DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
INTRODUCTION
Aspects of the present application relate to processes for preparing crystalline form I of dabigatran etexilate mesylate. Aspects of the present application also relate to novel impurity compounds that are formed in the preparation of dabigatran etexilate mesylate.

The drug compound having the adopted name “dabigatran etexilate mesylate” is a direct thrombin inhibitor and is the active ingredient in products marketed by Boehringer Ingelheim as PRADAXA®, for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. A chemical name for dabigatran etexilate mesylate is N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl] carbonyl]-N-2-pyridinyl-ß-Alanine ethylester methanesulfonate. Dabigatran etexilate mesylate can structurally be represented as formula I.

The synthesis of dabigatran etexilate and the other substituted (4-benzimidazol-2-ylmethylamino) benzamidines were first described in an international patent application bearing the publication number WO 98/37075.

The synthesis of mesylate salt of dabigatran etexilate was disclosed in an international patent application having the publication number WO 03/74056 under example 3. The resulting product is a crystalline form characterized by melting point of 178-179°C.

Dabigatran etexilate mesylate exhibits polymorphism. WO2005/028468 discloses dabigatran etexilate mesylate polymorph I, II, and hemihydrate crystals characterized by melting point and X-ray powder diffraction. WO2011/110876 discloses dabigatran etexilate mesylate form IV characterized by powder diffraction peaks. WO2012/027543 discloses novel solid state forms of dabigatran etexilate mesylate designated as forms A, B, C, D, G, H, and III characterized by PXRD. Further, WO2013/124385 discloses crystalline form A of dabigatran etexilate mesylate characterized by X-ray diffraction. Furthermore, WO2013/144971 discloses crystalline dabigatran etexilate mesylate form III characterized by powder X-ray diffraction and differential scanning calorimetry (DSC) thermogram.

The process for the preparation of crystalline form I of dabigatran etexilate mesylate was disclosed in WO2005/028468, WO2012/027543, WO2012/077136, and WO2013/150545.

The above-mentioned documents collectively disclose diverse forms of dabigatran etexilate mesylate and processes for preparing respective polymorphic forms thereof. Still there is an unmet need in the field for the provision of a simple and robust process for the preparation of crystalline form I of dabigatran etexilate mesylate, which is not only cost effective but also amenable to scale-up and afford a stable form which suitable for the preparation of solid pharmaceutical dosage forms.
SUMMARY
In an aspect, the present application provides an improved process for the preparation of crystalline form I of dabigatran etexilate mesylate, comprising:
a) providing a solution of dabigatran etexilate in acetone;
b) slowly adding a solution of methanesulfonic acid; and
c) isolating the crystalline form I of dabigatran etexilate mesylate.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1: Powder X-Ray diffraction pattern of compound of formula I obtained according to example: 2.

DETAILED DESCRIPTION
In an aspect, the present application provides an improved process for the preparation of crystalline form I of dabigatran etexilate mesylate, comprising:
a) providing a solution of dabigatran etexilate in acetone;
b) slowly adding a solution of methanesulfonic acid; and
c) isolating the crystalline form I of dabigatran etexilate mesylate.

In embodiments of step a), providing a solution includes:
i) direct use of a reaction mixture containing dabigatran etexilate that is obtained in the course of its synthesis that comprises acetone, or by adding acetone to a reaction mixture; or
ii) dissolving dabigatran etexilate, prepared according to any of the processes available in the state of art, in a solvent comprising acetone; or
iii) heating a suspension containing dabigatran etexilate, prepared according to any of the processes available in the state of art, and a solvent comprising acetone to a required temperature to obtain a clear solution.

In embodiments of step a), any physical form of dabigatran etexilate may be utilized for providing the solution of dabigatran etexilate in step a).

In embodiments of step a), dabigatran etexilate can be dissolved in acetone.. The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of dabigatran etexilate is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, Candy, Micro, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

In embodiments of step b), methanesulfonic acid may be added to the solution obtained in step a) in the form of a solution or in the form of pure compound.
In embodiments of step b), methanesulfonic acid solution may be prepared by adding methanesulfonic acid to solvent comprising acetone at a temperature less than about 40°C, less than about 20°C, less than about 0°C, less than about -10°C, or any other suitable temperature and maintaining the solution at a temperature less than about 40°C, less than about 20°C, less than about 0°C, less than about -10°C, or any other suitable temperature over a required period to facilitate a proper dissolution.

In embodiments of step b), methanesulfonic acid solution may be added slowly to the dabigatran etexilate solution obtained in step a) at a temperature less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, or any other suitable temperature and maintaining the solution at a temperature less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, or any other suitable temperature over a required period to facilitate completion of the reaction.

In embodiments of step b), methanesulfonic acid solution may be added slowly onto the dabigatran etexilate solution obtained in step a) or vice versa.

In embodiments of steps a) and b), acetone used may be pretreated to afford required moisture content. The water content in acetone should be less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01%. The water content was determined via Karl Fischer (KF) measurement.

In embodiments of step c), crystalline form I of dabigatran etexilate is isolated from the solution obtained in step b). Isolation of crystalline form I of dabigatran etexilate in step c) may involve methods including cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

In embodiments of step c), optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step b). Anti-solvent as used herein refers to a liquid in which dabigatran etexilate mesylate is less soluble or poorly soluble.

In embodiments of step c), suitable temperatures for isolation may be less than about 40°C, less than about 20°C, less than about 0°C, less than about -10°C, or any other suitable temperatures.

The crystalline form I of dabigatran etexilate may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, Agitated Nutsche Filter dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the dabigatran etexilate is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.

Crystalline forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methods, e.g., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Crystal forms of the application can be further processed to modulate particle size. For example, the crystal forms of the application can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation and formulation.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.

Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±.0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ±.0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ±.0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2??±.0.2o) of 7.9o" means "having a diffraction peak at a diffraction angle (2?) of 7.7o to 8.1o. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of XRD is meant to encompass that peak assignments can vary by plus or minus about 0.2.degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not. All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation.

DEFINITIONS
The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise.
As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended.
The terms "about," “substantially” and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The terms “optional” and “optionally” mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

Crystalline dabigatran etexilate mesylate obtained according to the process of the present invention may be substantially free of one or more of its corresponding impurities e.g., amidine amide impurity of formula (i), des amino pyridine impurity of formula (ii), hexyl amide of formula (iii), dihexyl impurity of formula (iv), diaryl triazinone of formula (v) and their corresponding mesylate salts impurities thereof. For example each impurity in dabigatran etexilate mesylate obtained according to the process of the present invention may be present in an amount of less than about 1% or less than about 0.5% or less than about 0.3% or less than about 0.1% or less than about 0.05% or less than about 0.01% as determined by HPLC.

A high performance liquid chromatography (HPLC) method for the analysis of amidine amide impurity of formula (i), des amino pyridine impurity of formula (ii), hexyl amide of formula (iii), dihexyl impurity of formula (iv), diaryl triazinone of formula (v) and their corresponding mesylate salts impurities thereof utilizes a C-18 or equivalent column and additional parameters are described below.

Column: Poroshell 120, EC C-18 150mm X 4.6 mm X 2.7µm
Flow rate : 0.7 mL /min
Column Oven Temperature : 30°C
Wave length : 230 nm
Injection volume : 10 µL
Run Time : 75 min
Diluent : Acetonitrile: Water (3:7)
Elution : Gradient
Gradient program:
Time (minutes) 0.01 5.0 30.0 40.0 65.0 65.1 75
% of mobile phase-A 65.0 65.0 35.0 10.0 10.0 65.0 65.0
% of mobile phase-B 35.0 35.0 65.0 90.0 90.0 35.0 35.0
EXAMPLES

Example-1: Preparation of dabigatran etexilate mesylate
Part-I: Pretreatment of acetone for moisture content reduction
Acetone (1500 mL) and 3A-molecular sieves (150 g) were charged into a round bottom flask and maintained the same at ambient temperature until the moisture content in acetone was less than 0.05% when measured by Karl Fischer method. The resulted acetone was decanted into another flask, filtered through pressure nutsche filter (PNF) and subsequently filtered through 0.45µ filter.
Yield: Acetone having moisture content of 0.04%.

Part-II: Preparation of dabigatran etexilate mesylate form I
Dabigatran etexilate (15 g) and acetone (225 mL) were charged into a round bottom flask under N2 atmosphere and heated to 35-40°C to obtain a clear solution. The reaction mass was filtered to get particle free solution and the residue was washed with acetone (15 mL). The obtained particle free solution was cooled to around 15-20°C. Methanesulfonic acid (2.25 g) dissolved in acetone (30 mL) was added slowly to the reaction mass using an addition funnel over a period of around 60-90 minutes at 15-20°C. After addition, the funnel was rinsed with acetone (7.5 mL). The reaction mass was cooled to 5-10°C and the solid obtained was filtered through PNF and subsequently washed with acetone (30 mL). The compound was press dried under N2 atmosphere and the compound was dried in an oven under vacuum at 50-55°C to afford the title compound.
Yield: 15.4 g; Purity by HPLC: 99.79%

Example-2: Preparation of dabigatran etexilate mesylate in large scale
Part-I: Pretreatment of acetone
Acetone (700 L) and 3A-molecular sieves (70 Kg) were charged into a reactor and maintained the same for about 2 hours under N2 atmosphere at 25-35°C. A small sample of acetone was collected from the reactor and micro filtered into an air tight bottle under N2 atmosphere at 25-35°C. The sample was analyzed for water content (water content: 0.02% w/v). The acetone was filtered through PNF, candy and micro filters by applying N2 pressure of 1.0±0.5 Kg/cm2 and collected the filtrate (630 L) into a vessel.

Part-II: Preparation of dabigatran etexilate mesylate
All the reactors, filters, and other equipments were sequentially pretreated with acetone, applied N2 pressure of 1.5±0.1 Kg/cm2, heated to 35-40°C, and subsequently cooled to ambient temperature.
Acetone (345 L) and dabigatran etexilate (23 Kg) were charged into a reactor R1 and maintained the reaction mass for about 15 minutes at 25-35°C under N2 atmosphere. The reaction mass was heated to 35-40°C and maintained for about 15 minutes at the same temperature. Then the reaction mass was filtered into another reactor R2 through the candy and micron filter at 35-40°C. Acetone (46 L) was charged into reactor R1 under N2 atmosphere and cooled to 15-20°C. Methanesulfonic acid (3.45 Kg) was added to the acetone in reactor R1 under N2 atmosphere at 15-20°C and maintained the reaction mass for about 15 minutes at the same temperature. The methanesulfonic acid solution in reactor R1 was filtered through micron filter and subsequently added to the reaction mass in the reactor R2 at 15-20°C over a period of 1-2 hours under N2 atmosphere. The reaction mass was cooled to 0-10°C under N2 atmosphere and transferred the same to Agitated Nutsche Filter Dryer (ANFD) at 0±5°C under N2 atmosphere. The resultant product was press dried for about 3 hours using N2 pressure of 1.5±0.5 Kg/cm2 from top and subsequently suck dried for 3 hours from the bottom of the ANFD at 0±5°C under N2 atmosphere. Finally the product was dried for 2 hours at 15-20°C and another 2 hours at 20-25°C under vacuum to afford dabigatran etexilate mesylate form I.
Yield: 24 Kg; Purity by HPLC: 99.84%
,CLAIMS:We Claim

Claim 1: An improved process for the preparation of crystalline form I of dabigatran etexilate mesylate, comprising:
a) providing a solution of dabigatran etexilate in acetone;
b) slowly adding a solution of methanesulfonic acid to mixture of step;
c) isolating the crystalline form I of dabigatran etexilate mesylate at a temperature of less than 20oC.

Claim 2: The process of claim 1, wherein acetone employed in step a) is pretreated with a dehydrating agent.

Claim 3: The process of claim 2, wherein molecular sieves are employed as a dehydrating agent.

Claim 4: The process of claim 1, wherein step b) is carried at a temperature less than 20oC.

Claim 5: The process of claim 1, wherein isolation in step c) can be materialized by cooling, evaporation, addition of anti-solvent, addition of seed crystals or combinations thereof.

Claim 6: The process of claim 1, wherein isolation in step c) is done at a temperature less than 10oC.