FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
NOVEL POLYMORPH OF GLIMEPIRIDE AND PROCESS FOR PREPARING
THE SAME
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House, 166 C.S.T. Road,
Santacruz East, Mumbai - 400 098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Title: Novel polymorph of glimepiride and process for preparing the same
FIELD OF INVENTION:
The present invention relates to novel polymorphic form of glimepiride and a process for preparing the same.
BACKGROUND OF THE INVENTION:
Glimepiride chemically known as 3-ethyl-4-methyl-N-(4-(N-((trara-4-methylcyclohexyl)-carbamoyl)sulfamoyl)phenethyl)-2-oxo-2,5-dihydro-1 H-pyrrole-1 -carboxamide of formula I is approved by the United States Food and Drug Administration (FDA) as an anti-diabetic medication for treating type 2 diabetes mellitus and is marketed as under the trade name Amaryl.

Formula I
Glimepiride is a sulphonyl urea agent that stimulates insulin release from pancreatic β-cells and may act via extra pancreatic mechanisms. It is administered once daily to patients with type 2(non-insulin-dependent)-diabetes mellitus in whom-glyeemieis not controlled by diet and exercise alone, and may be combined with insulin in patients with secondary sulphonyl urea. Sulfonylureas are used mainly based on their low cost, well-established glucose-lowering action and a longstanding experience in clinical practice. Both the prevalence and incidence of type 2 diabetes are increasing worldwide, particularly in developing countries, in conjunction with increased obesity rates and the modernization of lifestyle.
Polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical

properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. The solubility of each polymorph may vary and consequently identifying the existence of polymorphs of an active pharmaceutical ingredient (API) is essential for providing pharmaceutical compositions with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as infrared spectrometry. Additionally, the properties of polymorphic forms of the same active pharmaceutical ingredient are well known in the pharmaceutical art to have an effect on the manufacture of drug product compositions comprising the API. For example, the solubility, stability, flowability, tractability and compressibility of the API as well as the safety and efficacy of drug product can be dependent on the crystalline or polymorphic form.
US Patent US4379785 discloses heterocyclic substituted sulfonyl ureas including glimepiride, their use as medicament for lowering the blood sugar and further discloses processes for the manufacture of these sulfonyl ureas.
Crystalline polymorphic form I of glimepiride was disclosed in Acta Crystallographica Section C, 53(3), 329-331 (1997), and is prepared by grown the crystals by diffusing ethanol into a solution of glimepiride in chloroform at room temperature.
Crystalline polymorphic form II of glimepiride is disclosed in STP Pharma Sciences, 13(4), 281-286 (2003), wherein the form II is prepared by recrystallization of glimepiride from ethanol/water system.
Chinese patent application CN106866486 discloses glimepiride a crystal form and a method for preparing the same.
Chinese patent application CN106883161 discloses glimepiride p crystal form and a method for preparing the same.
Chinese patent application CN106699631 discloses glimepiride y crystal form and its preparation by crystallization from isopropanol.
Chinese patent application CN106866485 discloses glimepiride 8 crystal form and a method for preparing the same.

Korean patent KR100698595 discloses glimepiride in amorphous form and a method for its preparation from crystalline glimepiride.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.
The present inventors have developed a novel polymorphic form III of glimepiride, which is crystalline and thermodynamically more stable.
OBJECTIVES OF THE INVENTION:
An objective of the present invention is to provide a novel crystalline polymorph of glimepiride designated as form III.
Another objective of the present invention is to provide a process for preparation of crystalline form III of glimepiride.
SUMMARY OF THE INVENTION:
Main aspect of the present invention relates to novel polymorph of glimepiride designated as form III.
_ Another aspect of the present invention relates to novel crystalline polymorph, form III of glimepiride characterised by its powder X-ray diffraction (PXRD) pattern Having peaks at about 3.47, 6.72, 13.45, 14.65, 15.99, 16.27, 19.69, 20.21, 21.25, 24.76, 25.32, 26.03, 27.07, 28.57, 30.15, 30.59, 32.26, 36.38, 36.84, 37.51, 38.11, 39.68 ± 0.2° 20.
In another aspect, the present invention provides a process for preparation of crystalline form III of glimepiride, wherein said process comprising the steps of
a) suspending crude glimepiride in an organic solvent,
b) stirring the suspension obtained in step a);
c) cooling the solution at 25°C to -25°C; and,
d) isolating crystalline form III of glimepiride.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: XRPD diffractogram of novel crystalline polymorph form III of glimepiride.
Figure 2: DSC thermogram of novel crystalline polymorph form III of glimepiride.
Figure 3: Infrared spectrum of novel crystalline polymorph form III of glimepiride.
Figure 4: Thermogravimetric analysis of novel crystalline polymorph form III of glimepiride.
DETAILED DESCRIPTION OF THE INVENTION:
Main embodiment of the present invention relates to crystalline polymorph form III of glimepiride.
Another embodiment of the present invention relates to crystalline polymorph form III of glimepiride characterised by its powder X-ray diffraction (PXRD) pattern having peaks at about 3.47, 6.72, 13.45, 14.65, 15.99, 16.27, 19.69, 20.21, 21.25, 24.76, 25.32, 26.03, 27.07, 28.57, 30.15, 30.59, 32.26, 36.38, 36.84, 37.51, 38.11, 39.68 ± 0.2° 20.
In most preferred embodiment, the present invention relates to crystalline polymorph form III of glimepiride that exhibits a PXRD pattern as shown in Figure 1.
In addition, crystalline polymorph form III of glimepiride can be characterized by DSC as shown in Figure 2.
Yet another embodiment of the present invention related fo process for the preparation of
crystalline polymorph form III of glimepiride comprising the steps of:
1. suspending crude glimepiride in an organic solvent;
2. stirring suspension obtained in step a);
3. cooling the solution at 10°C to -15°C; and
4. isolating crystalline form III of glimepiride.
In an embodiment of the present invention, the organic solvent used in step a) is selected from N-methyl-2-pyrrolidone, acetone, ethanol, N,N-dimethylacetamide or a mixture thereof.

In an embodiment of the present invention, stirring the suspension in step b) is carried out at a temperature of 25°C to 70°C.
In an embodiment of the present invention, cooling the solution in step c) is carried out at a temperature of 10°C to -15°C.
An analytical study of polymorph III was performed by using different techniques like IR, DSC, and XRD and discussed in detail. Glimepiride polymorph form III 29 and d-spacing values are given in the following table.

Sr. No. 26 Value d-spacing value
1 3.47 25.41
2 6.72 13.12
3 13.45 6.58
4 14.65 6.04
5 15.99 5.54
6 16.27 5.44
7 19.69 4.5
8 20.21 4.39
9 21.25 4.17
10 24.76 3.59
11 25.32 3.51
12 26.03 3.42
13 27.07 3.29
14 18 57 3.12
15 30.15 2.96
16 30.59 2.92
17 32.26 2.77
18 36.38 2.47
19 36.84 2.43
20 37.51 2.39
21 38.11 2.35
22 39.68 2.25

The DSC thermogram of Glimepiride Form III showed an endotherm at 276 °C and enthalpy is -938.18 J/g. The Reported literature value of Glimepiride Form I, an endotherm at 216°C, and Form II shows an endotherm at 213°C.
The TGA thermogram of Glimepiride Form III showed there is no loss up to 105°C shows that the compound is not hydrated or solvated means free from water and solvent used for the recrystallization. Further weight loss of about 63.78% at 590°C,
FTIR analysis for Form I and III were performed. Experimental and literature data of form I, II indicates that there is a change in spectral Region 3000-3500 cm"1 and as described in the literature for form I and II that changes are due to differences of inter and intra hydrogen bonding observed and the same phenomenon also observed for Form III which shows absorption at 3325.28 cm-1.
The melting point for Glimepiride form I and II is 216°C and 213°C respectively as stated in the literature, while the polymorph Glimepiride III shows melting at 276°C. These comparative melting point values are given in Table. It was demonstrated previously that the DSC thermogram of polymorphic form III differs in pattern and event concerning Glimepiride form I and Glimepiride form II. Hence, it can be concluded that there is a polymorphic transformation occurring when applied processes I and II.

Sr. No. Instrument Glimepiride Form I Glimepiride Form II Glimepiride Form III
1 IR (cm1) 3290,3370 3330,3100 3325.28
2 DSC (°C) 216 213 276.55
3 6.46.9:52, 10.48, 10.95 -7784710:47,11.95, 12.40 6.72, 30.658
marker peak of Form III
[Marker peak of form I absent
6.46, 9.52, 10.48, 10.95,12.4 &
Marker peak of form II absent
7.84,10.47,11.95]

XRD (20)

The XRD Diffractogram of Glimepiride Form III revealed a marker peak at 20 6.7, whereas Form I revealed a marker peak at 20 6.40, and glimepiride form II shows a peak at 20 7.84. All these peaks are distinct from each other.
The particle size of glimepiride Form III results for particle size distribution and of the polymorph mean value is 12.4 μm Dio-2.8 μm, Dso-12.4 jxm, and D90-51. 6μm specific surface area is 1.14 m2/g.

The morphology of Glimepiride Form III was examined using an image analyzer from Microtrac. The photographic result shows a fine spherical shape, and smooth surface, and the particle size was within the Fig. Particle size distribution by Microtrac image analyzer.
Inventors of the present application have come across a novel crystalline form of glimepiride, which is consistently reproducible, does not have the tendency to convert to other forms, and found to be more stable.
Advantages of the present invention:
1. Novel crystalline polymorph Form III of glimepiride is stable.
2. Novel crystalline polymorph Form III of glimepiride is stable at ambient temperature and at elevated temperatures.
3. The novel crystalline polymorph Form III of glimepiride is substantially anhydrous and is stable at ambient storage conditions.
The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.
EXAMPLES:
Example 1:
A flask was charged 50 gm of glimepiride polymorph form I was taken into 200ml N-methyl-2-Pyrrolidone as a solvent medium under constant stirring using a magnetic stirrer with a hot plate at 60°C to 75 °C for 1 hour and then the sample was kept at a deep freezer at a temperature of about sign before 10°C to -15°C for 24 hours. The crystalline novel form was obtained by filtering the reaction mass through Whatman filter paper No. 41 with 20 μm pore size, and subsequently drying at 105°C in the oven for 8 hours to obtain 35 gm of glimepiride polymorph form III.

Example 2:
50 gm of Glimepiride polymorph form I was taken into 200 ml of a mixture of acetone and ethanol 50:50 v/v as a solvent medium, and pH was adjusted to 9 with aqueous ammonia under constant stirring using a magnetic stirrer with a hot plate at 25°C for 1 hour and then the sample was kept at a deep freezer at a temperature of about sign before 10°C to -15°C for 8 hours. The crystalline novel form was obtained by filtering the reaction mass through Whatman No. 41 filter paper with 20 μm pore size and subsequent drying at 105°C in the oven for 8 hours to obtain 30 gm of glimepiride polymorph form III.

We claim,
1. Crystalline polymorph form III of glimepiride having characteristics X-ray diffraction peaks at 3.47, 6.72, 13.45, 14.65, 15.99, 16.27, 19.69, 20.21, 21.25, 24.76,25.32,26.03,27.07,28.57,30.15,30.59,32.26, 36.38,36.84,37.51,38.11, 39.68 ± 0.2° 20.
2. The crystalline form III of glimepiride characterized by, having substantially the same X- ray diffraction pattern as depicted in Figure 1.
3. The crystalline form III of glimepiride as claimed in claim 1, which exhibits DSC as shown in Figure 2.
4. The form as claimed in claim 1, is anhydrous in nature.
5. A process of preparing crystalline form III of glimepiride comprising the steps of:

a) suspending crude glimepiride in an organic solvent,
b) stirring the suspension obtained in step a);
c) cooling the solution at 10°C to -15°C; and
d) isolating crystalline form III of glimepiride.

6. The process as claimed in claim 5, wherein the organic solvent is selected from N-methyl-2-pyrrolidone, acetone, ethanol, N,N-dimethylacetamide or a mixture thereof.
7. The process as claimed in claim 5, stirring the suspension in step b) is carried out at a temperature of 25°C to 70°C.
8. The process as claimed in claim 5, cooling the solution in step c) is carried out at a temperature of 10°C to -15°C.