FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
THE PATENTS RULES,2003
COMPLETE SPECIFICATION
(See section 10 and rule 13 )
"NOVEL PROCESS FOR PREPARATION OF
1 . TITLE OF INVENTION POLYMORPHS OF
DABIGATRAN ETEXILATE MESYLATE"
2 . APPLICANT(S)

Name Nationality Address
MAHENDRA INDUSTRIAL ESTATE, GROUND
AARTI DRUGS LIMITED MUMBAI FLOOR, PLOT NO. 109-D, ROAD NO. 29, SION (EAST), MUMBAI - 400 022, MAHARASHTRA, INDIA.
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the
invention and the manner in which it is to performed

4. DESCRIPTION (Description shall start from next page.) FORM 2 THE PATENTS ACT, 1970 (39 of 1970) AND The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule13) 1. TITLE OF THE INVENTION: “NOVEL PROCESS FOR PREPARATION OF AMORPHOUS AND CRYSTALLINE FORM I OF DABIGATRAN ETEXILATE MESYLATE” 2. APPLICANT: (a) NAME: AARTI DRUGS LIMITED (b) NATIONALITY: Indian Company incorporated under the Indian Companies Act, 1956 (c) ADDRESS: Mahendra Industrial Estate, Ground Floor, Plot No. 109-D, Road No. 29, Sion (East), Mumbai – 400 022, 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 OF INVENTION: The present invention relates to a simple and industrially scalable process for preparation of amorphous and crystalline form I of Dabigatran Etexilate Mesylate in good yield and purity. BACKGROUND AND PRIOR ART: Dabigartan Etexilate, chemically known as Ethyl 3-{[(2-{[(4-{N'-hexyloxycarbonylcarbamimidoyl}phenyl)amino]methyl}-1- methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino) propanoate, is an oral anticoagulant from the class of the direct thrombin inhibitors. Dabigatran etexilate mesylate is marketed under the trade name Pradaxa® by Boehringer Ingelheim for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran and Dabigatran etexilate is first described in Patent Publication WO 98/37075. The method described therein for the preparation of Dabigatran and Dabigatran etexilate is cumbersome, has many technological challenges, e.g. purity of intermediate products, complicated purifying operations leading to loss of yield and purity of the final product. US7202368, European Patent Applications EP1966171A and EP1968949A, PCT Patent Application WO 2010/045900 describe alternative process for the synthesis of Dabigatran etexilate or its salts. There are prior arts which describe Dabigatran etexilate or its salt in different polymorphic forms and their process of preparation. WO2003/074056, WO2005/028468, WO 2008/043759 and WO2005/023249 disclose mono mesylate salt of Dabigatran etexilate, as well as crystalline and polymorphic forms. WO2005/028468 discloses three polymorphic forms of Dabigatran etexilate mesylate obtained from the base by crystallization (Form I, II and hemihydrate) using acetone as solvent. It is further disclosed in WO’468 that

polymorphic form II can be obtained by heating polymorphic form I (BIBR 1048 MS) in acetone at 45-50°C. WO2008/059029 relate to various polymorphs of ethyl 3-[(2-{[4- (hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyhdin-2-yl-amino]-propionate such as anhydrous form III, anhydrous form IV, monohydrate I, monohydrate Il and solvate I. The various polymorphs are obtained by dissolving the base in solvents selected from diisopropylether, THF, 1,4dioxane, DMSO, cyclohexanone, acetonitrile, acetone, nitrobenzene alone or in combination thereof. In WO2006/14415, six salts of Dabigatran etexilate are described, such as the hydrochloride, citrate, tartarate, malonate, maleate and salicylate salts. WO2012027543 describe crystalline forms of Dabigatran etexilate and Dabigatran etexilate mesylate and the processes for preparing the same. Accordingly, Dabigatran etexilate mesylate form III is prepared by a process comprising crystallizing Dabigatran etexilate mesylate form III from a solvent selected from lower alcohols, such as, for example, ethanol, propanol, isopropanol, 1- butanol and 2-butanol, or mixtures thereof; with ethers such as, for example, t-butyl- methyl ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran; or esters such as, for example, ethyl acetate or n-butyl acetate; and ketones such as, for example, acetone, methyl ethyl ketone (MEK) or methyl isobutyl ketone, or mixtures thereof with ethers or esters. Further, WO’543 disclose amorphous Dabigatran etexilate mesylate which is prepared by solid state dry grinding. It is further disclosed in said WO’543 that the amorphous form has low water content, of about 2% to 3%, and is stable towards degradation. However, particle size of amorphous form in said WO’543 is not mentioned. Further, in pharmaceutical industry, it is desired to prepare pharmaceutical compounds which have advantageous properties such as flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents. Moreover, it is desired to prepare the active substance in high purity and in a yield acceptable in the industrial scale and with reproducible quality. In view of the above, there still remains a need in the art to provide a novel, improved, simple and industrially scalable process for the preparation of amorphous and crystalline form I of Dabigatran etexilate and its salt thereof with advantageous properties for pharmaceutical use. SUMMARY OF THE INVENTION: In an aspect, the present invention provides a simple and

efficient process for preparation of amorphous form of Dabigatran etexilate mesylate in good yield and purity. In another aspect, the present invention provides a simple and efficient process for preparation of stable crystalline Form I of Dabigatran etexilate mesylate in good yield and purity. In another aspect, the present invention provides a process for preparation of amorphous Dabigatran etexilate mesylate salt in micronized form with a particle size having d90 less than 10µ from crystalline Form I. In yet another aspect, the present invention provides a pharmaceutical composition comprising any of aforesaid forms of Dabigatran etexilate mesylate prepared by the process of instant invention in combination with pharmaceutically acceptable excipients. Description of Figures Fig 1 depicts PXRD of amorphous Dabigatran etexilate mesylate Fig 2 depicts PXRD of crystalline Form I Dabigatran etexilate mesylate Fig 3 depicts DSC of crystalline Form I Dabigatran etexilate mesylate 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. The present invention discloses industrially scalable and commercially attractive process for the preparation of amorphous and crystalline form I of Dabigatran etexilate mesylate salt in good yield having advantageous properties for pharmaceutical use. In accordance with the above, the present invention discloses a simple, industrially scalable process for preparation of amorphous form of Dabigatran etexilate mesylate in good yield and purity comprising; a.preparing a solution of Dabigatran etexilate in methylene dichloride; b.converting to its mesylate salt and recovering the amorphous form of mesylate salt of Dabigatran etexilate from methylene dichloride by slow solvent evaporation under vacuum or by spray drying. According to the process, to a solution of Dabigatran Etexilate in methylene dichloride maintained at 25-30°C under inert atmosphere was added dropwise methane sulphonic acid dissolved in methylene dichloride over a period of 10-20 minutes at same temperature. This was followed by evaporation of the solvent under vacuum for 7-8 hours to obtain the amorphous powder which was collected under nitrogen atmosphere and further dried under vacuum. The water content is in the range 1-3%, preferably 1.5%. Alternately, Dabigatran etexilate mesylate was dissolved in methylene dichloride to obtain a clear solution which was pumped through a 0.7 mm nozzle of spray dryer at approximately 2 to 3ml/minute at an inlet

gas temperature of 100°C and an outlet gas temperature of approximately 65 to 75°Cto obtain the amorphous powder. The amorphous Dabigatran etexilate mesylate obtained by the process of instant invention is characterized by PXRD (fig 1). In another embodiment, the present invention aims to provide a simple, industrially scalable process for preparation of crystalline Form I of Dabigatran etexilate mesylate which is stable and does not get converted to other polymorphic forms under heat or treatment with various other solvents. Accordingly, the present invention discloses a simple and industrially scalable process for preparation of crystalline Form I of Dabigatran etexilate mesylate which is stable at a temperature up to 50°C and to various other solvents, which includes the following steps; a.adding to a solution of Dabigatran etexilate base dissolved in methyl isobutyl ketone, at room temperature, a solution of methane sulfonic acid in methyl isobutyl ketone over a period of about 15 minutes and stirring; b.maintaining the above mixture for about 2 hrs at the same temperature under nitrogen atmosphere, filtering to obtain crystalline Form I solid followed by washing with methyl isobutyl ketone and drying. According to the procedure, solution of Dabigatran etexilate in methyl isobutyl ketone was stirred for 15 minutes. A solution of methane sulfonic acid in methyl isobutyl ketone was slowly added to the above reaction mixture over a period of 15 minutes at room temperature. After completion of addition, the reaction mixture was stirred, maintained for about 2 hours at the same temperature under nitrogen atmosphere. The crystalline Form I powder was filtered and dried at 40-45°C under vacuum for 2- 3 hours. The Crystalline Dabigatran etexilate mesylate Form I prepared by the process of instant invention is characterized by PXRD data (fig 2)and DSC (fig.3). Further, crystalline Form I of Dabigatran etexilate mesylate is having PSD characterized by d90 590 microns. In yet another embodiment, the present invention discloses a process for preparation of amorphous Dabigatran etexilate mesylate in a micronized form with a particle size characterized by d90 less than 10 micron comprising micronizing pure crystalline Form I of Dabigatran etexilate mesylate having PSD characterized by d90 590 microns in a Jet Mill at room temperature using dry oil-free air as the carrier gas and at micronization pressure of 6 bar. In an embodiment, the present invention further encompasses a pharmaceutical composition comprising any of aforesaid forms of Dabigatran etexilate mesylate prepared by the process of instant invention in combination with

pharmaceutically acceptable excipients and to the use of said pharmaceutical composition for treating or preventing blood clots in a patient suffering from or susceptible to the formation of blood clots. The present invention further provides a method of treating or preventing blood clots in a patient suffering from or susceptible to the formation of blood clots using said pharmaceutical composition of aforesaid forms of Dabigatran etexilate mesylate. The present invention is not to be limited in its scope by the exemplified embodiments which are intended as illustrations only. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Examples: Example 1: Preparation of Amorphous Form of Dabigatran Etexilate Mesylate A solution of Dabigatran etexilate (5 gm) in methylene dichloride (30 ml) was stirred for 15 minutes at 25-30°C under inert atmosphere. 0.75 gm of methane sulphonic acid in (5 ml) methylene dichloride was added drop wise to the above reaction mixture over a period of 15 minutes at 25-30°C and after completion of addition, stirred for another 15 minutes at the same temperature. The mixture was slowly evaporated by applying vacuum for 7-8 hours. The amorphous powder was collected under nitrogen atmosphere and dried at 40-45°C under vacuum for 2 hours to yield title amorphous compound. Dry Wt – 5.5 gm; Purity by HPLC – 99.64% Example 2: A solution of Dabigatran etexilate (10 gm) in methylene dichloride (60 ml) was stirred for 15 minutes at 25-30°C under inert atmosphere. 1.5 gm of methane sulphonic acid in (10 ml) methylene dichloride was added drop wise to the above reaction mixture over a period of 15 minutes at 25-30°C and after completion of addition, stirred for another 15 minutes at the same temperature. The reaction mixture was cooled up to 5°C to 10°C. The mixture was slowly evaporated by applying vacuum for 7-8 hours. The amorphous powder was collected under nitrogen atmosphere and dried at 40-45°C under vacuum for 2 hours to yield title amorphous compound. Dry Wt – 10.5 gm; Purity by HPLC – 99.80% Example 3: A solution of Dabigatran etexilate (50 gm) in methylene dichloride (300 ml) was stirred for 30 minutes at 25-30°C under inert atmosphere. 7.5 gm of methane sulphonic acid in (50 ml) methylene dichloride was added drop wise to the above reaction mixture over a period of 15 minutes at 25-30°C and after completion of addition, stirred for another 15 minutes at the same temperature. The mixture was slowly evaporated by applying vacuum for 7-8 hours. The

amorphous powder was collected under nitrogen atmosphere and dried at 40-45°C under vacuum for 2 hours to yield dried amorphous form. Dry Wt – 55 gm; Purity by HPLC – 99.70% Example-4: Dissolved (10.0 gm) Dabigatran etexilate mesylate in methylene dichloride (100 ml) and stirred for 1 hour. The resulting clear solution was taken for spray drying in ALU228 Mini Spray Dryer by pumping the feed solution through a 0.7 mm nozzle at approximately 2 to 3 ml/minute. The system was operated at an inlet gas temperature of 100°C and an outlet gas temperature of approximately 65 to 75°C. The solvent was removed to yield 9.0 gm of solid amorphous form.. Dry Wt– 9.0 gm; Purity by HPLC – 99.85% Example-5: Preparation of amorphous form of Dabigatran etexilate mesylate in micronized form. Crystalline Form I of pure Dabigatran etexilate mesylate (of the instant invention) having PSD characterized by d90 590micron is micronized in a Jet Mill at room temperature (20-25°C) using dry oil-free air as the carrier gas and under micronization pressure of 6 bar to yield micronized amorphous form of Dabigatran etexilate mesylate having PSD characterized by d90 less than 10 µ. Example 6: Preparation of crystalline Form I of Dabigatran Etexilate Mesylate Dissolved (10 gm) Dabigatran etexilate (base) in methyl isobutyl ketone (56 ml) and stirred for 15 minutes at 25-30°C. A solution of methane sulfonic acid (1.5 gm) in 10 ml of methyl isobutyl ketone was slowly added to the above reaction mixture over a period of 15 minutes at 25-30°C and stirred for 15 minutes at the same temperature. A solution of methane sulfonic acid (1.5 gm) in (10 ml) of methyl isobutyl ketone was slowly added to the above reaction mixture over a period of 15 minutes at 25-30°C and stirred for 15 minutes at the same temperature. Maintained the mixture for 2 hours at 25-30°C. Filtered the obtained crystalline Form I solid, washed with methyl isobutyl ketone and dried to yield title compound. Dry Wt – 11 gm; Purity by HPLC – 99.64% PXRD & DSC showed the material to be predominantly crystalline Form I of Dabigatran etexilate mesylate and is comparable to referenced Form I given below. Example 7: A solution of Dabigatran etexilate (10 gm) was prepared in Methyl isobutyl ketone (55 ml) and stirred for 15 minutes at RT. A solution of methane sulfonic acid (1.5 gm) in 10 ml of Methyl isobutyl ketone was slowly added to the above reaction mixture over a period of 15 minutes at 25-30°C and after completion of addition, the reaction mixture was stirred for another 15 minutes at the same temperature. Stirred & maintained for 2 hours at 25-30°C under nitrogen

atmosphere. Filtered Form I powder and dried at 40-45°C under vacuum for 2- 3 hours. Dry Wt – 10.5 gm; Purity by HPLC – 99.88% PXRD & DSC showed the material to be predominantly crystalline form I of Dabigatran etexilate mesylate and is comparable to referenced Form I given below. Reference example1: (IN231731) At room temperature was dissolved Dabigatran etexilate base (31.4 gm) in ethyl acetate (350 ml) and stirred for 15 minutes. A solution of methane sulfonic acid (4.8 gm) in 25 ml of ethyl acetate was slowly added to the above reaction mixture over a period of 15 minutes at 25-30°C and stirred for 15 minutes at the same temperature. Maintained the reaction mixture for 1 hour & cooled to 0-5°C. Filtered the solid and washed with chilled ethyl acetate. The so formed Form I of dabigatran etexilate mesylate was dried at 40-45°C under vacuum for 2- 3 hours. Dry wt – 36 gm; Purity by HPLC – 99.85% Reference example 2: Dissolved (10 gm) (Form I) Dabigatran etexilate mesylate prepared by the method disclosed in US7932273 in 88 ml ethyl acetate & stirred for 15 minutes. The reaction mixture was heated up to 50-55°C. Maintained the reaction mixture for 8 hours. Cooled the reaction mixture up to 20-25°C. Filtered the obtained solid, washed with ethyl acetate and dried at 40-45°C under vacuum to obtain the title Form I compound. Dry Wt – 10.5 gm; Purity by HPLC – 99.88% Thus, it is apparent from above that the present invention provides a simple and industrially scalable process for preparation of amorphous and crystalline form I of Dabigatran etexilate mesylate in good yield and purity with advantageous properties for pharmaceutical use.

5. CLAIMS (not applicable for provisional specification.) We claim, 1.A simple and industrially scalable process for preparation of amorphous form of Dabigatran etexilate mesylate in good yield and purity comprising preparing a solution of Dabigatran etexilate in methylene dichloride, converting to its mesylate salt and recovering the amorphous form of mesylate salt of Dabigatran etexilate from methylene dichloride by slow solvent evaporation under vacuum or by spray drying. 2.The simple and efficient process according to claim 1, wherein the process for preparation of amorphous Dabigatran etexilate mesylate optionally comprises dissolving Dabigatran etexilate mesylate in methylene dichloride to obtain a clear solution followed by pumping the solution through a 0.7 mm nozzle of spray dryer at approximately 2 to 3 ml/minute at an inlet gas temperature of 100°C and an outlet gas temperature of approximately 65 to 75°C to yield the amorphous powder. 3.A simple and industrially scalable process for preparation of crystalline Form I of Dabigatran etexilate mesylate which is stable at a temperature up to 50°C and to various other solvents comprising adding to a solution of Dabigatran etexilate base dissolved in methyl isobutyl ketone, at room temperature, a solution of methane sulfonic acid in methyl isobutyl ketone over a period of about 15 minutes, stirring and maintaining the above mixture at the same temperature under nitrogen atmosphere, filtering to yield crystalline Form I solid followed by washing with methyl isobutyl ketone and drying. 4.A pharmaceutical composition comprising Dabigatran etexilate mesylate according to any of preceding claims and at least one pharmaceutically acceptable excipient. Dated this 29th day of May, 2014 Andreya Fernandes (Regn.No.: IN/PA 1777) Agent for the Applicant Gopakumar Nair Associates
6. DATE AND SIGNATURE (to be given at the end of last page of specification)