometry (2.2.24). B. 2-(Dimethylarnino)ethyl methacrylate. Liquid
Comparison basic butylated methacrylate copolymer CRS. chromatography (2.2.29).
B. It complies with the limits of the assay.