FORM2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF INVENTION:
"A PROCESS FOR PURIFICATION OF GLIMEPIRIDE"
2. APPLICANT:
(a) NAME: FDC Limited.
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1913
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field
The present invention relates ,„ a novel process for purification of Glimepiride
Background and prior art
Glimepiride is a member of the second-generation sulfonylurea drug class used for the management of type 2 diabetes mellitu, It is a long-acting, third-generation sulfonylurea with hypoglycemic activity. Compared to other generations of sulfonylurea compounds, glimepiride is very potent and has a longer duration of action. Glimepiride has chemical name as, 3-Ethyl-4-methyl-
N-[2-(4-{[(trans-4-methylcyclohexyl)carbamoyl]sulfamoyl}phenyl)ethyl]-2-oxo-2,5-d1hydro-lH-pyrrole-l-carboxamide and has structural formula as follow

US 4,379,785 discloses heterocyclic substituted sulfonyl ureas, particularly 3-Ethyl-2,5-dihydro-4-methy.-N-[2-[4-[[[[(trans- 4 methyl cyclohexyl)amino] carbonyl] amino] sulfonyl]phenyl] ethyl] -2-oxo- 1 H-pyrrole- 1 - carboxamide i.e. Glimepiride. The patent teaches the preparation of Glimepiride starting from 3-Ethyl-4-methyl-3-pyrolidine-2-one and 2-phenyl ethyl isocyanate to give [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene. The [2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene is converted to the 4-[2-(3- Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide, by reacting with chlorosulphonic acid, followed by treatment with ammonia solution. This intermediate compound is then finally reacted with trans -4-methylcyclohexyl isocyanate prepared from trans-4-methyl cyclohexylamine HC1 to form Glimepiride. US4379785 further discloses purification of Glimepiride by dilute acetone.

The main object of patent WO2005049532 is to provide a process for purification of a thiazolidinedione derivatives which is intermediate for Pioglitazone, Rosiglitazone and Troglitazone and, purification of Glimepiride Further WO2005049532 discloses preparation of Glimepiride from intermediate 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzeme sulfonamide. Glimiperide so prepared was subjected to purification o, Glimepiride using a methanolic ammonia, which was further washed with tetrahydrofuran.
JP2008534576 discloses purification of the glimepiride. Wherein glimepiride is purified by dissolving in an alcohol with a base; the clear solution thus obtained is optionally passed through a charcoal process; acid was add to adjust pH of 5.5-6.0.
WO2006103690 discloses a process of purification of intermediates trans-4-methyl cyclohexylamin HC1 and 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide. The said purified intermediates further used in preparation of Glimepiride, subsequently Glimepiride was purified with methanolic ammonia and glacial acetic acid to obtain Glimepiride Form I in substantially pure form. WO2006103690 discloses a multistep purification process wherein each intermediate is separately purified and final product Glimepiride is also subsequently purified, this multistep purification is bound to affect the yield of the final product.
IN243843 discloses a process wherein 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide is refluxed with acetone which is further, reacted with ethyl chloroformate in presence of organic base hydrocarbon and, chlorinated hydrocarbon solvent to form the respective carbamate. The said carbamate is isolated using acetone and toluene to give a purified carbamate having impurity less than 0.2%.The said carbamate is converted to Glimepiride by reaction with trans-4-methyl cyclohexylamine in presence of activation

catalyst. The said process involves purification of carbamate intermediate ,wherem the purified intermediate is subsequently used to obtain Glimepiride.
The aforesaid processes describe purification of Glimepiride either by water and acetone as a solvent or a mixture of alcohol and ammonia or by multistep purification of intermediates and the final product. The said processes suffer from the respective drawbacks of low yield and purity containing substantial amounts of impurity specifically 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide also referred to as impurity B. Impurity B which is the sulphonamide compound that is unavoidably retained during the process of preparation of Glimiperide, which thereby affects the purity and yield of the final product . In view of there being no satisfactory process to simplify the punfication without compromising the yield and purity of the product, there is need to provide a simpler and effective method of purification of the final product.
In the present invention it has been surprisingly found that micronized Ghmepmde can be advantageous in purifying and reducing impurity B substantially.
In the present invention it was further found that the micronization reduces particle size of impurity B making it more soluble in methanol.
Summary of the invention
The present invention provides an improved process for purification of Ghmepiride by effectively reducing Impurity B that is 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide. The said impurity is retained during the process of preparation of Glimepiride and is hard to eliminate. The present invention provides a simple, cost effective and viable method of purification of Glimepiride on commercial scale with an high yield; by

using micronized Glimepiride and further leeching it with alcohol and thereby isolating it to get final product with a purity greater than 99.5%.
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
In the main embodiment of the present invention is to provide the process for purification of Glimepiride with high yield and purity.
Another embodiment of the present invention is to provide simple process to reduced impurity B thereby giving final product Glimepiride with a purity greater than 99.5% and impurity B not more than 0.2%.
Accordingly, the present invention describes a novel process for purification of Glimepiride with high purity which comprises of following steps:
1. Charge the micronized 3-Ethyl-4-methyl-N-[2-(4-{[(trans-4-
methylcyclohexyl) carbamoyl]sulfamoyl}phenyl)ethyl]-2-oxo-2,5-
dihydro-lH-pyrrole-1-carboxamide (Glimepiride) in methanol wherein, the particle size is D90 not more than 10 μm and D100 not more than 15 μm and impurity B that is ((4- 2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide) is not less than 0.4%.
2. Heating the mixture of step 1 at a temperature of about 65°-70°C, digest the reaction mass for 1-2 hrs at 65°-70°C
3. Reaction mixture of step 2 is cooled to 25°-30°C
4. Filter the solid and further wash it with methanol.
5. Drying the solid obtained in step 4 at a temperature of about 60°-70°C to obtain 3-Ethyl-4-methyl-N-[2-(4-{[(trans-4-methylcyclohexyl) carbamoyl]sulfamoyl}phenyl)ethyl]-2-oxo-2,5-dihydro-lH-pyrrole-l-carboxamide (Glimepiride ) having a purity greater than 99.5% , and impurity B not more than 0.2%.

Particle size analysis and High Performance Liquid Chromatography (HPLC)was performed to illustrate impurity B was reduced during purification of Glimepiride as per the present invention. Description of Particle size analysis and High Performance Liquid Chromatography (HPLC) are as shown in Table 1
Table 1:

Figure 1 Graph showing particle size of Glimepiride as per example 1
Figure 2 Graph showing particle size of Glimepiride as per example 2
Figure 3

HPCL graph showing Impurity B Standard
Figure 4 HPLC graph of Glimepiride obtained as per example 1
 HPLC graph shows purity of Glimepiride 99.35% and impurity B greater than 0.4%
Figure 5 HPLC graph of Glimepiride obtained as per example 2
 HPLC graph shows purity of Glimepiride 99.72% and impurity B Less than 0.2 %.
The present invention is exemplified by the following examples which are provided for illustration only and, should not be construed to limit the scope of the invention.

EXAMPLES: -
Example 1: Preparation of 3-Ethyl-4-methyl-N[2-(4-{[(frans-4-methylcyclohexyl) carbamoyl]sulfamoyl}phenyl)ethyl]-2-oxo-2,5-dihydro-1H-pyrrole-l-carboxamide (Glimepiride)

In reaction vessel containing 20 L THF, 4-[2-(3-Ethyl-4-methyI-2-carbonyl pyrrolidine amido) ethyl] benzene sulphonamide 1 Kg (2.964 mol) and Potassium Carbonate 0.56 Kg (4.051 mol) was added and heated to 60°-65°C for 1-2 hrs. A solution of Trans-4-methyl cyclohexyl isocynate 0.55 Kg (3.951 mol) in Toluene (5 L) was prepared and added to the above reaction mixture. This reaction mixture was maintained for 10-12 hrs at 60°-65°C, and then cooled. The reaction mixture was filtered. This filtered solid was added to the vessel containing Methanol 6 L and dry Ammonia gas was purged to get 10-12 pH of reaction mixture. The reaction mixture was filtered out and pH of filtrate was adjusted to 5.5 to 6.0 by adding Acetic acid at 25°-30°C. The solid obtained was filtered and washed with Methanol. The 3-Ethyl-4-methyl-JV-[2-(4-{[(trans-4-methylcyclohexyl) carbamoyl]sulfamoyl}phenyl)ethyl]-2-oxo-2,5-dihydro-lH-pyrrole-1-carboxamide was obtained and then dried at 60°-70°C till constant weight. Yielding 85-90% product with 99% purity. The said Glimepiride is micronized to give glimepiride of particle size is D90 not more than 10 μm and D100 not more than 15 μm and impurity B((4-that is 2-(3-Ethyl-4-methyI-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide) is not less than 0.4%.

Example 2: Purification of 3-Ethyl-4-methyI-N[2-(4-{[(trans-4-methylcyclohexyl) carbamoyl] sulfamoyl} phenyl) ethyl]-2-oxo-2, 5-dihydro-1H-pyrrole-l-carboxamide using micronized Glimepiride

1 Kg of Glimepiride obtained as per Example 1 was added to the vessel containing 3 L Methanol. The reaction mixture was heated to 65°-70°C and maintained for 1-2 hrs. Further the reaction mixture was cooled, filtered and the solid was washed with Methanol. The solid filtered out; was then dried at 60°-70°C to obtain 0.95 Kg Glimepiride of purity 99.72% , and the impurity B was below 0.15%.
The table below shows the analytical data and study of the particle size and purity of the final product before and after purification:-
Table 2

Sr.
No. Details of sample Particle size in u.m Purity % Impurity-B %
1. Glimepiride of Example 1 D (0.1): 0.531 μn D(0.5): 1.144 μm D (0.9): 2.420 μm 99.35 % 0.42 %
2. Purified Glimepiride of Example 2 D(0.1): 1.212 μm D (0.5): 4.123 μm D (0.9): 8.655 μm 99.72 % 0.15%

We claim:
1. A process for purification of Glimepiride consisting of
a) Charge the micronized 3-Ethyl-4-methyl-N-[2-(4-{[(trans-4-methylcyclohexyl) carbamoyl]sulfamoyl}phenyl)ethyl]-2-oxo-2,5-dihydro-lH-pyrrole-1-carboxamide (Glimepiride) in methanol
b) Heating the mixture of step a at a temperature of about 65°-70°C, digest the reaction mass for 1-2 hrs at 65°-70°C
c) Reaction mixture of step b is cooled to 25°-30°C
d) Filter the solid and further wash it with methanol.
e) Drying the solid obtained in step d at a temperature of about 60°-70°C to obtain pure Glimepiride.

2. The process for purification of Glimepiride as claimed in of claim 1 wherein, the Glimepiride used in step a having particle size of about D90 not more than 10μm and D100 not more than 15 μm.
3. The process for purification of Glimepiride as claimed in of claim 1 wherein, Glimepiride used in step a has impurity B not less than 0.4%.
4. The process for purification of Glimepiride as claimed in of claim 1 wherein, Glimepiride obtained in step d has purity not less than 99.5% , and impurity B not more than 0.2%.