WO2018042320A1

WO2018042320A1 - Salts of betrixaban and processes for preparation thereof

Info

Publication number: WO2018042320A1
Application number: PCT/IB2017/055168
Authority: WO
Inventors: Srinivas ORUGANTI; Bhaskar KANDAGATLA
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2016-08-30
Filing date: 2017-08-29
Publication date: 2018-03-08

Abstract

The present application relates to novel acid addition salts of Betrixaban and processes for their preparation thereof. It further relates to crystalline forms including its solvates and hydrates of Betrixaban novel acid addition salts. The application further concerns pharmaceutical compositions comprising the novel acid addition salts of the Betrixaban, useful as potent fXa inhibitors.

Description

SALTS OF BETRIXABAN AND PROCESSES FOR PREPARATION THEREOF

FIELD OF THE APPLICATION

The drug compound having the adopted name "Betrixaban" and it has chemical name: N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl) benzamido)-5-methoxybenzamide; and a structure depicted by Formula I.

Formula I

International Patent Application Publication Nos. WO 2001019788A2, WO 2001064643A2, WO2001064642 A3 which are incorporated herein in their entirety reported Betrixaban and its related compounds as a potent fXa inhibitors. Such compounds inter alia can be used for the potential extended- duration prophylaxis and treatment of venous thrombosis in acute medically ill patients. International Patent Application Publication Nos. WO 2008/057972A1 and WO 201 1/084519A1 disclose processes for preparing Betrixaban and its salts.

International Patent Application Publication No. WO 2007/056517A2 and WO 2012/031017A1 disclose crystalline forms of the compound of Formula (I).

Use of a substance for pharmaceutical purposes places high demands on the substance quality. The most efficient purification operation is crystallization. In the case of preparation of substances in amorphous form it is very difficult to achieve internationally appreciated quality criteria defined by the ICH guidelines. In those cases purification by way of preparation of acid addition salts could be very useful which on neutralization will lead to substances with improved purity. Therefore, various Betrixaban salt forms could be used to enhance the purity of Betrixaban or its maleate salt.

Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. In addition, polymorphism is very common among pharmaceutical substances. It is commonly defined as the ability of any substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Different polymorphic forms of the same pharmaceutically active moiety also differ in their physical properties such as melting point, solubility, etc.

Pharmaceutical stability is believed to depend on simultaneous influence of various factors, of which some important factors are the sizes of the crystals, shape of the crystals, water content, residual solvents and impurities. Towards this end, it has been the endeavor of pharmaceutical scientists to provide novel salts and stable forms of drug substances, which would have the strengths of the crystalline forms, viz. thermodynamic stability, and those of the amorphous form, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.

Therefore there remains a need to provide and characterize new Betrixaban salts and their polymorphs. Further, it would be desirable to have reliable processes for producing these Betrixaban salt forms.

SUMMARY OF THE INVENTION

In the first embodiment, the present application provides novel acid addition salts of Betrixaban with acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid, methane sulfonic acid and oxalic acid.

In the second embodiment, the present application provides crystalline forms including hydrates or solvates of the acid addition salts of Betrixaban with acids selected from maleic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid, methane sulfonic acid and oxalic acid.

In the third embodiment, the present application provides a process for the preparation of acid addition salts of Betrixaban, comprising: a) providing a mixture of Betrixaban free base or its salt in a suitable solvent;

b) adding free acid or a source of anion to the mixture of step a);

c) isolating and recovering the salt of Betrixaban from the mixture of step b); and

d) optionally drying the resulting salt of Betrixaban.

In the fourth embodiment, the present application provides a pharmaceutical composition comprising one of the acid addition salts of Betrixaban with acids selected from maleic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid, methane sulfonic acid and oxalic acid; and one or more pharmaceutically acceptable excipients. These acid addition salts can be crystalline or amorphous in nature.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban maleate prepared according to example 3.

FIG. 2 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban citrate prepared according to example 4.

FIG. 3 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban oxalate prepared according to example 5.

FIG. 4 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban mesylate prepared according to example 6.

FIG. 5 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban hydrochloride prepared according to example 7.

FIG. 6 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban sulfate prepared according to example 8.

FIG. 7 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban hydrobromide prepared according to example 9.

FIG. 8 is an illustration of powder X-ray diffraction ("PXRD") pattern of Betrixaban trifluoroacetate prepared according to example 10.

DETAILED DESCRIPTION

In the first embodiment, the present application provides novel acid addition salts of Betrixaban with maleic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid, methane sulfonic acid and oxalic acid.

In the second embodiment, the present application provides crystalline forms including hydrates or solvates of these novel acid addition salts of Betrixaban.

In yet preferred aspects of second embodiment, Betrixaban salts can be characterized by Figures provided therein. For example,

Betrixaban citrate that can be characterized by its PXRD pattern, as illustrated in Figure 2.

Betrixaban oxalate that can be characterized by its PXRD pattern, as illustrated in Figure 3.

Betrixaban mesylate that can be characterized by its PXRD pattern, as illustrated in Figure 4.

Betrixaban hydrochloride that can be characterized by its PXRD pattern, as illustrated in Figure 5.

Betrixaban sulfate that can be characterized by its PXRD pattern, as illustrated in Figure 6.

Betrixaban hydrobromide that can be characterized by its PXRD pattern, as illustrated in Figure 7.

Betrixaban trifluoroacetate that can be characterized by its PXRD pattern, as illustrated in Figure 8.

In the third embodiment, the present application provides a process for the preparation of acid addition salts of Betrixaban, comprising:

a) providing a mixture of Betrixaban free base or its salt in a suitable solvent;

b) adding free acid or a source of anion to the mixture of step a);

d) optionally drying the salt.

The mixture comprising Betrixaban free base or its salt in step a) may be a suspension or a solution. The mixture of step a) may be obtained, for example, by providing free base or a salt of Betrixaban of any form in a solvent. The said base or salt may be obtained by a previous step of the process which can be a final reaction and/or purification. If it is intended to obtain a clear solution of Betrixaban free base or its salt, the reaction mixture can be heated to dissolution temperature that can be any temperature as long as the stability of the Betrixaban free base or its salt is not compromised and a substantially clear solution is obtained. For example, the dissolution temperature may range from about 20°C to about the reflux temperature of the solvent.

If Betrixaban salt is employed in step a) as an input material then it will be different from the finally obtained Betrixaban salt of step c) and step d).

Solvents employed for preparation of salts of Betrixaban include, but are not limited to: alcohols, such as, for example, methanol, ethanol, or 2-propanol; esters, such as, for example, ethyl acetate, isopropyl acetate, or t-butyl acetate; ketones such as acetone or methyl isobutyl ketone; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, THF, or methyl THF; halogenated hydrocarbons, such as, for example, dichloromethane, dichloroethane, chloroform, or the like; hydrocarbons, such as, for example, toluene, xylene, or cyclohexane; nitriles such as acetonitrile; dipolar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide or like; water; or any mixtures thereof.

Appropriate solvents or non-solvents may be determined by solubility tests in various solvents.

Step b) involves addition of free acid or source of anion to the mixture of step a). The free acid employed could be inorganic or organic. Inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid and like; and organic acids include but are not limited to trifluoroacetic acid, citric acid, methane sulfonic acid, oxalic acid, maleic acid and like. Source of anion employed in step b) could be inorganic salts or organic salts. Such salts include but are not limited to sodium sulfate, ammonium chloride, ammonium bromide, ammonium oxalate or the like. The source of anion or free acid can be directly added as solid/liquid or its mixture in a solvent can be employed. Suitable solvents are same as that employed in step a). Non-dissolved particles from a mixture of step b) can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material. The acids are employed in salt preparation-depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired-in an equimolar quantitative ratio or one differing therefrom.

Thus, within the acid addition salts of this invention the acid and the free compound may be substantially in 1 : 1 stoichiometry or one differing therefrom, such as e.g. from about 1 :2 to about 2:1 stoichiometry. Non-stoichiometric ratios may also be possible, such as e.g. 1 : 1 .5 or 1.5: 1 .

The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for a time from about 10 minutes to about 5 hours or longer. Suitable temperatures for crystallization are from about 0°C to about 50°C, from about 10 to about 30°C, or any other temperatures may be used. Suitable times for crystallization will vary, and can be from about 10 minutes to about 10 hours, or longer.

Step c) involves isolation and recovery of Betrixaban salts from the reaction mixture. The isolation of salts of Betrixaban may be induced by using conventional techniques known in the art. For example, useful techniques include but are not limited to, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent by using a technique includes but is not limited to tray drying, spray drying, fluidized bed drying, thin film drying under reduced pressure, or thin film drying at atmospheric pressure. The recovery of salts of Betrixaban can be done by decantation, centrifugation, gravity filtration, suction filtration and like.

Particularly, crystalline forms may also be obtained by heating or melting a form obtained followed by gradual or fast cooling; in this manner one polymorph or one crystalline form may be converted to another.

The salts of the present invention if desired can be purified by re- crystallization from an appropriate re-crystallization solvent or mixture of solvents by methods customary to one of skill in the art, and/or. If required, the process further comprises, at a suitable stage, removing or separating any undesired material or impurities, and finally, optionally, the salts may be washed and/or dried.

The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.

Once obtained, crystals of Betrixaban salts may be used as the nucleating agent or "seed" crystals for subsequent crystallizations of salts of Betrixaban from solutions.

Salts of the present invention can be converted to another salts, e.g. by reaction with an appropriate acid or by means of a suitable ion exchanger. Likewise, salts obtained can be converted into the free compounds (e.g. via neutralization with a suitable base, with or without isolation of the free base, e.g. by extraction), which can in turn be converted into salts, by acidification. In this manner, formation of the selected Betrixaban salts of the application might be an efficient way of purifying Betrixaban free base and further, physiologically unacceptable salts can be converted into physiologically acceptable salts.

In a further aspect, the present invention relates to salts of the invention (including their solvates and hydrates) in solid forms, including amorphous, semi-amorphous, polymorphous, semi-crystalline and crystalline forms, as well as mixtures thereof. In a preferred aspect, salts of the present invention are Betrixaban hydrochloride, Betrixaban sulfate, Betrixaban hydrobromide, Betrixaban trifluoroacetate, Betrixaban citrate, Betrixaban mesylate and Betrixaban oxalate as characterized by PXRD in Figures 1 to 7.

The solid form of Betrixaban salts of the present application may be characterized by means of Powder X-ray Diffraction Pattern (PXRD). Other techniques, such as solid state NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) may also be used.

Betrixaban employed as a starting material for preparation of Betrixaban salt can be obtained by any processes known in the art, including processes disclosed in US6376515, US7598276 and US8524907 which are incorporated herein by reference in their entireties, as well as by other processes known in the art.

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. PXRD data reported herein was obtained using CuKa radiation, having the wavelength 1 .5406 A and were obtained using a PANalytical X'Pert PRO instruments. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64: 1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:91 1 -929.

Generally, a diffraction angle (2Θ) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. 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 ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2Θ ± 0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (2Θ) of 7.7^Lo to 8.1 ^Lo". 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 PXRD 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 PXRD 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).

Optionally Betrixaban salts of the present invention can be subjected to particle size reduction by conventional techniques like jet-milling, micronization and like to obtain suitable particle size distribution. The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise, D10 refers to 10 volume percent of the particles having a size smaller than the said value. D50 refers to 50 volume percent of the particles having a size smaller than the said value. Methods for determining D10, D50, and D90 include laser diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.

In the fourth embodiment, the present application provides a pharmaceutical composition comprising novel acid addition salts of Betrixaban and one or more pharmaceutically acceptable excipients.

Such further excipients and adjuvants are known to the person skilled in the art and may include one or more fillers; diluents, for example microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate, pregelatinized starch and the like; binders such as PVP, HPMC, HPC and the like; disintegrants, for example, sodium starch glycolate, crospovidone, croscarmellose sodium and the like; lubricants, for example, magnesium stearate, sodium stearyl fumarate and the like; sweeteners, for example, sucrose, saccharin and the like; flavoring agents, for example, peppermint, methyl salicylate, orange flavoring and the like; colorants; preservatives; buffers; and/or other excipients depending on the dosage form used.

The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension. The pharmaceutical dosage form can be prepared by methods known in the art, such as direct compression or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.

The pharmaceutical dosage form according to the present invention may be is coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The abbreviation "MC" mean moisture content. Moisture content can be conveniently measured, for example, by the Karl Fischer method.

"Amorphous form" as used herein refers to a solid state wherein the amorphous content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.

All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25°C and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.

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 unless the context suggests otherwise.

All ranges recited herein include the endpoints, including those that recite a range "between" two values.

Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. 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.

Where this document refers to a material, such as in this instance, Betrixaban acid addition salt, and their solid state forms thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted in their positions, relative intensities and/or values due to a number of factors known to those of skill in the art.

In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that solid state form, within any associated and recited margin of error, for purposes of identification.

When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.

As used herein, the term "room temperature" refers to a temperature of from about 20°C to about 35°C, from about 25°C to about 35°C, from about 25°C to about 30°C, or for example, about 25°C. As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.

The "polymer" or "carrier" or "excipient" as used herein interchangeably refers to any substance or mixture of substances which are pharmaceutically acceptable inactive ingredients.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

As used herein, the terms "salt(s) of Betrixaban," "Betrixaban salt(s)" and other similar phrases encompass crystalline and amorphous forms, solvates, hydrates, stereoisomers, both individual and in mixtures thereof.

EXAMPLES

Example 1 : Preparation of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)- 5-methoxybenzamide

A flask was charged with 2-Amino-N-(5-Chloro pyridine-2-yl)-5-methoxy benzamide (100 g), THF (1 .5L), and pyridine (1 1 .63 mL) at room temperature. To this a solution of 4-cyano benzoyl chloride (65.58 g) in THF (400 mL) was slowly added over a period of 45 min under inert atmosphere. The mixture was stirred for 4 hours at 20-22°C followed by filtration of the solid. The solid was washed with THF (100 mL) and was slurried in ethanol (500 mL), followed by subsequent filtration and washing with ethanol (100 mL). The solid was dried under vacuum at 35°C for 2 hours and then water (500 mL) was added and the mixture was cooled to 0-5°C followed by pH adjustment to ~12 with 20% ammonia solution (79 mL) at the same temperature. The mixture was stirred at 25°C for 1 h followed by filtration of solid, washing with methanol (200 mL) and drying under vacuum at 55°C for 18 hours to afford the title compound in about 77% yield.

Example 2: Preparation of Betrixaban

A flask was charged with N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5- methoxybenzamide in THF (2.5 L) and mixture was cooled to -15 °C. To this, a lithiated solution separately prepared by treating pre-cooled (-10°C) dimethyl amine (862.0 mL) slowly with n-Hexyl lithium (738.8 mL), was added over a period of 45 minutes under inert atmosphere. The mixture was stirred for 2 hours at about the same temperature. After completion of reaction as monitored by TLC, saturated solution of sodium carbonate and sodium bicarbonate (1 :1 , 1 .2 L) was added at about 2°C and mixture was stirred for 30 minutes at 25°C. The salts were filtered over celite bed and washed with ethyl acetate (l OOOmL). The layers were separated and organic layer was washed with brine solution (750 mL). The organic layer was dried and subjected to complete distillation under vacuum at 35oC followed by trituration with ethyl acetate (100 mL) and then drying of the product under vacuum at 35°C for 1 hour to afford the title compound as pale yellow solid in ~79% yield.

Example 3: Preparation of Betrixaban Maleate

A flask was charged with Betrixaban (150 g), ethanol (1500 mL) and stirred at 26°C for 15 minutes. To this mixture, maleic acid (57.78 g) was slowly added portion wise and mixture was stirred at 27°C for 4 hours. The solid was filtered and washed with ethanol (150 mL), followed by drying under vacuum at 35°C for 2 hours to afford the title compound as pale yellow solid in ~78.41 % yield, as depicted in Figure 1 .

Example 4: Preparation of Betrixaban Citrate

A flask was charged with Betrixaban (1 g), ethanol (10 mL) at 28°C. To this mixture, citric acid (637 mg) was added and mixture was stirred at the same temperature for 24 hours. The solid was filtered and washed with ethanol (5 mL), followed by drying under vacuum at 38°C to afford the title compound as off white solid in ~76% yield, as depicted in Figure 2.

Example 5: Preparation of Betrixaban Oxalate

A flask was charged with Betrixaban (1 g), ethanol (10 mL) at 28°C. To this mixture, oxalic acid (298 mg) was added and mixture was stirred at the same temperature for 24 hours. The solid was filtered and washed with ethanol (5 mL), followed by drying under vacuum at 38°C to afford the title compound as off white solid in ~91 .81 % yield, as depicted in Figure 3.

Example 6: Preparation of Betrixaban Mesylate

A flask was charged with Betrixaban (1 g), ethanol (10 mL) at 28°C. To this mixture, methane sulfonic acid (298 mg) was added at 0-5°C and the mixture was stirred at 28°C for 24 hours. The solid was filtered and washed with ethanol (5 mL), followed by drying under vacuum at 38°C to afford the title compound as pale yellow solid in ~54% yield, as depicted in Figure 4.

Example 7: Preparation of Betrixaban Hydrochloride

A flask was charged with Betrixaban (1 g), ethanol (10 mL) at 28°C. To this mixture, ethanolic hydrochloric acid (10 mL) was added and the mixture was stirred at 28°C for 24 hours. The solid was filtered and washed with ethanol (5 mL), followed by drying under vacuum at 38°C to afford the title compound as yellow solid in ~93.51 % yield, as depicted in Figure 5.

Example 8: Preparation of Betrixaban Sulfate

A flask was charged with Betrixaban (1 g), ethanol (10 mL) at 28°C. To this mixture, sulfuric acid (10 mL) was added at 28°C and the mixture was stirred for 24 hours. The solid was filtered and washed with ethanol (5 mL), followed by drying under vacuum at 40°C to afford the title compound as yellow solid in ~92.56% yield, as depicted in Figure 6.

Example 9: Preparation of Betrixaban Hydrobromide

A flask was charged with Betrixaban (1 g), ethanol (10 mL) at 28°C. To this mixture, aqueous hydrobromic acid solution (47%, 0.375 mL) was added at 28°C and the mixture was stirred for 24 hours. The solid was filtered and washed with ethanol (5 mL), followed by drying under vacuum at 40°C to afford the title compound as yellow solid in ~79.48% yield, as depicted in Figure 7.

Example 10: Preparation of Betrixaban Trifluoroacetate

A flask was charged with Betrixaban (1 g), ethanol (10 mL) at 28°C. To this mixture, trifluoroacetic acid (0.254 mL) was added at 28°C and the mixture was stirred for 24 hours. The solid was filtered and washed with ethanol (5 mL), followed by drying under vacuum at 40°C to afford the title compound as white solid in ~82.4% yield, as depicted in Figure 8.

Claims

Claim 1 : A pharmaceutically acceptable acid addition salt of Betrixaban selected from the group consisting of crystalline hydrochloric acid, crystalline hydrobromic acid, crystalline sulfuric acid, crystalline citric acid, crystalline methane sulfonic acid, trifluoroacetic acid and oxalic acid.

Claim 2: The crystalline Betrixaban hydrochloride of claim 1 , having PXRD pattern as shown in Figure 5.

Claim 3: The crystalline Betrixaban hydrobromide of claim 1 , having PXRD pattern as shown in Figure 7.

Claim 4: The Betrixaban sulfate of claim 1 , which is in crystalline form.

Claim 5: The crystalline Betrixaban sulfate of claim 4, having PXRD pattern as shown in Figure 6.

Claim 6: The Betrixaban citrate of claim 1 , which is in crystalline form.

Claim 7: The crystalline Betrixaban citrate of claim 6, having PXRD pattern as shown in Figure 2.

Claim 8: The Betrixaban mesylate of claim 1 , which is in crystalline form.

Claim 9: The crystalline Betrixaban mesylate of claim 8, having PXRD pattern as shown in Figure 4.

Claim 10: The Betrixaban trifluroacetate of claim 1 , which is in crystalline form.

Claim 1 1 : The crystalline Betrixaban trifluoroacetate of claim 10, having PXRD pattern as shown in Figure 8.

Claim 12: The Betrixaban oxalate of claim 1 , which is in crystalline form. Claim 13: The crystalline Betrixaban oxalate of claim 12, having PXRD pattern as shown in Figure 3.

Claim 14: A pharmaceutical composition comprising acid addition salts of Betrixaban of claims 1 -14 and one or more pharmaceutically acceptable excipients.