WO2014056434A1

WO2014056434A1 - Crystalline form and amorphous form of apixaban and preparation thereof

Info

Publication number: WO2014056434A1
Application number: PCT/CN2013/084923
Authority: WO
Inventors: Shouzhu LIAO; Zhongqing Wang
Original assignee: Sunshine Lake Pharma Co., Ltd.
Priority date: 2012-10-10
Filing date: 2013-10-09
Publication date: 2014-04-17
Also published as: CN104797580A

Abstract

A novel crystalline form and amorphous form of Apixaban, pharmaceutical composition comprising the crystalline form and amorphous, and preparation process or use thereof are provided.

Description

CRYSTALLINE FORM AND AMORPHOUS FORM OF APIXABAN AND

PREPARATION THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to and benefits of Chinese Patent Application Serial No.

201210380868.X, filed with the State Intellectual Property Office of P. R. China on October 10, 2012, the entire content of which is incorporated herein by reference.

FIELD

The present disclosure relates to the field of pharmaceutical chemistry. More particularly, the invention relates to a novel crystalline form and amorphous form of Apixaban, pharmaceutical composition comprising the crystalline form and amorphous, and preparation process or use thereof. BACKGROUND

Apixaban, also known as

4,5 ,6,7-tetrahydro- 1 -(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo- 1 -piperidinyl)]

-lH-Pyrazolo[3,4-c]pyridine-3-carboxamide, having formula (I) , is a highly potent and selective inhibitor of Factor Xa and thus is useful in preventing or treating thromboembolic disorders.

Apixaban dimethyl formamide solvate and formamide solvate have been disclosed in US 20070203178, and crystalline form of Apixaban, form N-1 and form H2-2 hydrate have been disclosed in WO2007/001385. However, those solvates and hydrates disclosed in the references are unstable, and difficult for pharmaceutical preparation and industrial process.

A drug such as Apixaban may exist in different crystalline forms, which may have significant differences from each other in appearances, solubility, melting points, dissolution rates, bioavailability, stability, efficacy and the like. Therefore, there is a need for novel crystalline form of Apixaban having better physicochemical properties, especially, relatively higher solubility, bioavailability and/or efficacies. There is also a continuing need for a low cost and industrial friendly process for preparing polymorphs of Apixaban.

SUMMARY

Embodiments of the present disclosure seek to solve at least one of the problems existing in the prior art to at least some extent, or to provide a consumer with a useful commercial choice.

According to embodiments of a first broad aspect of the present disclosure, there is provided a substantially pure crystalline form I of Apixaban, which may show the following feature:

an X-ray powder diffraction pattern comprising a peak at about 16.98 degree in term of two theta; or

an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44, 26.98, 13.92 and 22.11 degrees in term of two theta; or

an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44, 26.98, 13.92, 22.11, 21.12, 12.84, 22.26 and 21.56 degrees in term of two theta; or

an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44,

26.98, 13.92, 22.11, 21.12, 12.84, 22.26, 21.56, 24.75, 18.81, 19.57, 29.93, 28.69 and 16.24 degrees in term of two theta; or

an X-ray powder diffraction pattern substantially as depicted in Figure 1 wherein the peak at about 16.98 degree in term of two theta has a relative intensity of at least about 50%, at least about 60%), at least about 70%>, at least about 80%>, at least about 90%> or at least about 99% with respect to the strongest peak in the X-ray powder diffraction pattern as depicted in Figure 1.

It is surprisingly found by the inventors that the crystalline form I of Apixaban of the present disclosure may possess at least one of the following advantageous properties: high chemical purity, high flowability, high solubility, high morphology or high crystal habit, stability - such as storage stability, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

In one embodiment of present disclosure, the substantially pure crystalline form I of Apixaban may be slightly hygroscopic.

In one embodiment of present disclosure, wherein the particle shape of the crystalline form I is lath which is showed in Figure 9.

In some embodiments of present disclosure, more than 70% of the crystalline form I has a length/width ratio from 2.0: 1.0 to 8.0: 1.0. In certain embodiment of present disclosure, more than 80% of the crystalline form I has a length/width ratio from 2.0: 1.0 to 9.0: 1.0. In some embodiment of present disclosure, more than 90% of the crystalline form I has a length/width ratio from 1.1 : 1.0 to 10.0: 1.0. The length/width ratio of the crystalline form I is depicted in Figure 10, Figure 11 or Figure 12.

In one embodiment of present disclosure, the substantially pure crystalline form I of Apixaban for use in preventing or treating a thromboembolic disorder is provided.

According to embodiments of a second broad aspect of the present disclosure, there is provided a pharmaceutical composition comprising the substantially pure crystalline form I of Apixaban described above. It was found by the inventor that this composition may be used for preventing or treating a thromboembolic disorder.

In one embodiment of present disclosure, the substantially pure crystalline form I of Apixaban is in form of particle with a D90 (90% of the volume) of about 40 μιη to 70 μιη.

According to embodiments of a third broad aspect of the present disclosure, there is provided a method of preventing or treating a thromboembolic disorder comprising:

administrating to a patient in need thereof a therapeutically effective amount of the substantially pure crystalline form I of Apixaban.

According to embodiments of a forth broad aspect of the present disclosure, there is provided use of the substantially pure crystalline form I of Apixaban described above or the pharmaceutical composition described above for the manufacture of a medicament preventing or treating a thromboembolic disorder.

According to embodiments of a fifth broad aspect of the present disclosure, there is provided a process for preparing the substantially pure crystalline form I of Apixaban described above comprising:

1) mixing Apixaban or a salt thereof with at least one selected from a group consisting of amide solvent and carboxylic acid solvent to form a mixture;

2) heating the mixture to a temperature of about 50 to 90 degrees Celcius to form a solution;

3) forming crystal in the solution; and

4) isolating the crystal to obtain the substantially pure crystalline form I of Apixaban.

It was found by the inventor that the process may allow substantially pure crystalline form I of Apixaban be easily purified and obtained in a high purity, and the process complies with the factory GMP production requirements, and then the process may be suitable for industrial process and may be environment friendly. In one embodiment of present disclosure, the step of forming crystal in the solution is performed by adding anti-solvent and optional decreasing temperature.

In one embodiment of present disclosure, when the carboxylic acid solvent is acetic acid, and the anti-solvent is at least one selected from a group consisting of ethanol, isopropanol, acetone, ethyl acetate, and isopropyl acetate.

In one embodiment of present disclosure, when the amide solvent is DMF, and the anti-solvent is at least one selected from a group consisting of ethanol, isopropanol, acetone, ethyl acetate, and isopropyl acetate.

According to embodiments of a sixth broad aspect of the present disclosure, there is provided a substantially pure amorphous form of Apixaban. In one embodiment, the substantially pure amorphous form of Apixaban may show a powder diffraction pattern substantially as depicted in Figure 5. In one embodiment, a substantially pure amorphous form of Apixaban for use in preventing or treating a thromboembolic disorder is provided.

It was found by the inventor surprisingly that the inventive amorphous form of Apixaban may exhibit at least one following advantages: an improved solubility and thermal stability, higher bioavailability, better dissolution profile and better stability, which allows the amorphous form of Apixaban easy for storage and meet the requirement of pharmaceutical industry.

According to embodiments of a seventh broad aspect of the present disclosure, there is provided a process for preparing the substantially pure amorphous form of Apixaban described above, comprising:

dissolving Apixaban in alcohol solvent to form a solution; and

spray drying the solution to form the substantially pure amorphous form of Apixaban.

In one embodiment of present disclosure, the alcohol solvent may be methanol.

It was found by the inventor that the process may allow substantially amorphous form of Apixaban be easily purified and obtained in a high purity, and the process complies with the factory GMP production requirements, and then the process may be suitable for industrial process and may be environment friendly.

According to embodiments of a eighth broad aspect of the present disclosure, there is provided a pharmaceutical composition comprising the substantially pure amorphous form of Apixaban described above. It was found by the inventor that this composition may be used for preventing or treating a thromboembolic disorder.

According to embodiments of a ninth broad aspect of the present disclosure, there is provided a method of preventing or treating a thromboembolic disorder comprising:

administrating to a patient in need thereof a therapeutically effective amount of the substantially pure amorphous form of Apixaban described above.

According to embodiments of a tenth broad aspect of the present disclosure, there is provided use of the substantially pure amorphous form of Apixaban of described above or the pharmaceutical composition comprising the substantially pure amorphous form of Apixaban for the manufacture of a medicament preventing or treating a thromboembolic disorder.

The above summary of the present disclosure is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The Figures and the detailed description which follow more particularly exemplify illustrative embodiments.

Additional aspects and advantages of embodiments of present disclosure will be given in part in the following descriptions, become apparent in part from the following descriptions, or be learned from the practice of the embodiments of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects and advantages of embodiments of the present disclosure will become apparent and more readily appreciated from the following descriptions made with reference to the accompanying drawings, in which:

Figure 1 depicts the X-ray powder diffractogram of the crystalline form I of Apixaban in one embodiment of present disclosure.

Figure 2 depicts the DSC profile of the crystalline form I of Apixaban in one embodiment of present disclosure.

Figure 3 depicts the TGA profile of the crystalline form I of Apixaban in one embodiment of present disclosure.

Figure 4 depicts the infrared (IR) spectrum of the crystalline form I of Apixaban in one embodiment of present disclosure.

Figure 5 depicts the X-ray powder diffractogram of the amorphous form of Apixaban in one embodiment of present disclosure.

Figure 6 depicts the DSC profile of the amorphous form of Apixaban in one embodiment of present disclosure.

Figure 7 depicts the TGA profile of the amorphous form of Apixaban in one embodiment of present disclosure. Figure 8 depicts the infrared (IR) spectrum of the amorphous form of Apixaban in one embodiment of present disclosure.

Figure 9 shows the particle shape of the crystalline form I of Apixaban in one embodiment of present disclosure.

Figure 10 shows the length/width ratio of the crystalline form I of Apixaban in one embodiment of present disclosure.

Figure 11 shows the length/width ratio of the crystalline form I of Apixaban in another embodiment of present disclosure.

Figure 12 shows the length/width ratio of the crystalline form I of Apixaban in a further embodiment of present disclosure.

DETAILED DESCRIPTION

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified methods and may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting which will be limited only by the appended claims.

All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. However, publications mentioned herein are cited for the purpose of describing and disclosing the protocols, and reagents which are reported in the publications and which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

Definition

Otherwise stated, the following definitions may be use throughout the disclosure.

As used herein, the term "crystalline form" of a compound refers to a unique ordered arrangement and/or conformations of molecules in the crystal lattice of the compound.

As used herein, a crystalline form that is "substantially pure" refers to a crystalline form that is substantially free of one or more other crystalline forms, i.e., the crystalline form has a purity of at least about 60%, at least about 70%>, at least about 80%>, at least about 85%, at least about 90%>, at least about 93%>, at least about 95%, at least about 98%>, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%; or the crystalline form has less than 20%, less than 10%>, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the one or more other crystalline forms, based on the total volume or weight of the crystalline form and the one or more other crystalline form.

As used herein, a crystalline form that is "substantially free" of one or more other crystalline forms refers to a crystalline form containing less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the one or more other crystalline form, based on the total volume or weight of the crystalline form and the one or more other crystalline form.

As used herein, an X-ray powder diffraction pattern that is "substantially as depicted" in a figure refers to an X-ray powder diffraction pattern having at least 50%, at least 60%, at least 70%, at least 80%>, at least 90%>, at least 95%, or at least 99% of the peaks shown in the figure.

As used herein, the term "relative intensity" refers to the intensity of a peak with respect to the intensity of the strongest peak in the X-ray powder diffraction (XRPD) pattern which is regarded as 100%.

As used herein, the term "good-solvent" refers to a solvent that the solubility of Apixaban in the good-solvent is greater than 1 g/L, greater than 2 g/L , greater than 3 g/L, greater than 4 g/L, greater than 5 g/L, greater than 6 g/L, greater than 7 g/L, greater than 8 g/L, greater than 9 g/L, greater than 10 g/L, greater than 15 g/L, greater than 20 g/L, greater than 30 g/L, greater than 40 g/L, greater than 50 g/L, greater than 60 g/L, greater than 70 g/L, greater than 80 g/L, or greater than 100 g/L.

As used herein, the term "anti-solvent" refers to a solvent which can promote supersaturation and/or crystallization. In some embodiments, the solubility of Apixaban in the anti-solvent is less than 0.001 g/L, less than 0.01 g/L, less than 0.1 g/L, less than 0.2 g/L, less than 0.3 g/L, less than 0.4 g/L, less than 0.5 g/L, less than 0.6 g/L, less than 0.8 g/L, less than 1 g/L, less than 2 g/L, less than 3 g/L, less than 4 g/L, less than 5 g/L, less than 6 g/L, less than 7 g/L, less than 8 g/L, less than 9 g/L, or less than 10 g/L of the anti-solvent. In some embodiments, the solubility of Apixaban in the good-solvent is greater than that in anti-solvents. In certain embodiments, the solubility difference between the good solvent and anti-solvent is about 10%, 20%, 30%, 40%, 50%), 60%), 70%), 80%) or 90%, based on the solubility of the good solvent. In some embodiments, the solubility of the good solvent is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% higher than anti-solvent.

As used herein, the term "room temperature" refers to a temperature from about 18 °C to about 35 °C or a temperature from about 20 °C to about 24 °C or a temperature at about 22 °C.

As used herein, the term "over night" refers to a period of from about 13 hours to about 24 hours, or from about 16 hours to about 24 hours.

As used herein, when referring to a spectrum and/or to data presented in a graph, the term "peak" refers to a feature that one skilled in the art would recognize as not attributable to background noise.

In the following description, all numbers disclosed herein are approximate values, regardless whether the word "about" is used in connection therewith. The value of each number may differ by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%>. Therefore, whenever a number having a value N is disclosed, any number having the value N+/-l%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, N+/-15% or 20 N+/-20% is specifically disclosed, wherein "+/-" refers to plus or minus. Whenever a numerical range with a lower limit, RL, and an upper limit, RU, is disclosed, any number falling within the range is specifically disclosed. In particular, the following numbers within the range are specifically disclosed: R=RL+k*(RU-RL), wherein k is a variable ranging from 1% to 100% with a 1% increment, i.e., k is 1%, 2%, 3%, 4%, 5%,..., 50%, 51%, 52%,..., 95%, 96%o, 97%), 98%o, 99%o, or 100%. Moreover, any numerical range defined by two R numbers as defined above is also specifically disclosed.

As described herein, as described herein, the term" spray drying" refers to the process to pulverize the mixture of solution and to remove the solvent form the mixture.

As described herein, the term "Inlet temperature" refers to the temperature of the solution into the spray dryer; "Outlet temperature" refers to the temperature of the gas leaving the spray dryer.

If necessary, the inlet /outlet temperature could be changed according to the differ condition of equipment, gas, or other experimental parameters. As well known, outlet temperature may depend on the condition of rate of aspirator, air humidity, inlet temperature, atomizing air flow rate, feed rate, or the concentration, therefore, the skilled in the art can set the outlet temperature with the change of those condition aforementioned.

According to the present invention, the two theta of X-ray powder diffraction (XRPD) is in degree (°).

It should be noted that, for the X-ray powder diffraction peaks of a particular crystalline form, the two theta values may change slightly from one machine to another, from one sample to another. The difference in value may be about 1 degree, about 0.8 degrees, about 0.5 degrees, about 0.3 degrees, or about 0.1 degrees. Therefore, the above-mentioned values of the two theta cannot be regarded as absolute.

It should be noted that, the DSC thermograms may change slightly from one machine to another and from one sample to another. The difference in value may be about no more than 5 °C, about no more than 4 °C, or about no more than 3 °C, or about no more than 2 °C. Therefore, the melting points analysis by DSC given above cannot be regarded as absolute.

It should be noted that, for the IR peaks of a particular crystalline form, the values may change slightly from one machine to another, from one sample to another. The difference in value may be form about no more than 4 units to 8 units, about 1 unit, or no more than 1 unit, or no more than 0.5 unit. Therefore, the above-mentioned values cannot be regarded as absolute.

As outlined above, the present disclosure provides a novel crystalline form of Apixaban, designated Form I or form I in present disclosure. Crystalline form I of Apixaban disclosed herein is substantially pure.

In some embodiments, the Form I has an X-ray powder diffraction pattern (XRPD) comprising a peak at about 16.98±0.2 degrees 2Θ.

In some embodiments, form I has an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44, 26.98, 13.92 and 22.11±0.2 degrees 2Θ.

In certain embodiments, form I has an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44, 26.98, 13.92, 22.11, 21.12, 12.84, 22.26 and 21.56±0.2 degrees 2Θ.

In some embodiments, form I has an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44, 26.98, 13.92, 22.11, 21.12, 12.84, 22.26, 21.56, 24.75, 18.81,

19.57, 29.93, 28.69 and 16.24 ±0.2 degrees 2Θ.

In certain embodiments, form I has an X-ray powder diffraction pattern substantially as depicted in Figure 1 wherein the peak at about 16.98 degree in term of two theta has a relative intensity of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 99% with respect to the strongest peak in the X-ray powder diffraction pattern.

In certain embodiments, the characteristics of form I can be detected, identified, classified or characterized using well-known techniques such as, but not limited differential scanning calorimetry (DSC), Thermal Gravimetric Analysis (TGA) and infrared spectroscopy(IR).

In some embodiments, form I shows a melting point of at about 238 °C by DSC analysis. In some embodiments, the DSC of form I is substantially as depicted in Figure 2. In some embodiments, the TGA of form I is substantially as depicted in Figure 3.

In some embodiments, the IR of form I comprises one or more peaks at about 3483, 3311, 1682, 1630, 1595, 1545, 1461, 1295, 1222, 1144, 1038, 848, 813, 668 cm^"1.

In some embodiments, the IR spectrum of form I is substantially as depicted in Figure 4. In certain embodiments, the particle shape of the crystalline form I is lath which is substantially as depicted in Figure 9. The crystalline form I has a particle size with a D90 40μιη to 70 μιη.

It was found by the inventor surprisingly that the crystalline form I of Apixaban of the present disclosure may have at least one advantageous property selected from high chemical purity, high flowability, high solubility, high morphology or high crystal habit, stability - such as storage stability, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

The present disclosure also provides a process for preparing the crystalline Form I of

Apixaban. According to embodiments of present disclosure, this process may comprise the following steps:

1) Firstly, mix Apixaban or a salt thereof with at least one selected from a group consisting of amide solvent and carboxylic acid solvent to form a mixture. In one embodiment of present disclosure, the Apixaban may be added to the solvent, namely amide solvent, carboxylic acid or mixture thereof.

2) Then heat the mixture to a temperature of about 50 to 90 degrees Celcius to form a solution.

3) Then Form crystal in the solution, namely in this step the crystallization is promoted; and 4) Finally, isolate the crystal to obtain the substantially pure crystalline form I of Apixaban, namely collect the crystal formed in the previous step to obtain final crystalline form I of Apixaban.

According to embodiments of present disclosure, the start material of this process is not particularly limited. In some embodiments of present disclosure, Apixaban used as starting material in step 1) may be any forms including crystal, amorphous or solvate or a combination thereof. In one embodiment of present disclosure, starting material Apixaban in step 1) may be prepared with the methods that well known to those skilled in the art, for example the starting material Apixaban may be prepared according to the process disclosed in US 20030191115, US 20030181466 or US 20060069085.

In some embodiments of present disclosure, in step 2) the mixture may be further stirred, heated to reflux, ultrasonic and vibrated, to affiliate the formation of solution.

In some embodiments of present disclosure, the step of forming crystal in the solution is performed by adding anti-solvent and optional decreasing temperature. Namely, the crystalline form disclosed herein may be prepared by anti-solvent crystallization (aka precipitation crystallization, salting out or drowning out), during the procedure, the compound may be solubilized into a good solvent to afford a solution, followed by adding of an anti-solvent to decrease the solubility of the compound in the solution and to afford the formation of crystals.

In some embodiments, the anti-solvent crystallization can be carried out by a batch, semi-batch or continuous process or operation. The batch or semi-batch process generally includes adding either the anti-solvent to the product solution (also named as "normal addition") or the product solution to the anti-solvent (also named as "reverse addition"). When an anti-solvent is added to the product solution, supersaturation will be developed. The amount of supersaturation created prior to nucleation generally is system specific and depends on the addition rate, mixing, primary or secondary nucleation rate, growth rate, feed location and the amount and type of impurities or seeds present in solution.

In some embodiments, a crystal seed may be added to promote a particular form of crystalline Apixaban such as form I. Crystal seed refers to a small single crystal from which a larger crystal of the same or different crystalline form is to be grown. In certain embodiments, the small single crystal and the larger crystal are of the same form. In some embodiments, the small single crystal and the larger crystal may be of the different forms.

To achieve crystal growth while minimizing the possibility for seed dissolution, the anti-solvent addition is stopped and seed is added at a point where the system is slightly supersaturated. An in-situ measuring devices based on a spectroscopy technique such as Fourier transform infrared or ultraviolet can be used to determine when the concentration reaches such a supersaturated point.

In some embodiments, the resulting solution of step 2) may be added to the anti-solvent, then a nucleation-controlled environment and formation of very fine particles is achieved.

In some embodiments, seeding may be used to avoid excessive nucleation, the seeding may be added to the anti-solvent or resulting solution of step 2) in form of in slurry with the anti-solvent or powder. In some embodiments, the seed may be conditioned via Oswald ripening. In certain embodiments, the seed is added in form of powder or slurry at a point within the metastable zone of the system.

According to embodiments of present disclosure, when anti-solvent is used, whether adding the resulting solution of step 2) to the anti-solvent or adding anti-solvent to the resulting solution of step 2), the solution or anti-solvent may be added to another one at an constant rate or variable rate, for example at an initial slow addition rate followed by a gradually increased rate.

In some embodiments, the anti-solvent crystalline is carried out by a continuous operation, which may promote small mean crystal size and narrow size distribution. In some embodiments, an in-line mixing device or a stirred vessel may be used in the continuous processing. Certain non-limiting examples of in-line mixing equipment include impinging jet mixers, vortex mixers, Y mixers, homogenizers and rotor-stator configurations. The anti-solvent and product solution (which may contain seeds) may be mixed with the in-line mixing equipment.

In certain embodiments, an impinging jet system is used wherein the system comprises an impinging jet mixer and a ripening tank for receiving and ripening the product following the contact of the product and anti-solvent streams in the impinging jet mixer. The ripening tank may comprise a stirrer. The ripening tank is designed to facilitate diffusion of the trapped mother liquor in the nucleated solids and may be batch or continuous. In some embodiments, seeds are added to the anti-solvent stream or the ripening vessel.

In some embodiments, the process further comprises the addition of one or more anti-solvents to the solution before or in cooling step to promote crystallization, wherein the solubility of Apixaban in the anti-solvent is lower than the good solvent. The solubility difference between the good solvent and anti-solvent is about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%. The anti-solvent may be polar or non-polar solvent.

In some embodiments, the amide solvent is N, N-dimethylformamide (DMF), N, N-diethyl formamide, formamide or a combination thereof. In some embodiments, the carboxylic acid solvent is selected from acetic acid, formic acid, propionic acid, butyric acid, malonic acid or a combination thereof.

The anti-solvent may be one or more polar solvents, one or more non-polar solvents or a combination thereof. In some embodiments of present disclosure, the anti-solvent may be selected from water, alcohol solvents, ether solvents, ketone solvents, ester solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, nitrile solvents, or combination thereof. In some embodiments, the alcohol solvent may be selected from methanol, ethanol, 1,3 -propanediol, 1 ,2-propylene glycol, chlorobutanol or a combination thereof. In some embodiments, the ether solvent may be selected from tetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane or a combination thereof. In some embodiments, the ketone solvent may be selected from acetone, cyclohexanone, methyl isobutyl ketone, methyl ethyl ketone, or 4-methyl-2-pentanone or a combination thereof. In some embodiments, ester solvent may be selected from ethyl acetate, isopropyl acetate, n-butyl acetate or tert-butyl acetate or a combination thereof. In some embodiments, halogenated hydrocarbon solvent may be selected from chlorobenzene, dichlorobenzene, methylene chloride or chloroform, or combination thereof. In some embodiments, the aromatic hydrocarbon may be selected from benzene, toluene, xylene or ethylbenzene or a combination thereof. In some embodiments, the nitriles solvent may be selected from acetonitrile, malononitrile or a combination thereof.

In some embodiments, the anti-solvent is at least one selected form water, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, methylene chloride, acetonitrile, 1,4-dioxane, ethyl acetate, isopropyl 4-methyl-2-amyl ketone or methyl tert-butyl ether. In some embodiments, the carboxylic acid solvent is acetic acid, and the anti-solvents are ethanol, isopropanol, acetone, ethyl acetate, isopropyl acetate or a combination thereof; in some embodiments, the amide solvent is DMF, and the anti-solvent are ethanol, isopropanol, acetone, ethyl acetate or isopropyl acetate or a combination thereof.

In some embodiments, the temperature for crystallization may be in a range of from about

-10 °C to about 40 °C. In certain embodiments, the temperature may be in a range of from about -10 °C to about 25 °C. In certain embodiments, the temperature may be in a range of from about -10 °C to about 0 °C. In some embodiments, the temperature may be in a range of from about 0 °C to about 10 °C.

The crystals may be isolated and/or purified by vacuum filtration, gravity filtration, suction filtration and a combination thereof. The isolated crystal may carry mother liquor. Therefore, the isolated crystals may be further washed by suitable solvent and then dried. In certain embodiments, washing is done with the same solvent used in the process. In another embodiment, washing is done with an anti-solvent.

In illustrative embodiments of the present invention, novel crystalline form I of Apixaban is substantially pure. It was found by the inventor that the process may allow substantially pure crystalline form I of Apixaban be easily purified and obtained in a high purity, and the process complies with the factory GMP production requirements, and then the process may be suitable for industrial process and may be environment friendly.

The present disclosure still provides the substantially pure amorphous form of Apixaban.

In some embodiments, the X-ray powder diffraction pattern (XRPD) of Apixaban amorphous is substantially as depicted in Figure 5.

In one embodiment, a substantially pure amorphous form of Apixaban for use in preventing or treating a thromboembolic disorder is provided.

In certain embodiments, the characteristics of amorphous can be detected, identified, classified or characterized using well-known techniques such as, but not limited differential scanning calorimetry (DSC), Infrared spectroscopy (IR) and Thermogravimetric analysis (TGA). In some embodiments, the IR may comprise one or more peaks at about 3468, 2943, 1513, 1330, 1298, 1251, 1144, 1021, 836 cm^"1.

In some embodiments, the IR spectrum of amorphous is substantially as depicted in Figure 6.

In some embodiments, the DSC of amorphous is substantially as depicted in Figure 7.

In some embodiments, the weight loss is about 2.7 % at from about 25 °C to about 119 °C by

TGA analysis; in some embodiments, the TGA profile of amorphous is substantially as depicted in Figure 8.

It was found by the inventor surprisingly that the inventive amorphous form of Apixaban may exhibit at least one following advantages: an improved solubility and thermal stability, higher bioavailability, better dissolution profile and better stability, which allows the amorphous form of

Apixaban easy for storage and meet the requirement of pharmaceutical industry.

The present disclosure also provides a process for preparing the amorphous form of Apixaban comprising: dissolving Apixaban in alcohol solvent to form a solution; and spray drying the solution to form the substantially pure amorphous form of Apixaban.

As described above for the process of preparing Form I, the starting material for the substantially pure amorphous form of Apixaban may be prepared with the methods that well known to those skilled in the art or with the process disclosed in US 20030191115, US

20030181466 or US 20060069085.

As described herein, the solvent is not particularly limited as long as the Apixaban could be dissolved. In some embodiments, the solvent is water, DMF, alcohol solvents, ester solvents, or halogenated hydrocarbon or combination thereof; in some embodiments, the solvent is methanol, ethanol, methylene chloride or water or combination thereof. The present disclosure further provides herein, there is provided a pharmaceutical composition comprising the substantially pure crystalline form I or amorphous form of Apixaban described above. It was found by the inventor that this composition may be used for preventing or treating a thromboembolic disorder. In some embodiments of present disclosure, the composition may further comprise a pharmaceutically acceptable carrier, excipients or diluent.

As described herein, the pharmaceutical composition comprises at least one of crystalline form I or amorphous form of Apixaban, and the pharmaceutical compositions may be formulated into any oral dosage form, such as tablet, capsule (each of tablet and capsule may include sustained release or time-controlled release formulations), pill, powder, tincture, suspension, syrup or emulsifier. And also can be used as parenteral includes intravenous (infusion), intraperitoneal, intramuscular or subcutaneous, all of these dosage forms are well known to the ordinary skilled in the art.

In some embodiments, when the dosage form is tablet or capsule, the pharmaceutical compositions may further comprise oral, non-toxic and pharmaceutically acceptable excipients or carriers, wherein the excipients or carriers comprise lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol or sorbitol; for oral solution form, the pharmaceutical compositions may include oral, non-toxic and pharmaceutically acceptable excipients or carriers, wherein the excipients or carriers comprise ethanol, glycerine or water. Moreover, if necessary, the excipient or carriers may further comprises binders, lubricants, disintegrating agents, or colorants or combination thereof. In one embodiment, the binders include starch, gelatin, natural sugars such as glucose or β- lactose, corn sweeteners, natural or synthetic gums such as acacia and sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or combination thereof; wherein the lubricant include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or combination thereof. In one embodiments, disintegrants include agar-agar, calcium carbonate, alginic acid, certain silicates, sodium carbonate, low substituted hydroxypropyl cellulose, starch, methyl cellulose, bentonite, xanthan gum or combination thereof.

Also provided herein is a method of preventing or treating a thromboembolic disorder, and this method may comprises administrating to a patient in need thereof a therapeutically effective amount of the substantially pure crystalline form I of Apixaban above described or substantially pure amorphous form of Apixaban above described.

According to embodiments of a tenth broad aspect of the present disclosure, there is provided use of the substantially pure crystalline form I of Apixaban, the substantially pure amorphous form of Apixaban of described above, or the pharmaceutical composition comprising the substantially pure amorphous form of Apixaban or the substantially pure amorphous form of Apixaban of described above for the manufacture of a medicament preventing or treating a thromboembolic disorder.

Then present disclosure provide the crystalline form I and amorphous form of Apixaban, both of them exhibit increased solubility and thermal stability; and/or thermally stable characteristics that are suitable for industrial production. Also provided herein, use of a pharmaceutical composition comprising a therapeutically effective amount of Apixaban and one or more pharmaceutically acceptable carriers, excipients or diluents to treat thromboembolic disease.

EXAMPLES

The embodiments of the present disclosure firstly disclose crystalline form I and amorphous form of Apixaban. Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way is obvious to the skilled in this art and is deemed to included in the present invention. Numeric ranges are inclusive of the numbers defining the range. Furthermore, numeric ranges are provided so that the range of values is recited in addition to the individual values within the recited range being specifically recited in the absence of the range.

Example 1

Preparation of crystalline form I of Apixaban

Apixaban (0.5g) was added to the DMF (4 mL); the mixture was heated to 80 °C and stirred to form a solution. Isopropanol (8 mL) was added slowly to the solution, after a significant amount of solid was separated out, the solution was then slowly cooled to about 30 °C and stirred for 3 h (i.e. hour), filtered, the solid was dried under vacuum at 80 °C to obtain crystalline form I of Apixaban (0.42 g), yield 84 %, form I has an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44, 26.98, 13.92 and 22.11±0.2 degrees 2Θ, which is shown in Fig. 1.

Example 2

Preparation of crystalline form I of Apixaban

Apixaban (1.0 g) was added to the methanol (150 mL), ultrasound to form a solution, after standing at room temperature for 5 days, the solid was separated out, filtered, the solid was dried under vacuum at 50 °C to obtain a crystalline form I of Apixaban (0.8 g), yield 80 %, the X-ray powder diffractogram of the crystalline form I is showed in figure 1, which is the same as Example 1.

Example 3

Preparation of crystalline form I of Apixaban

Apixaban (29 g) was added to DMF (250 mL); the mixture was heated to 65 °C and stirred to form a solution. Water (750 mL) was added slowly to the solution, after a solid was separated out, the mixture was then slowly cooled to 20 °C and stirred for 2 h, filtered, the solid was dried under vacuum at 80 °C to obtain Apixaban (26 g), yield 89.7 %. The solid was found to be crystalline form I of Apixaban having an XRPD as depicted in Figure 1 , which is the same as Example 1.

Example 4

Preparation of crystalline form I of Apixaban

Apixaban (0.5 g) was added to acetic acid (2 mL); the mixture was heated to 80 °C and stirred to form a solution. Ethanol (14 mL) was added slowly to the solution, after a solid was separated out, the solution was then slowly cooled to 30 °C and stirred for 3 h, filtered, the solid was dried under vacuum at 80 °C to obtain Apixaban (0.31 g), yield 82 %. The solid was found to be crystalline form I of Apixaban having an XRPD as depicted in Figure 1, which is the same as Example 1.

Example 5

Preparation of crystalline form I of Apixaban

Apixaban (0.5 g) was added to acetic acid (2 mL), the mixture was heated to 80 °C and stirred to form a solution. Isopropanol (10 mL) was added slowly to the solution, after lots of solid was separated out, the solution was then slowly cooled to 30 °C and stirred for 3 h, filtered, the solid was dried under vacuum at 80 °C to obtain Apixaban (0.35 g), yield 70 %. The solid was found to be crystalline form I of Apixaban having an XRPD as depicted in Figure, which is the same as Example 1.

Example 6

Preparation of crystalline form I of Apixaban

Apixaban (0.5 g) was added to acetic acid (2 mL), the mixture was heated to 80 °C and stirred to form a solution. Ethyl acetate (10 mL) was added slowly to the solution, after lots of solid was separated out, the solution was then slowly cooled to 30 °C and stirred for 3 h, filtered, the solid was dried under vacuum at 80 °C to obtain Apixaban (0.35 g), yield 90 %, HPLC purity 99.5 %. The solid was found to be crystalline form I of Apixaban having an XRPD as depicted in Figure 1 , which is the same as Example 1.

Example 7

Preparation of crystalline form I of Apixaban

Apixaban (2.0 g) was added to acetic acid (4 mL), the mixture was heated to 80 °C and stirred to form a solution. Isopropyl acetate (10 mL) was added slowly to the solution, after lots of solid was separated out, the solution was then slowly cooled to 30 °C and stirred for 3 h, filtered, the solid was dried under vacuum at 80 °C to obtain crystalline form I of Apixaban (1.72 g), yield 86 %. The solid was found to be crystalline form I of Apixaban having an XRPD as depicted in Figure 1 , which is the same as Example 1.

Example 8

Preparation of crystalline form I of Apixaban

Apixaban (0.5 g) was added to DMF (4 mL), the mixture was heated to 80 °C and stirred to form a solution. MTBE (8 mL) was added slowly to the solution, lots of solid was separated out, the solution was then slowly cooled to 30 °C and stirred for 3 h, filtered, the solid was dried under vacuum at 80 °C to obtain Apixaban (0.43 g), yield 86 %. The solid was found to be crystalline form I of Apixaban having an XRPD as depicted in Figure 1 , which is the same as Example 1.

Example 9

The stability test of crystalline form I of Apixaban

Thermal Stability

A layer of crystalline form I having a thickness of less than 5 mm was placed in a flat weighing bottle. The layer was placed at 60 °C for 30 days. Samples were taken out at day 15, day 30 and examined for purity by HPLC, appearance and crystalline form.

Humidity Stability

A layer of crystalline form I having a thickness of less than 5 mm was place in a flat weighing bottle. The layer was placed at 25 °C and relative humidity (RH) of 90% +1-5% for 15 days. Samples were taken out at 15 days and 30 days and examined for purity by HPLC, appearance and crystalline form.

Light Stability

A layer of crystalline form I having a thickness of less than 5 mm was place in a flat weighing bottle. The layer was illuminated by light having an illuminance of 4500+/-500 Lux for 30 days. Samples were taken out at 15 days and 30 days and examined for purity by HPLC, appearance and crystalline form.

The conditions for the HPLC measurements are as shown below.

Instrument: Agilent 1200HPLC

Column: Agilent ZORBAX RX-C8 250*4.6 mm, 5 μιη

Detection wavelength: 280 nm

Mobile phase: A phase 10 mM Potassium dihydrogen phosphate( pH=3.8): acetonitrile (v/v)=90: 10 and B phase acetonitrile

Stop time: 25 minutes

Column temperature: 30 °C

Table 1 : Elution conditions:

Table 2: The results of the thermal, humidity and light stabilities of crystalline form I of Apixaban prepared in above Example:

Appearance DSC XRD Impurity ( RT, min )

Apixaban

13.68 23.31 30.47

Light yellow

O day N/A N/A 99.50% 0.06 0.23 0.13

powder

15 Light yellow the same with the same with

99.49% 0.06 0.23 0.13

Thermal days powder O day O day

Stability 30 Light yellow the same with the same with

99.49% 0.06 0.23 0.13 days powder O day O day

Light 15 Light yellow the same with the same with

99.50% 0.06 0.23 0.13 Stability days powder O day O day 30 Light yellow the same with the same with

99.49% 0.06 0.23 0.13 days powder O day O day

15 Light yellow the same with the same with

99.51% 0.06 0.23 0.13

Humidity days powder O day O day

Stability 30 Light yellow the same with the same with

99.59% 0.06 0.23 0.13 days powder O day O day

As showed in table 2, the HPLC purity, appearance and crystalline form of crystalline form I is consistent with 0 day after placed at 60 °C, placed at 25 °C and relative humidity (RH) of 90% +1-5% or was illuminated by light having an illuminance of 4500+/-500 Lux for 30 days.

Example 10

Test for Hygroscopicity

Use a glass weighing vessel 50 mm in external diameter and 15 mm high. Weigh the vessel and stopper (m¹). Place the amount of substance prescribed for the test for loss on drying or water in the vessel and weigh (m²). Place the unstoppered vessel in a desiccator at 25 °C containing a saturated solution of ammonium chloride or ammonium sulfate or place it in a climatic cabinet set at 25 ± 1 °C and 80 ± 2 per cent relative humidity. Allow to stand for 24 h. Stopper the weighing vessel and weigh (m³). Calculate the percentage increase in mass using the expression:

rrr - rrr

x 100

m²- m¹

The result is interpreted as follows:

— deliquescent: sufficient water is absorbed to form a liquid,

— very hygroscopic: increase in mass is equal to or greater than 15 per cent,

— hygroscopic: increase in mass is less than 15 per cent and equal to or greater than 2 per cent,

— slightly hygroscopic: increase in mass is less than 2 per cent and equal to or greater than 0.2 per cent. Table 3 : The Hygroscopicity test result of crystalline form I of Apixaban prepared in above Examples:

Example 11

The solubility test of crystalline form I

The solubility of crystalline form I of Apixaban was measured in accordance with the solubility test described in the (Chinese Pharmacopoeia 2010} .The form I of Apixaban was grinded into powder. The powder (about 50 mg) was added to a solvent at 25 ± 2 ° C. The solid was dissolved by shaking for 30 seconds every 5 minutes and then the solubility of the solid was observed with eyes. The total test time was 30 minutes. The solid was deemed as dissolved when no solid was detected in the mixture by human eyes.

Table 4: the solubility test result of crystalline form I of Apixaban prepared in above Examples

Example 12

Particle shape and size characterization

Particle shape characterization

Instrument: polarization microscope: DM100-SC30

The particle shape of crystalline form I of Apixaban was depicted in accordance with the test described in USP<776>; Ph.Eur. (2.9.37).

The parameter of DM100-SC30: ocular lens ^objective lens:=20 * 10 Test result: the particle shape is lath: long, thin, blade-like particle. And more than 70 % of the crystalline form I has a length/width ratio from 2.0: 1.0 to 8.0: 1.0. And more than 80 % of the crystalline form I has a length/width ratio from 2.0: 1.0 to 9.0: 1.0. And more than 90 % of the crystalline form I has a length/width ratio from 1.1 : 1.0 to 10.0: 1.0. The length/width ratio of the crystalline form I is depicted in Figure 10 , Figure 11 or Figure 12.

Particle size characterization

The particle size of crystalline form I of Apixaban was measured in accordance with the test described in USP<429>; Ph.Eur.(2.9.31); Chinese Pharmacopoeia 2010

Instrument: Laser Particle Size Analyzer: MS2000

Table 5 : Particle Size Distribution

Example 13

Preparation of amorphous form of Apixaban

Apixaban (10 g) was added to methanol (1800 mL) to form a mixture, the mixture was heated to 50 °C and stirred to form a solution, sampling the solution for spray drying using BUCHI Mini Spray Dryer ( B-290 ) . The inlet temperature is at about 100 °C, the outlet temperature is at about 60 °C, the pumping speed is 100%, and pump speed capability is 30%. The particles were collected and the X-ray data was collected on a PANalytical Empyrean Diffractometer, and X-ray powder diffraction pattern substantially as depicted in Figure 5.

Example 14

Characterization of the amorphous form of Apixaban prepared in Example 13

Instrument and condition:

X-ray powder diffraction

The X-ray data were collected on a PANalytical Empyrean diffractometer, the X-ray data was collected over a 2 theta range of 3° to 40°, the step size is 0.0168°, scan rate lOs/step, using CuK.alpha radiation( =1.54A). The sample was rotated continuously in order to reduce the impact of preferred orientation. Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) experiments were performed in a TA Instruments™ model Q2000. The weight of the sample was measured in an aluminum pan accurately and recorded, and transferred to the DSC. The instrument was purged with nitrogen gas. Data were collected between 40 and 300 °C at 10 °C/min heating rate. The plot was made with the endothermic peaks.

Thermal gravimetric analysis (TGA)

Thermal gravimetric analysis (TGA) experiments were performed in a TA Instruments™ model Q500. The sample was placed in a platinum pan previously tared. The weight of the sample was measured accurately and recorded; the furnace was purged with nitrogen gas. Data were collected between room temperature and 350 °C at 10 °C/min heating rate.

Infrared spectroscopy (IR)

The IR spectrum experiments were performed in a Brooke TENSOR27 Fourier transform infrared spectrometer. The sample (about 1 mg) and dried potassium bromide was mixed, the mixture was grinded in agate mortar and compacted into a tablet. Data were collected between scan ranges from 4000 cm^"1 to 400 cm^"1.

Result

The IR spectrum of amorphous is depicted in Figure 6 comprising peaks at about 3468, 2943, 1513, 1330, 1298, 1251, 1144, 1021, 836 cm^"1.

DSC of amorphous is depicted in Figure 7.

TGA profile of amorphous is depicted in Figure 8, and shows a weight loss of about 2.7 % at from about 25 °C to about 119 °C by TGA analysis.

Thus it was found by the inventor surprisingly that the inventive amorphous form of Apixaban may exhibit at least one following advantages: an improved solubility and thermal stability, higher bioavailability, better dissolution profile and better stability, which allows the amorphous form of Apixaban easy for storage and meet the requirement of pharmaceutical industry.

Those illustrative embodiments herein are used to help understand the method and core ideas about this present invention. In should be noted that many adaptation and modifications may be made without departing from the scope of the appended claims in accordance with the common general knowledge of those of ordinary skilled in the art. Reference throughout this specification to "an embodiment," "some embodiments," "one embodiment", "another example," "an example," "a specific example," or "some examples," means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as "in some embodiments," "in one embodiment", "in an embodiment", "in another example," "in an example," "in a specific example," or "in some examples," in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples.

Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. A substantially pure crystalline form I of Apixaban, characterized by

26.98, 13.92 and 22.11 degrees in term of two theta; or

an X-ray powder diffraction pattern comprising one or more peaks at about 16.98, 18.44, 26.98, 13.92, 22.11, 21.12, 12.84, 22.26, 21.56, 24.75, 18.81, 19.57, 29.93, 28.69 and 16.24 degrees in term of two theta; or

an X-ray powder diffraction pattern substantially as depicted in Figure 1 wherein the peak at about 16.98 degree in term of two theta has a relative intensity of at least about 50%, at least about 60%o, at least about 70%>, at least about 80%>, at least about 90%> or at least about 99% with respect to the strongest peak in the X-ray powder diffraction pattern as depicted in Figure 1.

2. The substantially pure crystalline form I of Apixaban of claim 1, being slightly hygroscopic.

3. The substantially pure crystalline form I of Apixaban of claim 1, wherein the particle shape of the crystalline form I is lath, which is showed in Figure 9.

4. The substantially pure crystalline form I of Apixaban of claim 1, wherein more than 70% of the crystalline form I has a length/width ratio from 2.0: 1.0 to 8.0: 1.0 or

more than 80% of the crystalline form I has a length/width ratio from 2.0: 1.0 to 9.0: 1.0 or more than 90% of the crystalline form I has a length/width ratio from 1.1 : 1.0 to 10.0: 1.0 or the length/width ratio of the crystalline form I is depicted in Figure 10 , Figure 11 or Figure 12.

5. The substantially pure crystalline form I of Apixaban of claim 1 for use in preventing or treating a thromboembolic disorder.

6. A pharmaceutical composition comprising the substantially pure crystalline form I of Apixaban of any one of claims 1 to 5.

7. The pharmaceutical composition of claim 6, wherein the substantially pure crystalline form I of Apixaban is in form of particle with a D90 of 40 μιη to 70 μιη.

8. A method of preventing or treating a thromboembolic disorder comprising:

administrating to a patient in need thereof a therapeutically effective amount of the substantially pure crystalline form I of Apixaban according to any one of claims 1 to 5.

9. Use of the substantially pure crystalline form I of Apixaban of claim 1 or the pharmaceutical composition of claim 6 or 7 for the manufacture of a medicament preventing or treating a thromboembolic disorder.

10. A process for preparing the substantially pure crystalline form I of Apixaban of any one of claims 1 to 5 comprising:

3) forming crystal in the solution; and

11. The process of claim 10, wherein the step of forming crystal in the solution is performed by adding anti-solvent and optional decreasing temperature.

12. The process of claim 11, wherein the carboxylic acid solvent is acetic acid, and the anti-solvent is at least one selected from a group consisting of ethanol, isopropanol, acetone, ethyl acetate, and isopropyl acetate.

13. The process of claim 11, wherein the amide solvent is DMF, and the anti-solvent is at least one selected from a group consisting of ethanol, isopropanol, acetone, ethyl acetate, and isopropyl acetate.

14. A substantially pure amorphous form of Apixaban.

15. The substantially pure amorphous form of Apixaban of claim 14, wherein the X-ray powder diffraction pattern thereof is substantially as depicted in Figure 5.

16. A process for preparing the substantially pure amorphous form of Apixaban according to claim 14 or 15, comprising:

dissolving Apixaban in alcohol solvent to form a solution; and

17. A process of claim 16, wherein the alcohol solvent is methanol.

18. The substantially pure amorphous form of Apixaban of claim 14 or 15 for use in preventing or treating a thromboembolic disorder.

19. A pharmaceutical composition comprising the substantially pure amorphous form of Apixaban of claim 14 or 15.

20. A method of preventing or treating a thromboembolic disorder comprising: administrating to a patient in need thereof a therapeutically effective amount of the substantially pure amorphous form of Apixaban of claim 14 or 15.

21. Use of the substantially pure amorphous form of Apixaban of claim 14 or 15 or the pharmaceutical composition of claim 19 for the manufacture of a medicament preventing or treating a thromboembolic disorder.