Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• 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.
• 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.
• 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.
• 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.
• a substantially pure crystalline form I of Apixaban which may show the following feature:
• 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
• 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.
• the substantially pure crystalline form I of Apixaban may be slightly hygroscopic.
• 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.
• the substantially pure crystalline form I of Apixaban for use in preventing or treating a thromboembolic disorder 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.
• the substantially pure crystalline form I of Apixaban is in form of particle with a D90 (90% of the volume) of about 40 ⁇ to 70 ⁇ .
• a method of preventing or treating a thromboembolic disorder comprising:
• 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 step of forming crystal in the solution is performed by adding anti-solvent and optional decreasing temperature.
• the carboxylic acid solvent is acetic acid
• the anti-solvent is at least one selected from a group consisting of ethanol, isopropanol, acetone, ethyl acetate, and isopropyl acetate.
• the anti-solvent is at least one selected from a group consisting of ethanol, isopropanol, acetone, ethyl acetate, and isopropyl acetate.
• a substantially pure amorphous form of Apixaban may show a powder diffraction pattern substantially as depicted in Figure 5.
• a substantially pure amorphous form of Apixaban for use in preventing or treating a thromboembolic disorder is provided.
• 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.
• a process for preparing the substantially pure amorphous form of Apixaban described above comprising:
• the alcohol solvent may be methanol.
• 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.
• 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.
• a method of preventing or treating a thromboembolic disorder comprising:
• 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.
• crystalline form of a compound refers to a unique ordered arrangement and/or conformations of molecules in the crystal lattice of the compound.
• 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.
• 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.
• 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.
• 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%.
• 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.
• the term "anti-solvent” refers to a solvent which can promote supersaturation and/or crystallization.
• 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.
• the solubility of Apixaban in the good-solvent is greater than that in anti-solvents.
• 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.
• the solubility of the good solvent is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% higher than anti-solvent.
• 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.
• over night refers to a period of from about 13 hours to about 24 hours, or from about 16 hours to about 24 hours.
• peak refers to a feature that one skilled in the art would recognize as not attributable to background noise.
• 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%.
• 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%.
• any numerical range defined by two R numbers as defined above is also specifically disclosed.
• spray drying refers to the process to pulverize the mixture of solution and to remove the solvent form the mixture.
• 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
• 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.
• the two theta of X-ray powder diffraction is in degree (°).
• 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.
• 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.
• 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.
• 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.
• the Form I has an X-ray powder diffraction pattern (XRPD) comprising a peak at about 16.98 ⁇ 0.2 degrees 2 ⁇ .
• XRPD X-ray powder diffraction pattern
• 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 2 ⁇ .
• 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 2 ⁇ .
• 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,
• 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.
• 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).
• DSC differential scanning calorimetry
• TGA Thermal Gravimetric Analysis
• IR infrared spectroscopy
• form I shows a melting point of at about 238 °C by DSC analysis.
• the DSC of form I is substantially as depicted in Figure 2.
• the TGA of form I is substantially as depicted in Figure 3.
• 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 .
• the IR spectrum of form I is substantially as depicted in Figure 4.
• 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 40 ⁇ to 70 ⁇ .
• the substantially pure crystalline form I of Apixaban for use in preventing or treating a thromboembolic disorder is provided.
• 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
• this process may comprise the following steps:
• the Apixaban may be added to the solvent, namely amide solvent, carboxylic acid or mixture thereof.
• the start material of this process is not particularly limited.
• Apixaban used as starting material in step 1) may be any forms including crystal, amorphous or solvate or a combination thereof.
• 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.
• step 2) the mixture may be further stirred, heated to reflux, ultrasonic and vibrated, to affiliate the formation of solution.
• the step of forming crystal in the solution is performed by adding anti-solvent and optional decreasing temperature.
• 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.
• 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”).
• the 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.
• 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.
• the small single crystal and the larger crystal are of the same form.
• the small single crystal and the larger crystal may be of the different forms.
• 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.
• 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.
• 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.
• the seed may be conditioned via Oswald ripening.
• the seed is added in form of powder or slurry at a point within the metastable zone of the system.
• the solution or anti-solvent 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.
• the anti-solvent crystalline is carried out by a continuous operation, which may promote small mean crystal size and narrow size distribution.
• 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.
• an impinging jet system comprising 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.
• seeds are added to the anti-solvent stream or the ripening vessel.
• 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.
• the amide solvent is N, N-dimethylformamide (DMF), N, N-diethyl formamide, formamide or a combination thereof.
• 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.
• 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.
• the alcohol solvent may be selected from methanol, ethanol, 1,3 -propanediol, 1 ,2-propylene glycol, chlorobutanol or a combination thereof.
• the ether solvent may be selected from tetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane or a combination thereof.
• the ketone solvent may be selected from acetone, cyclohexanone, methyl isobutyl ketone, methyl ethyl ketone, or 4-methyl-2-pentanone or a combination thereof.
• ester solvent may be selected from ethyl acetate, isopropyl acetate, n-butyl acetate or tert-butyl acetate or a combination thereof.
• halogenated hydrocarbon solvent may be selected from chlorobenzene, dichlorobenzene, methylene chloride or chloroform, or combination thereof.
• aromatic hydrocarbon may be selected from benzene, toluene, xylene or ethylbenzene or a combination thereof.
• the nitriles solvent may be selected from acetonitrile, malononitrile or a combination thereof.
• 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.
• the carboxylic acid solvent is acetic acid
• the anti-solvents are ethanol, isopropanol, acetone, ethyl acetate, isopropyl acetate or a combination thereof
• the amide solvent is DMF
• the anti-solvent are ethanol, isopropanol, acetone, ethyl acetate or isopropyl acetate or a combination thereof.
• the temperature for crystallization may be in a range of from about
• 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.
• 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.
• the X-ray powder diffraction pattern (XRPD) of Apixaban amorphous is substantially as depicted in Figure 5.
• a substantially pure amorphous form of Apixaban for use in preventing or treating a thromboembolic disorder is provided.
• 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).
• DSC differential scanning calorimetry
• IR Infrared spectroscopy
• TGA Thermogravimetric analysis
• the IR may comprise one or more peaks at about 3468, 2943, 1513, 1330, 1298, 1251, 1144, 1021, 836 cm "1 .
• the IR spectrum of amorphous is substantially as depicted in Figure 6.
• the DSC of amorphous is substantially as depicted in Figure 7.
• the weight loss is about 2.7 % at from about 25 °C to about 119 °C by
• the TGA profile of amorphous is substantially as depicted in Figure 8.
• 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
• 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.
• 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
• the solvent is not particularly limited as long as the Apixaban could be dissolved.
• 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.
• the composition may further comprise a pharmaceutically acceptable carrier, excipients or diluent.
• 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.
• 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.
• the binders include starch, gelatin, natural sugars such as glucose or ⁇ - 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.
• 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.
• 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.
• a pharmaceutical composition comprising a therapeutically effective amount of Apixaban and one or more pharmaceutically acceptable carriers, excipients or diluents to treat thromboembolic disease.
• 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 2 ⁇ , which is shown in Fig. 1.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• RH relative humidity
• 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 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.
• deliquescent sufficient water is absorbed to form a liquid
• 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.
• more than 70 % of the crystalline form I has a length/width ratio from 2.0: 1.0 to 8.0: 1.0.
• more than 80 % of the crystalline form I has a length/width ratio from 2.0: 1.0 to 9.0: 1.0.
• 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.
• 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%
• 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.
• DSC Differential scanning calorimetry
• DSC Differential scanning calorimetry
• TGA Thermal gravimetric analysis
• TGA Thermal gravimetric analysis
• 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 .
• 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 .
• 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.
• 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.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (1)

Family

ID=50476949

Family Applications (1)

Country Status (2)

Cited By (7)

Families Citing this family (3)

Citations (4)

Family Cites Families (3)

• 2013
  • 2013-10-09 CN CN201380052672.0A patent/CN104797580A/zh active Pending
  • 2013-10-09 WO PCT/CN2013/084923 patent/WO2014056434A1/fr not_active Ceased

Patent Citations (4)

Also Published As

Similar Documents

Legal Events