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F.G. 1
mi
O.O 5.0 10.0 15.O 20.O 25.O 3O.O 35.0
Patent Application Publication Jan. 27, 2011 Sheet 2 of 3 US 2011/0021634 A1
FIG. 2
15.0
1 O. O
mi
0.0 5.0 1 O,O 15.0 200 25.0 300 35.0
Patent Application Publication Jan. 27, 2011 Sheet 3 of 3 US 2011/0021634 A1
FIG. 3
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6.50
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process for preparing metformin hydrochloride that provides with dimethylamine hydrochloride of Formula (III)
reduced level of dimethylamine.
SUMMARY OF THE INVENTION (III)
H3C
0015. In one general aspect there is provided a process for SNHHCI
reducing dimethylamine content in metformin hydrochlo CH3
ride. The process includes providing metformin hydrochlo
ride having dimethylamine content more than 15 ppm, pull
verizing the metformin hydrochloride; slurrying the in one or more hydrocarbon Solvents;
metformin hydrochloride in one or more C-C alcohol Sol (a) extracting reaction mass with water to obtain a solution;
vents; and isolating the metformin hydrochloride. The steps (b) optionally treating the Solution with charcoal;
of pulverization and slurrying can be performed in any (c) removing water to obtain a residue;
sequential order. (d) treating the residue with one or more C-C alcohols to
The process may include further drying of the product obtain a slurry;
obtained. (e) pulverizing the slurry; and
0016. The process may produce the metforminhydrochlo (f) isolating the metforminhydrochloride substantially free of
dimethylamine.
ride containing dimethylamine content less than 10 ppm. In 0022. In another aspect there is provided metformin
particular, it may produce the metformin hydrochloride con hydrochloride substantially free from dimethylamine.
taining dimethylamine content less than 5 ppm. 0023. In another general aspect there is provided a phar
0017. In another general aspect there is provided a process maceutical composition comprising a therapeutically effec
for the purification of metformin hydrochloride. The process tive amount of metformin hydrochloride substantially free
includes obtaining a solution of metformin hydrochloride in from dimethylamine, and one or more pharmaceutically
water and recovering the metformin hydrochloride by acceptable carriers, excipients or diluents.
removal of the water. 0024. In another general aspect there is provided a method
0018 Removing the water may include, for example, one of treating diabetes in a warm-blooded animal, the method
or more of evaporation, distillation and distillation under comprising providing a dosage form to the warm-blooded
vacuum. The process may include further forming of the animal that includes metformin hydrochloride substantially
product so obtained into a finished dosage form. free from dimethylamine.
0019. The process may produce the metforminhydrochlo 0025. The details of one or more embodiments of the
ride having dimethylamine content less than the starting met inventions are set forth in the description below. Other fea
formin hydrochloride. tures, objects and advantages of the inventions will be appar
0020. In another general aspect there is provided a process ent from the description.
for the preparation of metformin hydrochloride substantially
free from dimethylamine. The process includes obtaining a BRIEF DESCRIPTION OF DRAWINGS
solution of metformin hydrochloride in water; optionally 0026 FIG.I: Chromatogram for metforminhydrochloride
clarifying the Solution by treating with charcoal; removing for determination of dimethylamine as per Example-1.
the water to obtain a residue: treating the residue with one or 0027 FIG. II: Chromatogram for metformin hydrochlo
more C-C alcohols to obtain slurry; pulverizing the slurry; ride for determination of dimethylamine as per Example-2.
and isolating the metformin hydrochloride substantially free 0028 FIG. III: Chromatogram for metformin hydrochlo
from dimethylamine. ride standard for determination of dimethylamine.
0021. In another aspect there is provided a process for the
preparation of metformin hydrochloride of Formula (I) DETAILED DESCRIPTION OF THE INVENTION
(0029. The term “substantially free” from dimethylamine
(I) as used herein refers to metformin hydrochloride containing
NH NH less than about 10 ppm of dimethylamine, for example less
is lull
NN N
H
than about 5 ppm of dimethylamine when measured by Ion
chromatography method.
0030 The term “pulverizing” as used herein refers to a
CH technique or a method by which particle size can be reduced
and includes techniques such as milling, grinding, microniz
ing, and the like.
substantially free from dimethylamine. The process includes: 0031. The inventors have developed a process for reducing
dimethylamine content in metforminhydrochloride. The pro
(a) reacting dicyanodiamide of Formula (II) cess includes the step of pulverizing metformin hydrochlo
ride having dimethylamine content more than 15 ppm, slur
rying the metformin hydrochloride in one or more C-C,
(II) alcohol solvents; and isolating the metformin hydrochloride.
NH
The pulverization and slurrying steps can be performed in any
NCN l N
H
NH
2
sequential order.
0032. The pulverizing of metformin hydrochloride can be
done by milling or grinding or micronizing metformin hydro
chloride to very fine particles.
US 2011/0021634 A1 Jan. 27, 2011
0033. The slurrying of metformin hydrochloride can be 0042 with dimethylamine hydrochloride of Formula (III)
done in one or more C-C alcohol solvents. A suitable alco
hol includes one or more of methanol, ethanol, propanol,
isopropanol, butanol and isobutaneol. HC (III)
0034. In another aspect there is provided a process for the 3 oHCI
purification of metformin hydrochloride. The process
CH3
includes obtaining a solution of metformin hydrochloride in
water and recovering the metformin hydrochloride by
removal of the water. The solution of water may be prepared 0043 in one or more hydrocarbon solvents;
under nitrogen atmosphere and may be heated at a tempera (b) extracting reaction mass with water to obtain a solution;
ture from about ambient temperature to about reflux tempera (c) optionally treating the Solution with charcoal;
ture. In particular, the solution may be prepared at about 80° (d) removing water to obtain a residue,
C. to about 95° C. (e) treating the residue with one or more C-C alcohols to
0035. The process may produce metformin hydrochloride obtain a slurry;
having reduced dimethylamine content than the starting met (f) pulverizing the slurry; and
formin hydrochloride. (g) isolating the metformin hydrochloride substantially free
0036. In another aspect there is provided a process for the from dimethylamine.
preparation of metformin hydrochloride substantially free 0044) The reaction of dicyanodiamide of Formula (II)
from dimethylamine. The process comprising: with dimethylamine hydrochloride of Formula (III) may be
(a) obtaining a solution of metforminhydrochloride in water; carried out in a hydrocarbon solvent. A suitable hydrocarbon
solvent includes one or more of toluene, xylene, ethylben
(b) optionally clarifying the solution by treating with char Zene, cyclohexane, hexane, cyclopentane, pentane, and hep
coal; tanes. In particular, toluene and Xylene may be used. The
(c) removing the water to obtain a residue; reaction mixture may be heated at a temperature from about
(d) treating the residue with one or more C-C alcohols to 50° C. to about 150° C.
obtain a slurry; 0045. After the completion of the reaction, the reaction
(e) pulverizing the slurry; and mass may be extracted with water at ambient temperature to
(f) isolating the metformin hydrochloride substantially free reflux temperature, for example, at about 80°C. to about 95°
from dimethylamine. C. The solution may be purged with nitrogen gas for about 15
minutes to one hour.
0037. In general, the solution of water may be prepared 0046. The solution can be optionally clarified to remove
under nitrogen atmosphere and may be heated at a tempera colored and other suspended matters by treatment with char
ture from about ambient temperature to about reflux tempera coal.
ture. In particular, the solution may be prepared at about 80° 0047. The water may be removed from the solution by a
C. to about 95°C. The nitrogen gas may be purged for about technique which includes, for example, distillation, distilla
15 minutes to 1 hour. In particular, it may be purged for about tion under vacuum, and evaporation. The residue obtained
30 minutes. Alternatively, such a solution may be obtained may be treated with one or more of C-C alcohols to obtain
directly from a reaction in which metforminhydrochloride is slurry. A suitable alcohol includes one or more of methanol,
formed. The solution may be heated under nitrogen atmo ethanol, propanol, isopropanol, butanol and isobutanol.
sphere. 0048. The present invention is further illustrated by the
0038. The solution can be optionally clarified to remove following example which is provided merely to be exemplary
colored and other suspended matters by treatment with char of the invention and do not limit the scope of the invention.
coal. Certain modifications and equivalents will be apparent to
0039. The water may be removed from the solution by a those skilled in the art and are intended to be included within
technique which includes, for example, distillation, distilla the scope of the present invention.
tion under vacuum, and evaporation. The residue obtained Example-1
may be treated with one or more of C-C alcohols to obtain
slurry. A suitable alcohol includes one or more of methanol, Preparation of Metformin Hydrochloride (I)
ethanol, propanol, isopropanol, butanol and isobutanol.
0040. The process may produce metformin hydrochloride 0049 Xylene (400 mL) and dicyanodiamide (100 g) were
which is substantially free from dimethylamine. taken in a round-bottom flask. The reaction mixture was
0041. In another aspect there is provided a process for the heated at 80°C. Dimethylamine hydrochloride (117 g) was
preparation of metformin hydrochloride substantially free added portion-wise within 2 hours. The reaction mass was
stirred for 3 hours. The reaction mixture was further heated to
from dimethylamine. The process includes: 100° to 105° C. followed by heating to 140°C. The reaction
(a) reacting dicyanodiamide of Formula (II) mass was stirred for 4 hours and cooled to 95°C. The reaction
mass was treated with water (200 mL) and layers were sepa
rated. The organic layer was again extracted with water (50
(II) mL). The combined aqueous layer was treated with charcoal
NH
(3 g) and stirred for 20 minutes. The reaction mass was
NCN lN
H
NH
2
filtered through a hyflowbed and washed with water (50 mL).
The filtrate was taken in around-bottom flaskat 50° C. and N.
gas was purged for 30 minutes. The filtrate was distilled to
remove water completely under vacuum at 65°C. The residue
US 2011/0021634 A1 Jan. 27, 2011
thus obtained was treated with methanol (110 mL) at 40°C. to Program for Standard:
45° C. and cooled to 20°C. to 25°C. The product was filtered 0054
and washed with chilled methanol (50 mL). The wet-cake
thus obtained was treated with water at 50° C. along with N
gas purging for 30 minutes. The solution was distilled to
remove water completely under vacuum at 65°C. The residue Time (min) Flow rate: ml/min %A % B %C
thus obtained was treated with methanol (80 mL) at 40°C. to O.OO 1.2 4 96 O
45° C. to prepare the slurry. The slurry was pulverized under 12.00 1.2 4 96 O
high-speed grinder for wet grinding for 25 minutes. The reac
tion mass was filtered and dried. The wet-cake was washed
with chilled methanol (30 mL). The product was dried at 65°
C. to 70° C. to obtain 160 g metformin hydrochloride having Program for Sample:
dimethylamine content less than 5 ppm. 0055
Example-2
Preparation of Metformin Hydrochloride (I) Time (min) Flow rate: ml/min %A % B %C
0050 Toluene (500 mL) and dicyanodiamide (100g) were O.OO 1.2 4 96 O
taken in around-bottom flaskat 25°C. to 35°C. The reaction 10.00 1.2 4 96 O
mixture was heated at 80° C. Dimethylamine hydrochloride 10.10 1.5 60 38 2
(117 g) was added portion-wise within 2 hours. The reaction 24.00 1.5 60 38 2
mass was stirred for 3 hours. The reaction mixture was further 21.10 1.2 4 96 O
35.00 1.2 4 96 O
heated to 100° to 105° C. followed by heating to reflux tem
perature. The reaction mass was stirred for 4 hours and cooled
to 95°C. The reaction mass was treated with water (200 mL)
and layers were separated. The organic layer was again Preparation of Standard:
extracted with water (50 mL). The combined aqueous layer
was treated with charcoal (3 g) and stirred for 20 minutes. The Primary Standard Stock:
reaction mass was filtered through hyflowbed and washed 0056 Weigh accurately about 45 mg of dimethylamine
with water (50 mL). The filtrate was taken in a round-bottom hydrochloride in a 100 ml volumetric flask. Dissolve and
flask at 50° C. and N gas was purged for 30 minutes. The dilute upto the mark with diluent and Mix.
filtrate was distilled to remove water completely under
vacuum at 65°C. The residue thus obtained was treated with Intermediate Standard Stock A:
methanol (110 mL) at 40°C. to 45° C. and cooled to 20° C. to
25° C. The product was filtered and washed with chilled 0057 Dilute 2 ml of primary standard stock solution to 50
methanol (50 mL). The wet-cake thus obtained was treated ml with diluent and mix.
with water at 50° C. along with Nagas purging for 30 minutes.
The solution was distilled to remove water completely under Intermediate Standard Stock B:
vacuum at 65°C. The residue thus obtained was treated with
methanol (80 mL) at 40°C. to 45° C. to prepare the slurry. The 0.058 Dilute 10 ml of the intermediate standard stock solu
slurry was pulverized under high-speed grinder for wet grind tion A to 100 ml with diluent.
ing for 25 minutes. The reaction mass was filtered and dried. Standard Solution:
The wet-cake was washed with chilled methanol (30 mL).
The product was dried at 65° C. to 70° C. to obtain 155g 0059. Dilute 7.5 ml of the intermediate standard stock
metformin hydrochloride having dimethylamine content less solution B to 100 ml with diluent.
than 5 ppm.
Example-3 Sample Preparation:
Estimation of Dimethylamine in Metformin Hydro 0060 Transferan accurately weighed quantity of about 50
chloride by Ion Chromatography mg of metforminhydrochloride sample to a 10 ml volumetric
flask, dissolve and dilute to volume with diluent and mix.
Chromatographic Conditions:
Calculations:
Column: IoncPac CG17 (Guard Column)+
0061 Dimethylamine Content (ppm):
0051 IoncPac CS 17 (Analytical Column
Eluent A: 50 mM Methanesulphonic acid
Eluent B: High purity water AT WS DT P 45.08
=-
As XX-
is XX-
WTXX- looxX 81ss X 1000
Eluent C: 90% Acetonitrile
0052 Detector: Conductivity detector AT=Area of Dimethylamine in sample
Suppressor: CSRS-3000, in external water mode AS=Average Area of Dimethylamine in standard
SRS current: 150 mA WS=Weight of the Dimethylamine hydrochloride in mg
Injection volume: For Exercise I: 20 ul WT=Weight of the sample ing
0053 For Exercise II: 100 ul. DS-Dilution of standard
Diluent: 2 mM Methanesulphonic acid DT-Dilution of sample
US 2011/0021634 A1 Jan. 27, 2011
45.08=Molecular weight of the Dimethylamine 14. The process as claimed in claim 10, wherein the
81.58-Molecular weight of the Dimethylamine Hydrochlo removal of water is carried out by one or more of evaporation,
ride distillation or distillation under vacuum.
Results are Expressed in Terms of “ppm 15. The process as claimed in claim 10, wherein the alcohol
0062. While the present invention has been described in comprises one or more of methanol, ethanol, propanol, iso
terms of its specific embodiments, certain modifications and propanol, butanol and isobutanol.
equivalents will be apparent to those skilled in the art and are 16. A process for the preparation of metformin hydrochlo
intended to be included within the scope of the present inven ride of Formula (I)
tion.
23. The process as claimed in claim 16, wherein the pull tially free from dimethylamine, and one or more pharmaceu
Verization is carried out by one or more of milling, grinding, tically acceptable carriers, excipients or diluents.
and micronizing. 27. A method of treating diabetes in a warm-blooded ani
24. Metformin hydrochloride substantially free from dim mal, the method comprising providing a dosage form to the
ethylamine. warm-blooded animal that includes metforminhydrochloride
25. Metformin hydrochloride according to claim 24, con substantially free from dimethylamine.
taining dimethylamine less than 5 ppm. 28. (canceled)
26. A pharmaceutical composition comprising a therapeu
tically effective amount of metforminhydrochloride substan