WO2018069936A1 - Polymorphes et dispersion solide de betrixaban et leurs procédés de préparation - Google Patents

Polymorphes et dispersion solide de betrixaban et leurs procédés de préparation Download PDF

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Publication number
WO2018069936A1
WO2018069936A1 PCT/IN2017/050466 IN2017050466W WO2018069936A1 WO 2018069936 A1 WO2018069936 A1 WO 2018069936A1 IN 2017050466 W IN2017050466 W IN 2017050466W WO 2018069936 A1 WO2018069936 A1 WO 2018069936A1
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Prior art keywords
solvent
hours
betrixaban
methyl
mixtures
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PCT/IN2017/050466
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English (en)
Inventor
Ramakoteswara Rao Jetti
Amit Singh
Anjaneyaraju Indukuri
Narasimha Murty PILLI
Vijaya Krishna RAVI
Chaitanya MUGGU
Hemant Malhari MANDE
Bhaskar Kumar TELAGAMSETTY
Vipin Kumar Kaushik
Sureshbabu JAYACHANDRA
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Mylan Laboratories Limited
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Publication of WO2018069936A1 publication Critical patent/WO2018069936A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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

Definitions

  • the present disclosure relates to novel polymorphic forms of betrixaban maleate designated as amorphous, crystalline form-Ml, form-M2, form-M3, and processes for the preparation of the same.
  • the present disclosure also relates to amorphous solid dispersion of betrixaban maleate and processes for the preparation thereof.
  • the present disclosure further relates to novel polymorphic forms of betrixaban designated as crystalline form-Ml, form-M2, form-M3, form- M4, amorphous form, and processes for the preparation of the same. DESCRIPTION OF RELATED ART
  • Betrixaban is chemically known as N-(5-chloropyridin-2-yl)-2-([4-(N,N-dimethyl carbamimidoyl)benzoyl] amino)-5-methoxybenzamide) and has the structure shown in Formula- I.
  • Betrixaban is a factor Xa inhibitor, marketed in the US under the brand name BEVYXXA ® .
  • BEVYXXA contains betrixaban in the form of its maleate salt, betrixaban maleate.
  • Betrixaban maleate has the structure shown in formula- II below.
  • BEVYXXA® is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.
  • VTE venous thromboembolism
  • Betrixaban and pharmaceutically acceptable salts thereof are disclosed in the U.S. Patent No. 6,376,515.
  • U.S. Patent No. 7,598,276 discloses betrixaban maleate crystalline form-I and processes for the preparation thereof.
  • U.S. Patent No. 8,946,269 discloses betrixaban maleate crystalline form-II, form-Ill, and processes for the preparation thereof.
  • Chinese patent application No. CN 104341343 discloses betrixaban crystalline form-A, form-B, form-C, and process for the preparation thereof.
  • polymorphs may provide different advantages in a variety of capacities, for example, in ease of formulation, stability of the polymorphic form, stability of the formulation, and in pharmacokinetic profiles. These advantages may arise from the different properties present in each polymorph.
  • the present invention provides novel polymorphic forms of betrixaban maleate and further relates novel polymorphic form of betrixaban.
  • preparation of pharmaceutical dosage forms is often procedurally complex, particularly when combining the active ingredient with excipients.
  • workability or stability issues may arise when different components of the pharmaceutical dosage form come into intimate contact with one another. It may, thus, be advantageous to supply the manufacturer of pharmaceutical dosage forms with a pre-combined mixture (pre-mix) of excipients and active pharmaceutical ingredient (API) to facilitate and simplify the final processing of dosages forms.
  • pre-mix pre-combined mixture
  • API active pharmaceutical ingredient
  • the present invention provides a solid dispersion of betrixaban maleate and processes for the preparation thereof.
  • the present invention provides amorphous betrixaban maleate.
  • amorphous betrixaban maleate may be characterized by the powder X-ray diffraction pattern in Figure 1.
  • amorphous betrixaban maleate may be prepared by a process that includes the steps of: a) dissolving betrixaban maleate in a first solvent;
  • the first solvent may be, for example, an alcohol solvent, a ketone solvent, or mixtures thereof.
  • suitable alcohol solvent include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-,3-pentanol, 2-methyl-l- propanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l-propanol, and mixtures thereof.
  • ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • the second solvent may be a non-polar solvent, for example, an ether solvent, a hydrocarbon solvent, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • the present invention provides a solid dispersion containing amorphous betrixaban maleate and one or more pharmaceutically acceptable excipients.
  • the solid dispersion contains amorphous betrixaban maleate and a co-polymer of N-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 40:60 w/w.
  • the solid dispersion contains amorphous betrixaban maleate and polyvinylpyrrolidone with a K value of about 30.
  • the present invention provides a process for preparing a solid dispersion of amorphous betrixaban maleate.
  • a solid dispersion of amorphous betrixaban maleate may be prepared by a process that includes the steps of: a) dissolving betrixaban maleate and a pharmaceutical excipient in a first solvent;
  • the first solvent may be, for example, an alcohol solvent, a ketone solvent, water, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • Suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • the second solvent may be, for example, an ether solvent, a hydrocarbon solvents, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, methyl cyclohexane, and mixtures thereof.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, polysaccharides, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C 6 polyalkylene glycols, copolymers of polyethylene glycol and polypropylene glycol, and mixtures thereof.
  • Suitable polysaccharides include, but are not limited to, hydroxypropyl methylcellulose, croscarmellose, carboxymethyl cellulose, a sodium salt of carboxymethyl cellulose, a calcium salt of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, optionally substituted a-cyclodextrins, optionally substituted ⁇ -cyclodextrins, optionally substituted ⁇ - cyclodextrins, and mixtures thereof.
  • amorphous betrixaban maleate prepared by methods disclosed herein, may be incorporated into an oral pharmaceutical dosage form.
  • the oral dosage form may further contain one or more pharmaceutically acceptable excipients.
  • the present invention provides crystalline betrixaban maleate form-Mi which may be characterized by a powder X-ray diffraction pattern having significant peaks at 3.5, 11.5, 12.0, 19.8, 25.2, and 26.7 ⁇ 0.2 ° ⁇ .
  • the present invention provides a process for preparing crystalline betrixaban maleate form-Mi.
  • crystalline betrixaban maleate form-Mi may be prepared by a process that includes the following steps: a) suspending betrixaban and maleic acid in a first solvent to create a suspension;
  • the first solvent may be, for example, an alcohol solvent, acetic acid, formic acid, water, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • the second solvent may be a non polar solvent, for example, an ether solvent.
  • suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • crystalline betrixaban maleate form-M 1 may be prepared by a process that includes the following steps: a) dissolving betrixaban and maleic acid in a solvent to form a solution; b) adding water; and
  • the solvent may be, for example, an alcohol solvent, a ketone solvent, an aprotic polar solvent, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, and mixtures thereof.
  • Suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • Suitable aprotic polar solvents include, but are not limited to, N,N- dimethylformamide, dimethylsulfoxide, ⁇ , ⁇ -dimethylacetamide, and mixtures thereof.
  • crystalline betrixaban maleate form-M 1 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in a first solvent;
  • the first solvent may be a polar solvent, for example, an alcohol solvent, water, tetrahydrofuran, acetic acid, formic acid, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide, or mixtures thereof.
  • a polar solvent for example, an alcohol solvent, water, tetrahydrofuran, acetic acid, formic acid, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, pentanol, and mixtures thereof.
  • the second solvent may be, for example, an ether solvent, a hydrocarbon solvent, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • the present invention provides crystalline betrixaban maleate form-M2, which may be characterized by a powder X-ray diffraction pattern having significant peaks at 4.6, 9.2, 12.1, 12.5, 13.1, 14.5, 14.9, 16.3, 16.8 20.2, 23.0 and 23.7 ⁇ 0.2 ° ⁇ .
  • the present invention provides a process for preparing crystalline betrixaban maleate form-M2.
  • crystalline betrixaban maleate form-M2 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in methanol to form a solution;
  • the anti-solvent may be, for example, a hydrocarbon solvent, an ether solvent, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and a mixtures thereof.
  • crystalline betrixaban maleate form-M2 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in methanol;
  • the anti-solvent may be, for example, a hydrocarbon solvent, an ether solvent, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and a mixtures thereof.
  • crystalline betrixaban maleate form-M2 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in methanol;
  • the first and second anti-solvents may be, for example, a hydrocarbon solvent, an ether solvent, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • the isolating step is carried out by lyophilization.
  • the present invention provides crystalline betrixaban maleate form-M3 which may be characterized by a powder X-ray diffraction pattern having significant peaks at 4.7, 9.3, 12.1, 12.8, 13.1, 13.9, 14.7, 15.0, 15.9, 16.6 20.4, 23.0 and 23.3 ⁇ 0.2 ° ⁇ .
  • the present invention provides a process for preparing crystalline betrixaban maleate form-M3.
  • crystalline betrixaban maleate form-M3 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in formic acid;
  • the anti-solvent may be, for example, a hydrocarbon solvent, an ether solvent, or mixtures thereof.
  • Suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • crystalline betrixaban maleate form-M3 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in a mixture of formic acid and acetic acid;
  • the anti-solvent may be, for example, a hydrocarbon solvent, an ether solvent, or mixtures thereof.
  • suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • hydrocarbon solvents examples include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • Figure 1 is a powder X-ray diffraction (PXRD) pattern of amorphous betrixaban maleate
  • Figure 2 is a PXRD pattern of an amorphous solid dispersion of betrixaban maleate with PLASDONE S-630 (50% w/w);
  • Figure 3 is a PXRD pattern of an amorphous solid dispersion of betrixaban maleate with Povidone K30 (50% w/w);
  • Figure 4 is a PXRD pattern of crystalline betrixaban maleate form-Mi ;
  • Figure 5 is a PXRD pattern of crystalline betrixaban maleate form-M2;
  • Figure 6 is a PXRD pattern of crystalline betrixaban maleate form-M3 ;
  • Figure 7 is a PXRD pattern of crystalline betrixaban form-Mi
  • Figure 8 is a PXRD pattern of crystalline betrixaban form-M2
  • Figure 9 is a PXRD pattern of crystalline betrixaban form-M3;
  • Figure 10 is a PXRD pattern of crystalline betrixaban form-M4;
  • Figure 11 is a PXRD pattern of amorphous betrixaban; and Figure 12 is a crystal structure of the betrixaban maleate form-M3 asymmetric unit.
  • the term “about” when modifying a temperature measurement is meant to mean the recited temperature plus or minus five degrees.
  • the term “about” when modifying an absolute measurement, such as time, mass, or volume means the recited value plus or minus 10% of that value.
  • the present invention provides polymorphic forms of betrixaban maleate, designated as amorphous, crystalline form-Mi, form-M2, and form-M3 and methods of production thereof.
  • the present disclosure also provides amorphous solid dispersion of betrixaban maleate and processes for the preparation thereof.
  • the present disclosure further provides polymorphic forms of betrixaban, designated as amorphous, crystalline form-Mi, form-M2, form-M3, and form-M4.
  • the present invention also provides processes for preparing each.
  • the polymorphic forms of betrixaban and betrixaban maleate, as well as solid dispersions of betrixaban maleate, disclosed herein may be characterized by powder x-ray diffraction (PXRD). Therefore, samples of each were analyzed with a BRUKER D-8 Discover powder diffractometer equipped with a goniometer of ⁇ /2 ⁇ configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40 kV and 30 mA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size, and 0.4 seconds step time. In one aspect, the present invention provides amorphous betrixaban maleate.
  • PXRD powder x-ray diffraction
  • amorphous betrixaban maleate prepared by methods disclosed herein, may be characterized as amorphous by the PXRD pattern in Figure 1.
  • amorphous betrixaban maleate may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in a first solvent;
  • betrixaban maleate may be dissolved in a first solvent.
  • the betrixaban maleate starting material may be of a variety of different forms, for example, any polymorphic or solvated form.
  • the first solvent may be a polar organic solvent.
  • the polar organic solvent may be an alcohol solvent, a ketone solvent, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • the first solvent may be removed. This may be carried out by employing any one of a variety of methods which are well known in the art. For example, in some embodiments, the first solvent is removed by distillation.
  • a second solvent may be optionally added.
  • suitable second solvents include, but are not limited to, ether solvents, hydrocarbon solvents, and mixtures thereof.
  • Suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • n-heptane or methyl tert-butyl ether is used as a second solvent.
  • a mixture of anisole and methyl tert-butyl ether is used as second solvent.
  • amorphous betrixaban maleate may be isolated from the solution. This may be carried out by methods well known in the art, for example, by filtering and drying the obtained solid.
  • Amorphous betrixaban maleate when prepared by methods disclosed herein, may exhibit enhanced stability. For example, samples of amorphous betrixaban maleate showed no significant change in PXRD pattern when stored for 2 months at 5 ⁇ 3 °C, indicating that amorphous betrixaban maleate is physically stable at 5 ⁇ 3 °C for two months. Data collected from this study is shown below in Table 1.
  • the present disclosure provides amorphous solid dispersions containing betrixaban maleate and processes for the preparation thereof.
  • an amorphous solid dispersion of betrixaban maleate may include, for example, betrixaban maleate and one or more pharmaceutically acceptable excipients.
  • the amorphous solid dispersion of betrixaban maleate consists essentially of, or consists of, betrixaban maleate and one or more pharmaceutically acceptable excipients.
  • Suitable pharmaceutical excipients include, but are not limited to, polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® tradename), and mixtures thereof.
  • PVAC polyvinylpyrrolidone
  • PVAC polyvinyl acetate
  • PVA polyvinyl alcohol
  • acrylic acid and their salts polyacrylamide
  • polymethacrylates vinylpyrrolidone-vinyl acetate copolymers
  • Suitable polysaccharides include, but are not limited to,, for example, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), optionally substituted a-cyclodextrins, optionally substituted ⁇ - cyclodextrins (e.g., hydroxypropyl ⁇ -cyclodextrin), optionally substituted ⁇ -cyclodextrins (e.g., hydroxypropyl ⁇ -cyclodextrin) and mixtures thereof.
  • substituted with respect to cyclodextrin means the addition of side chain groups such as hydroxyl, hydroxypropyl, or other Ci-C 6 alkyl and Ci-C 6 hydroxyalkyl groups.
  • the solid dispersion of betrixaban maleate may contain one or more pharmaceutical excipients from about 5 % w/w (pharmaceutical excipient/total composition mass) to about 90 % w/w, which may be about 10% w/w, 20% w/w, 30% w/w, 40% w/w, 50% w/w, 60% w/w, 70% w/w, 80% w/w, 90% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 10% - 80%, 10% - 70%, 10% - 60%, 10% - 50%, 10% - 40%, 10% - 30%, 10% - 20%, 20% - 90%, 20% - 80%, 20% - 70%, 20% - 60%, 20% - 50%, 20% - 40%, 20% - 30%, 30% - 90%, 30% - 70%, 30% - 60%, 30% - 50%, 30% - 40%, 40% - 90%, 40% - 90%, 40% - 90%, 40% - 90%, 40%
  • a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate is utilized as the pharmaceutically acceptable excipient.
  • Figure 2 shows a PXRD pattern of a sample of a solid dispersion of betrixaban maleate with 50% w/w PLASDONE S-630, prepared by processes disclosed herein.
  • useful polyvinylpyrrolidones are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof.
  • povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-90, and mixtures thereof are those with K-values ranging from about 12 to about 103, including povidone K-12, povidone K-15, povidone K-17, povidone K-25, povidone K-30, povidone K-
  • Povidone-K30 is utilized as the pharmaceutically acceptable excipient in amorphous solid dispersions of betrixaban maleate.
  • Figure 3 shows a PXRD pattern of a sample of a solid dispersion of betrixaban maleate with 50% w/w povidone K30, prepared by processes disclosed herein.
  • HPMC is utilized as the pharmaceutically acceptable excipient in amorphous solid dispersions of betrixaban maleate.
  • the present invention provides a method for preparing an amorphous solid dispersion of betrixaban maleate.
  • an amorphous solid dispersion of betrixaban maleate may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate and a pharmaceutical excipient in a first solvent;
  • betrixaban maleate and a pharmaceutical excipient may be dissolved in a first solvent.
  • the betrixaban maleate starting material may be of a variety of different forms, for example, any polymorphic or solvated form.
  • the first solvent may be, for example, water, an alcohol solvent, a ketone solvent, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-l -propanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • Suitable pharmaceutical excipients include, but are not limited to, polysaccharides, polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers, Ci-C 6 polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), copolymers of polyethylene glycol and polypropylene glycol (e.g., the families of block copolymers based on ethylene oxide and propylene oxide sold under the PLURONIC® tradename), and mixtures thereof.
  • PVAC polyvinylpyrrolidone
  • PVAC polyvinyl acetate
  • PVA polyvinyl alcohol
  • acrylic acid and their salts polyacrylamide
  • polymethacrylates vinylpyrrolidone-vinyl acetate copolymers
  • Suitable polysaccharides include, but are not limited to,, for example, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), croscarmellose, carboxymethyl cellulose (CMC) and salts thereof, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), optionally substituted a-cyclodextrins, optionally substituted ⁇ - cyclodextrins (e.g., hydroxypropyl ⁇ -cyclodextrin), optionally substituted ⁇ -cyclodextrins (e.g., hydroxypropyl ⁇ -cyclodextrin), and mixtures thereof.
  • substituted with respect to cyclodextrin means the addition of side chain groups such as hydroxyl, hydroxypropyl, or other Ci-C 6 alkyl and Ci-C 6 hydroxyalkyl groups.
  • the pharmaceutical excipient may be combined with betrixaban maleate from about 5% w/w (pharmaceutical excipient/total composition mass) to about 90 % w/w, which may be about 10% w/w, 20% w/w, 30% w/w, 40% w/w, 50% w/w, 60% w/w, 70% w/w, 80% w/w, 90% w/w, or between any of the aforementioned w/w percentages, including the ranges of about 10% - 80%, 10% - 70%, 10% - 60%, 10% - 50%, 10% - 40%, 10% - 30%, 10% - 20%, 20% - 90%, 20% - 80%, 20% - 70%, 20% - 60%, 20% - 50%, 20% - 40%, 20% - 30%, 30% - 90%, 30% - 80%, 30% - 70%, 30% - 60%, 30% - 50%, 30% - 40%, 40% - 90%, 40% - 80%, 40% - 70%, 40%, 40%, 20% -
  • a 40:60 w/w copolymer of N-vinyl- 2-pyrrolidone and vinyl acetate e.g., PLASDONE S-630
  • PLASDONE S-630 a 40:60 w/w copolymer of N-vinyl- 2-pyrrolidone and vinyl acetate
  • polyvinylpyrrolidone with a K-value of about 30 e.g., Povidone-K30
  • a K-value of about 30 e.g., Povidone-K30
  • HPMC is utilized as the pharmaceutically acceptable excipient.
  • the first solvent may next be removed by techniques well-known in the art, for example, by evaporation, distillation, or agitated thin film drying.
  • the first solvent is removed by distillation.
  • removal of the first solvent may result in formation of a solid.
  • a second solvent may be optionally added.
  • suitable second solvents include, but are not limited to, ether solvents, hydrocarbon solvents, and mixtures thereof.
  • addition of the second solvent may result in a suspension of the amorphous solid dispersion of betrixaban maleate in the solvent.
  • addition of the second solvent may facilitate subsequent steps in the preparation of the amorphous solid dispersion of betrixaban maleate, for example, the isolation step.
  • suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, cyclohexane, methyl cyclohexane, and mixtures thereof.
  • suitable ether solvents include, but are not limited to, isopropyl ether, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • methyl tert-butyl ether is used as a non- polar solvent.
  • an amorphous solid dispersion of betrixaban maleate may be isolated, for example, by filtering the solution to obtain a solid. The solid may then be dried under vacuum.
  • amorphous solid dispersions of betrixaban maleate with 50% w/w PLASDONE S-630, 50% w/w Povidone-K30, and 50% w/w HPMC may have a purity (as measured by HPLC) of more than 99%.
  • amorphous solid dispersions of betrixaban maleate with 50% w/w PLASDONE S-630, 50% w/w Povidone-K30, and 50% w/w HPMC, prepared according to methods disclosed herein, may exhibit enhanced physical and chemical stability.
  • the present invention also provides crystalline betrixaban maleate form-Ml.
  • Crystalline betrixaban maleate form-Ml as prepared by methods disclosed herein, may be characterized by a PXRD pattern with significant peaks at 2 ⁇ angles of 3.5, 11.5, 12.0, 19.8, 25.2, and 26.7 ⁇ 0.2°.
  • Crystalline betrixaban maleate form-Ml may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 3.5, 5.4, 6.0, 8.5, 9.9, 10.3, 11.5, 12.0, 13.8, 14.3, 14.7, 15.2, 15.9, 16.5, 17.3, 19.2, 19.8, 20.8, 21.3, 22.9, 23.6, 25.5, 26.7, 29.7, and 29.9 ⁇ 0.2°.
  • Crystalline betrixaban maleate form-Ml may be further characterized by the PXRD pattern in Figure 4.
  • the present invention also provides a process for the preparation of crystalline betrixaban maleate form-Ml.
  • crystalline form-Ml of betrixaban maleate may be prepared by a process that includes the steps of: a) suspending betrixaban and maleic acid in a polar solvent to create a suspension;
  • betrixaban and maleic acid may be suspended in a polar solvent.
  • suitable polar solvents include, but are not limited to, alcohol solvents, acetic acid, formic acid, water, and mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • betrixaban and maleic acid are suspended in a mixture of alcohol and water.
  • the suspension at a temperature of about 20 °C to reflux This includes about 20 °C to about 40 °C, which further encompasses about 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, or between any of the aforementioned temperatures, including the ranges of about 20 °C - 25 °C, 20 °C - 30 °C, 20 °C - 35 °C, 20 °C - 40 °C, 25 °C - 30 °C, 25 °C - 35 °C, 25 °C - 40 °C, 30 °C - 35 °C, 30 °C - 40 °C, and 35 °C - 40 °C.
  • the suspension is stirred for an extended period of time, for example, for about 1-3 hours, which may be 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, or between any of the aforementioned time frames, including the ranges of 1 - 1.5 hours, 1 - 2 hours, 1 - 2.5 hours, 1.5 - 2 hours, 1.5 - 2.5 hours, 1.5 - 3 hours, 2 - 2.5 hours, 2 - 3 hours, and 2.5 - 3 hours.
  • the second solvent may be added to the suspension.
  • addition of the second solvent results in a clear solution.
  • the second solvent may be, for example, a non-polar solvent.
  • suitable non-polar solvents include, but are not limited to, ether solvents (e.g., 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof).
  • the solution may be stirred for an extended period of time, for example, for about 1 - 2 hours, which may be 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, or between any of the aforementioned time frames, including the ranges of 1 - 1.25 hours, 1 - 1.5 hours, 1 - 1.75 hours, 1.25 - 1.5 hours, 1.25 - 1.75 hours, 1.25 - 2 hours, 1.5 - 1.75 hours, 1.5 - 2 hours, and 1.75 - 2 hours.
  • 1 - 2 hours which may be 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, or between any of the aforementioned time frames, including the ranges of 1 - 1.25 hours, 1 - 1.5 hours, 1 - 1.75 hours, 1.25 - 1.5 hours, 1.25 - 2 hours, 1.5 - 1.75 hours, 1.5 - 2 hours, and 1.75 - 2 hours.
  • the solvents may be partially removed to result in a concentrated reaction mass.
  • a concentrated reaction mass This may be carried out by known techniques which may include, but are not limited to, evaporation, distillation, spray drying, filtration, lyophilization, or agitated thin film drying.
  • crystalline betrixaban maleate form-Ml may be further purified or processed.
  • water is added to the above concentrated reaction mass which may be further concentrated by known techniques. This may be repeated as many times as needed to result in a final product with desired purity.
  • a slurry is formed. Said slurry may be stirred for an extended period of time to facilitate formation of a precipitate.
  • the slurry may be stirred for 15 - 25 hours, which may be about 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours or between any of the aforementioned time frames, including the ranges of 15 - 16 hours, 15 - 17 hours, 15 - 18 hours, 15 - 19 hours, 15 - 20 hours, 15 - 21 hours, 15 - 22 hours, 15 - 23 hours, 15 - 24 hours, 16 - 17 hours, 16 - 18 hours, 16 - 19 hours, 16 - 20 hours, 16 - 21 hours, 16 - 22 hours, 16 - 23 hours, 16 - 24 hours, 16 - 25 hours, 17 - 18 hours, 17 - 19 hours, 17 - 20 hours, 17 - 21 hours, 17 - 22 hours, 17 - 23 hours, 17 - 24 hours, 17 - 25 hours, 18 - 19 hours, 18 - 20 hours, 17 - 21 hours, 17 - 22 hours, 17 - 23 hours, 17
  • the isolation of crystalline betrixaban maleate form-Ml may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration. In some embodiments, the solid obtained is dried.
  • crystalline form-Ml of betrixaban maleate may be prepared by a process that includes the steps of: a) dissolving betrixaban and maleic acid in a solvent to form a solution;
  • betrixaban and maleic acid may be dissolved in a solvent.
  • suitable solvents include, but are not limited to, an alcohol solvent, a ketone solvent, an aprotic solvent, and mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, or mixtures thereof.
  • suitable aprotic polar solvent include, but are not limited to, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide (DMA), and mixtures thereof.
  • betrixaban and maleic acid are dissolved in DMSO.
  • it is found particularly useful to heat the solution for example, to a temperature of about 30 °C to reflux.
  • the solution obtained may then be adjusted to about 20 °C to about 40 °C, which may be about 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, or between any of the aforementioned temperatures, including the ranges of about 20 °C - 25 °C, 20 °C - 30 °C, 20 °C - 35 °C, 20 °C
  • the solution is adjusted to a temperature of about 25 °C to about 30 °C.
  • water may be added to the resulting solution.
  • the solution is stirred at a temperature of about 25 °C to about 30 °C, which may be about 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, 30 °C, or between any of the aforementioned temperatures, including the ranges of about 25 °C - 26 °C,
  • the solution may be stirred from about 12 hours to about 20 hours, which stirring times of about 12 hours, 13 hours, 14 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or between any of the aforementioned time frames, including the ranges of 12 - 13 hours, 12 - 14 hours, 12 - 15 hours, 12 - 16 hours, 12 - 17 hours, 12 - 18 hours, 12 - 19 hours, 12 - 20 hours, 13 - 14 hours, 13 - 15 hours, 13 - 16 hours, 13 - 17 hours, 13 - 18 hours, 13 - 19 hours, 13 - 20 hours, 14 - 15 hours, 14 - 16 hours, 14 - 17 hours, 14 - 18 hours, 14 - 19 hours, 14 - 20 hours, 15 - 16 hours, 15 - 17 hours, 15 - 18 hours, 15 - 19 hours, 15 - 20 hours, 16 - 17 hours, 16 - 18 hours, 16 - 19 hours, 16 - 20 hours, 17 - 18 hours, 17 - 19 hours,
  • this may result in precipitation crystalline betrixaban maleate form-Ml.
  • crystalline betrixaban maleate form-Ml may be isolated. This may be carried out by methods well known in the art, for example, by isolation of the precipitate by filtration followed by drying.
  • crystalline betrixaban maleate form-Ml may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in a polar solvent;
  • betrixaban maleate may be dissolved in a polar solvent.
  • suitable polar solvents include alcohol solvents, acetic acid, formic acid, tetrahydrofuran, ethylacetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide, and mixtures thereof.
  • alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3-pentanol, 2- methyl- 1 -propanol, 2-methyl- 1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • betrixaban maleate is dissolved in an alcohol solvent.
  • betrixaban maleate may be dissolved particularly in methanol under the heating, heating may be carried out at a temperature of about 20 °C to reflux.
  • a temperature of about 20 °C to about 70 °C which may be about 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65°C, 70 °C or between any of the aforementioned temperatures, including the ranges of about 20 °C - 70 °C, 20 °C - 65 °C, 20 °C - 60 °C, 20 °C - 55 °C, 20 °C - 50 °C, 20 °C - 45 °C, 20 °C - 40 °C, 20 °C - 35 °C, 20 °C - 30 °C, 20 °C - 25 °C, 25 °C - 70 °C, 25 °C - 65 °C, 25 °C - 60 °C, 25 °C - 55 °C, 25 °C - 50
  • the polar solvent may be removed to obtain a solid compound. This may be carried out by methods well known in the art, for example, distillation or a reduced-pressure evaporation method.
  • the reaction mass may then be optionally cooled. In particularly useful embodiments, the reaction mass is cooled to a temperature of about -30 °C to about 0 °C, which may be -30 °C, -25 °C, -20 °C, -15 °C, -10 °C, -5 °C, or 0 °C including ranges between these aforementioned temperatures including -30 °C - -5 °C, -30 °C - -10 °C, -30 °C - -15 °C, -30 °C - -20 °C, -30 °C - -25 °C, -25 °C - -5 °C, -25 °C - -10 °C, -25 °C - -15 °C, -25 °C -
  • a second solvent may be added.
  • the second solvent may be, for example, an ether solvent or a hydrocarbon solvent.
  • suitable ether solvents include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, anisole, and mixtures thereof.
  • suitable hydrocarbon solvents include toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • a mixture of anisole and methyl tert-butyl ether is used as a second solvent.
  • water may then be added.
  • stirring the reaction mixture for an extended period of time at a reduced temperature is found particularly useful.
  • the reaction mixture is stirred at about -20 °C to about -30 °C for about 1 hour to about 2 hours, which may be 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, or between any of the aforementioned time frames, including the ranges of 1 - 1.25 hours, 1 - 1.5 hours, 1 - 1.75 hours, 1.25 - 1.5 hours, 1.25 - 1.75 hours, 1.25 - 2 hours, 1.5 - 1.75 hours, or 1.5 - 2 hours, and 1.75 - 2 hours.
  • crystalline betrixaban maleate form-Mi may be isolated. This may be carried out by methods well known in the art, for example, by isolation of the solid by filtration. The solid may be further processed, for example, by drying.
  • the present invention provides crystalline betrixaban maleate form-M2
  • Crystalline betrixaban maleate form-M2 prepared by methods disclosed herein, may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 9.2, 12.5, 26.04, and 26.3 ⁇ 0.2 °. Crystalline betrixaban maleate form-M2 may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 4.6, 9.2, 12.1, 12.5, 13.1, 14.5, 14.9, 16.3, 16.8 20.2, 23.0 and 23.7 ⁇ 0.2 °.
  • Crystalline betrixaban maleate form-M2 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 4.6, 9.2, 10.6, 12.1, 12.5, 13.1, 14.1, 14.5, 14.9, 16.3, 16.8, 17.4, 18.1, 18.5, 19.3, 20.2, 20.5, 21.04, 21.3, 21.8, 22.17, 23.0, 23.7, 24.5, 25.3, 26.0, 26.3, 26.5, 27.4, 27.9, 28.5, 29.5 and 30.2 ⁇ 0.2 °. Crystalline betrixaban maleate form-M2 may be further characterized by the PXRD pattern shown in Figure 5.
  • crystalline form-M2 of betrixaban maleate is a methanol solvate of betrixaban maleate. It is further believed that the ratio of betrixaban maleate to methanol in crystalline betrixaban maleate form-M2 is 1 : 1.
  • the present invention provides a process for the preparation of crystalline betrixaban maleate form-M2.
  • crystalline betrixaban maleate form-M2 may be prepared by a process that includes the steps of: a) dissolving betrixaban maleate in methanol to form a solution;
  • betrixaban maleate may be dissolved in methanol.
  • betrixaban maleate is dissolved in methanol at an elevated temperature, for example, from about 40 °C to about reflux. In some embodiments, an elevated temperature of about 40 °C to about 60 °C is used.
  • the solution may then be cooled, for example, to a temperature of about 20 °C to about 40 °C, which may be 20 °C, 25 °C, 30 °C, 35 °C, or 40°C, or between any of the aforementioned ranges including the ranges of about 20 °C - 25 °C, 20 °C - 30 °C, 20 °C - 35 °C, 20 °C - 40 °C, 25 °C - 30 °C, 25 °C - 35 °C, 25 °C - 40 °C, 30 °C - 35 °C, 30 °C - 40 °C, and 35 °C - 40 °C.
  • an anti-solvent solvent may be added.
  • suitable anti-solvents include, but are not limited to, hydrocarbons, ethers, and mixtures thereof.
  • hydrocarbons include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • ethers solvents include, but are not limited to, 1,4- dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • cyclohexane is used as an anti-solvent.
  • crystalline betrixaban maleate form-M2 may be isolated. This may be carried out by methods well known in the art, for example, by removing the solvent.
  • Solvent removal may be carried out by methods well known in the art, for example evaporation, distillation, spray drying, lyophilization, agitated thin film drying, or any combination thereof.
  • crystalline betrixaban maleate form-M2 is isolated by lyophilization.
  • the solution is frozen prior to lyophilization. In such embodiments, it was found particularly useful to pre-freeze the solution to a temperature of about -40 °C to -70 °C before lyophilizing.
  • lyophilization is conducted utilizing a vacuum pressure below 10 Pa and a condenser temperature of -80 °C.
  • crystalline form-M2 of betrixaban maleate may be prepared by a process that includes the steps of: a) dissolving betrixaban maleate in methanol to form a solution;
  • Steps a) through d) may be carried out by methods disclosed above.
  • crystalline form-M2 of betrixaban maleate may be prepared by a that includes the steps of: a) dissolving betrixaban maleate in methanol;
  • betrixaban maleate may be dissolved in methanol.
  • betrixaban maleate is dissolved in methanol at an increased temperature, for example, from about 40 °C to about reflux.
  • a temperature of about 40 °C to about 60 °C is used, which may be about 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, or between any of the aforementioned temperatures, including the ranges of about 40 °C - 45 °C, 40 °C - 50 °C, 40 °C - 55 °C, 45 °C - 50 °C, 45 °C - 55 °C, 45 °C - 60 °C, 50 °C - 55 °C, and 55 °C - 60 °C.
  • an anti-solvent solvent may be added.
  • suitable anti-solvents include, but are not limited to, hydrocarbons, ethers, and mixtures thereof.
  • suitable hydrocarbons include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • suitable ethers include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • cyclohexane is used as the anti-solvent.
  • the solution may then be cooled, for example, to a temperature of about 20 °C to about 40 °C. In particularly useful embodiments, this is performed while stirring the solution from about 30 minutes to about 1 hour.
  • crystalline betrixaban maleate form-M2 seeding may be added to the reaction mass and stirred for about 30 minutes to 1 hour.
  • another volume of anti-solvent solvent may be added.
  • the anti-solvent may be the same anti-solvent as initially added or a different anti-solvent.
  • a second volume of cyclohexane is added.
  • the reaction mass is stirred for about 1 hour to about 3 hours at a temperature of about 5 °C to 25 °C, which may be 5 °C , 10 °C, 15 °C, 20 °C, 25 °C, or between any of the aforementioned temperatures, including the ranges of about 5 °C - 10 °C, 5 °C - 15 °C, 5 °C - 20 °C, 10 °C - 15 °C, 10 °C - 20 °C, 10 °C - 25 °C, 15 °C - 20 °C, 15 °C - 25 °C, and 20 °C - 25 °C.
  • the optional steps of stirring may help facilitate formation of betrixaban maleate form-M2.
  • Crystalline form-M2 of betrixaban maleate may next be isolated. This may be carried out by methods well known in the art, for example, by isolation of the solid by filtration. The solid may be further processed, for example, by drying.
  • the present invention provides crystalline betrixaban maleate form-M3.
  • Crystalline betrixaban maleate form-M3, prepared by methods disclosed herein, may be characterized by a PXRD pattern with significant peaks at 2 ⁇ angles of 9.3, 12.8, 13.1, and 25.4 ⁇ 0.2 °.
  • Crystalline betrixaban maleate form-M3 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 4.7, 9.3, 12.1, 12.8, 13.1, 13.9, 14.7, 15.0, 15.9, 16.6 20.4, 23.0 and 23.3 ⁇ 0.2 °.
  • Crystalline betrixaban maleate form-M3 may be furthermore characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 4.7, 9.3, 10.6, 11.3, 12.1, 12.8, 13.1, 13.9, 14.3, 14.7, 15.0, 15.9, 16.6, 17.0, 17.3, 18.3, 18.6, 19.4, 20.4, 21.0, 21.4, 22.3, 23.0, 23.3, 24.0, 24.6, 25.4, 25.8, 26.1, 26.2, 27.1, 27.4, 27.9, 28.5, 29.1, 29.9, 30.4 ⁇ 0.2°. Crystalline betrixaban maleate form-M3 may be further characterized by the PXRD pattern as shown in Figure 6. The polymorphs of betrixaban maleate may also be characterized by single crystal X-Ray
  • the crystal structure analysis of the sample of betrixaban maleate form-M3 shows that the asymmetric betrixaban maleate unit contains a salt (maleate) molecule and a formic acid solvent molecule and that the asymmetric unit is in a non-ionized state.
  • Figure 12 shows the x-ray crystal structure of the betrixaban maleate form-M3 asymmetric unit.
  • Figure 12 shows a view of each molecules in the betrixaban maleate form-M3 asymmetric unit including carbon numbering.
  • Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius.
  • the present invention provides a process for the preparation of crystalline betrixaban maleate form-M3.
  • crystalline betrixaban maleate form-M3 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in formic acid;
  • betrixaban maleate may be dissolved in formic acid. In particularly useful embodiments, this is carried out at an elevated temperature, for example at a temperature of about 30 °C to about reflux. In some embodiments, a temperature of about 30 °C to about 40 °C is used, which includes 30 °C, 32 °C, 34 °C, 36 °C, 38 °C, 40 °C, and any temperature between, including 30 °C - 38 °C, 30 °C - 36, 30 °C - 34 °C, 30 °C - 32 °C, 32 °C - 40 °C, 32 °C- 38 °C, 32 °C - 36 °C, 32 °C - 34 °C, 34 °C - 40 °C, 34 °C - 38 °C, 34 °C - 36 °C, 36 °C- 40 °C, 36 °C - 38 °C, and 38
  • the solution may then be cooled.
  • the solution is cooled to a temperature of about -5 °C to about 10 °C, which includes -5 °C, 0 °C, 5 °C, 10 °C, and any temperature between, including -5 °C - 5 °C, -5 °C - 0 °C, 0 °C - 10 °C, 0 °C - 5 °C, and 5 °C - 10 °C.
  • the solution is cooled to 0 °C to about 5 °C.
  • an anti-solvent solvent may be added.
  • suitable anti-solvents include, but are not limited to, hydrocarbons, ethers, and mixtures thereof.
  • hydrocarbons include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • ethers include, but are not limited to, 1,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • the anti-solvent is methyl tert-butyl ether.
  • the solution is stirred, for example, for about 1 hour to about 3 hours.
  • the solution may be heated to a temperature of about 15 °C to about 30 °C and stirred for an extended period of time. In particularly useful embodiments, the solution is heated to 20 °C to about 25° C and stirred for about 10 to 20 hours.
  • another lot of anti-solvent may be added. The anti-solvent may be the same or different than the first lot of anti-solvent. In particularly useful embodiments, a second lot of methyl tert-butyl ether is added.
  • reaction mixture may be stirred again, for example, for about 1 hour to about 3 hours.
  • steps of adding a second volume of anti-solvent, heating, and stirring are optional but, in some embodiments, may facilitate formation of crystalline betrixaban maleate form-M3.
  • Crystalline betrixaban maleate form-M3 may be isolated by methods well known in the art, for example, by isolation of the solid by filtration.
  • the solid may be further processed, for example, by drying.
  • crystalline betrixaban maleate form-M3 may be prepared by a process that includes the following steps: a) dissolving betrixaban maleate in a mixture of formic acid and acetic acid;
  • betrixaban maleate may be dissolved in mixture of formic acid and acetic acid. In some embodiments, this is carried out at an elevated temperature, for example about 30 °C to about reflux. In some embodiments, a temperature of about 30 °C was found to be particularly useful for dissolving betrixaban maleate in the mixture of formic acid and acetic acid.
  • an anti-solvent may be added.
  • the anti-solvent may be, for example, a hydrocarbon, an ether, or mixtures thereof.
  • hydrocarbons include, but are not limited to, toluene, heptane, hexane, cyclohexane, and mixtures thereof.
  • ethers include, but are not limited to, 1 ,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • methyl tert-butyl ether is used as the anti-solvent.
  • the solution may be stirred for an extended period of time, for example, from about 10 to about 20 hours.
  • This extended period of stirring may result in formation of crystalline betrixaban maleate form-M3.
  • Crystalline betrixaban maleate form-M3 may be isolated by methods well known in the art, for example, by isolation of the obtained solid by filtration.
  • the solid may be further processed, for example, by drying.
  • the physical stability of crystalline betrixaban maleate form-M3 was determined by storing samples at 40 °C/75% RH, at 25 °C/60% RH, and at 2-8 °for up to three months. The samples were analyzed by PXRD for physical stability.
  • crystalline betrixaban maleate form-M3 shows no change in PXRD pattern when stored for three months at 5 ⁇ 3 °C. Significant physical change was observed in samples stored at 25 °C/60% RH at 40 °C/75% RH conditions. This indicates that crystalline betrixaban maleate form-M3 is physically stable at 5 ⁇ 3 °C for three months. Table 3
  • the present invention provides crystalline form-Ml of betrixaban base.
  • Crystalline betrixaban base form-Ml prepared by methods disclosed herein, may be characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 6.4, 9.17, 10.12, 15.8, 21.3, and 22.0 ⁇ 0.2 °.
  • Crystalline betrixaban base form-Ml may be further characterized by PXRD pattern having significant peaks at 2 ⁇ angles of 6.4, 8.1, 9.1, 10.1, 10.9, 12.8, 13.8, 14.5, 15.3, 15.8, 16.3, 17.0, 17.2, 17.6, 17.8, 18.6, 19.1, 19.7, 20.3, 20.7, 20.9, 21.3, 22.0, 23.3, 23.4, 23.9, 24.7 and 25.2 ⁇ 0.2 °.
  • Betrixaban base crystalline form-Ml may be further characterized by the PXRD pattern in Figure 7.
  • crystalline betrixaban base form-Ml is an anisole solvate of betrixaban. It is further believed that the ratio of betrixaban to anisole in crystalline betrixaban base form-Ml is 1: 1.
  • the present invention provides a process for the preparation of crystalline betrixaban base form-Ml.
  • crystalline betrixaban base form-Ml may be prepared by a process that includes the following steps: a) suspending betrixaban base in anisole to form a suspension;
  • betrixaban may be suspended in anisole to form a suspension.
  • the suspension may then be heated, for example, to a temperature of about 40 °C to about reflux.
  • a temperature of about 40 °C to about 60 °C which may be about 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, or between any of the aforementioned temperatures, including the ranges of about 40 °C - 45 °C, 40 °C - 50 °C, 40 °C - 55 °C, 45 °C - 50 °C, 45 °C - 55 °C, 45 °C - 60 °C, 50 °C - 55 °C, and 55 °C - 60 °C, is used.
  • the suspension is maintained at this temperature for an extended period of time, for example, for about 12 hours to about 48 hours, which may be about 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, or between any of the aforementioned timeframes, including the ranges of 12 - 18 hours, 12 - 24 hours, 12 - 30 hours, 12 - 36 hours, 12 - 42 hours, 18 - 24 hours, 18 - 30 hours, 18 - 36 hours, 18 - 42 hours, 18 - 48 hours, 24 - 30 hours, 24 - 36 hours, 24 - 42 hours, 24 - 48 hours, 30- 36 hours, 30 - 42 hours, 30 - 48 hours, 36 - 42 hours, 36 - 48 hours, and 42 - 48 hours.
  • an extended period of time for example, for about 12 hours to about 48 hours, which may be about 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours, 48 hours, or between any of the aforementioned timeframes, including the ranges of 12 - 18 hours,
  • the suspension may then be cooled.
  • the suspension is cooled to a temperature of 35 °C or lower, for example, to a temperature of about 10 °C to about 35 °C, which may be about 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, or between any of the aforementioned temperatures, including the ranges of about 10 °C - 15 °C, 10 - 20 °C, 10 °C - 25 °C, 10 °C - 30 °C, 15 °C - 20 °C, 15 °C - 25 °C, 15 C - 30 °C, 15 °C - 35 °C, 20 °C - 25 °C, 20 °C - 30 °C, 20 °C - 35 °C, 25 °C - 30 °C, 25 °C - 35 °C, and 30 °C - 35 °C.
  • Crystalline betrixaban base form-Mi may then be isolated. Isolation may be carried out by methods well known in the art, for example, by isolation of the formed solid by filtration. The solid may be further processed, for example, by drying.
  • the present invention provides crystalline betrixaban base form-M2.
  • Crystalline betrixaban base form-M2 prepared by methods disclosed herein, may be characterized by a PXRD pattern with significant peaks at 2 ⁇ angles of 5.0, 11.3, 15.3, 18.1, 21.2, and 26.2 ⁇ 0.2 °. Crystalline betrixaban base form-M2 may be further characterized by a PXRD pattern having significant peaks at 2 ⁇ angles of 5.0, 7.2, 8.0, 11.3, 13.0, 14.3, 14.9, 15.3, 16.9, 18.1, 19.4, 20.5, 21.2, 22.9, 23.3, 24.2, 24.4, 25.4, 26.2, 26.8, 27.9, 29.0, and 29.3 ⁇ 0.2 °. Crystalline betrixaban base form-M2 may be further characterized by the PXRD pattern in Figure 8.
  • the present invention provides a process for the preparation of crystalline betrixaban base form-M2.
  • crystalline betrixaban base form-M2 may be prepared by a process that includes the following steps: a) suspending betrixaban base in acetone;
  • betrixaban may be suspended in acetone.
  • the suspension may be heated.
  • the suspension may be heated to a temperature of about 40 °C to about reflux.
  • a temperature of about 40 °C to about 60 °C which may be about 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, or between any of the aforementioned temperatures, including the ranges of about 40 °C - 45 °C, 40 °C - 50 °C, 40 °C - 55 °C, 45 °C - 50 °C, 45 °C - 55 °C, 45 °C - 60 °C, 50 °C - 55 °C, and 55 °C - 60 °C, is used.
  • the heating step is carried out without stirring or agitation of any kind.
  • the suspension is then adjusted to a temperature between about 40 °C and about 60 °C, which may be about 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, or between any of the aforementioned temperatures, including the ranges of about 40 °C - 45 °C, 40 °C - 50 °C, 40 °C - 55 °C, 45 °C - 50 °C, 45 °C - 55 °C, 45 °C - 60 °C, 50 °C - 55 °C, and 55 °C - 60 °C and maintained at this temperature for an extended period of time.
  • the suspension may then be cooled.
  • the suspension may be cooled to a temperature less than about 35 °C, for example, a temperature of about 10 °C to about 35 °C, which may be about 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, or between any of the aforementioned temperatures, including the ranges of about 10 °C - 15 °C, 10 °C - 20 °C, 10 - 25 °C, 10 °C - 30 °C, 15 °C - 20 °C, 15 °C - 25 °C, 15 C - 30 °C, 15 °C - 35 °C, 20 °C - 25 °C, 20 °C - 30 °C, 20 °C - 35 °C, 25 °C - 30 °C, 25 °C - 35 °C, and 30 °C - 35 °C,
  • the solution is cooled to a temperature of about 20 °C to about 35 °C.
  • this cooling step may result in formation crystalline betrixaban base form-M2.
  • Crystalline form-M2 of betrixaban base may then be isolated from this suspension. Isolation may be carried out by methods well known in the art, for example, by isolation of the formed solid by filtration. The solid may be further processed, for example, by drying.
  • the present invention provides crystalline betrixaban base form-M3.
  • Crystalline betrixaban base form-M3, prepared by methods disclosed herein, may be characterized by a PXRD pattern with significant peaks at 2 ⁇ angles of 4.9, 19.6, 21.2, 24.8, and 31.6 ⁇ 0.2 °.
  • Crystalline betrixaban base form-M3 may be further characterized by a PXRD pattern with significant peaks at 2 ⁇ angles of 4.9, 6.4, 10.8, 12.1, 13.4, 15.2, 15.8, 17.8, 19.1, 19.6, 20.4, 21.2, 22.2, 23.3 24.4, 24.8, 25.3, 25.9, 27.2, 28.6, 29.3, 30.5 and 31.6 ⁇ 0.2 °.
  • Crystalline betrixaban base form-M3 may be further characterized by the PXRD pattern in Figure 9.
  • the present invention provides crystalline betrixaban base form-M4.
  • Crystalline betrixaban base form-M4 prepared by methods disclosed herein, may be characterized by a PXRD pattern with significant peaks at 2 ⁇ angles of 4.8, 11.0, 12.9, 18.6, 24.6, and 31.7 ⁇ 0.2 °. Crystalline betrixaban base form-M4 may be further characterized by a PXRD pattern with significant peaks at 2 ⁇ angles of 4.8, 9.4, 10.2, 11.0, 12.2, 12.9, 15.9, 17.4, 18.6, 19.5, 21.3, 23.4, 23.7, 24.6, and 29.4 ⁇ 0.2 °. Crystalline betrixaban base form-M4 may be further characterized by the PXRD pattern in Figure 10. It is believed that crystalline betrixaban base form-M4 is a hydrated form of betrixaban. In another aspect, the present invention provides a process for the preparation of crystalline betrixaban base form-M4.
  • crystalline betrixaban base form-M4 may be prepared by a process that includes the following steps: a) dissolving betrixaban base in a first solvent;
  • betrixaban base may be dissolved in a first solvent.
  • the first solvent may be a polar solvent.
  • the solvent may be an alcohol solvent, a ketone solvent, an aprotic polar solvent, or mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • suitable aprotic polar solvents include, but are not limited to, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide (DMA), and mixtures thereof.
  • ⁇ , ⁇ -dimethylacetamide is used as the first solvent.
  • dissolution is facilitated by heating the mixture of betrixaban base and first solvent, for example, to about 40 °C to about reflux.
  • this temperature range includes about 40 °C to about 90 °C, which may be about 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, or between any of the aforementioned temperatures, including the ranges of about 40 °C - 45 °C, 40 °C - 50 °C,
  • the second solvent may be, for example, an ether solvent, a hydrocarbon solvent, or mixtures thereof.
  • hydrocarbon solvent include, but are not limited to, toluene, heptane, hexane, and mixtures thereof.
  • ether solvents include, but are not limited to, 1 ,4-dioxane, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, and mixtures thereof.
  • the solution is cooled and stirred while maintaining the temperature at about 20 °C to about 40 °C, which may be about 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, or between any of the aforementioned temperatures, including the ranges of about 20 °C - 25 °C, 20 °C - 30 °C, 20 °C - 35 °C, 20 °C - 40 °C, 25 °C - 30 °C, 25 °C - 35 °C, 25 °C - 40 °C, 30 °C - 35 °C, 30 °C - 40 °C, and 35 °C - 40 °C.
  • the stirring/temperature may be maintained for about 1 hour to about 4 hours, which may be about 1 hour, 2 hours, 3 hours, 4 hours, or between any of the aforementioned timeframes, including 1 - 2 hours, 1 - 3 hours, 1 - 4 hours, 2 - 3 hours, 2 - 4 hours, and 3 - 4 hours.
  • the solution is cooled even further, to a temperature of about 0 °C to about 10 °C, which may be about 0 °C, 2 °C, 4 °C, 6 °C, 8 °C, 10 °C, or between any of the aforementioned temperatures, including the ranges of about 0 °C - 2 °C, 0 °C - 4 °C, 0 °C - 6 °C, 0 °C - 8 °C, 2 °C - 4 °C, 2 °C - 6 °C, 2 °C - 8 °C, 2 °C - 10 °C, 6 °C - 8 °C, 6 °C - 10 °C, and 8 °C - 10 °C.
  • the solution is cooled to a temperature of about 0 °C to about 5 °C.
  • these aforementioned cooling steps are optional but may facilitate precipitation crystalline betrixaban base form-M4.
  • Crystalline form-M4 of betrixaban base may then be isolated from this suspension. Isolation may be carried out by methods well known in the art, for example, by isolation of the solid by filtration. The solid may be further processed, for example, by drying.
  • the present invention provides amorphous betrixaban base.
  • amorphous betrixaban base as prepared by methods disclosed herein may be characterized as amorphous by the PXRD pattern in Figure 11.
  • the present invention provides a process for the preparation of amorphous betrixaban base.
  • amorphous betrixaban base may be prepared by a process that includes the following steps:
  • betrixaban base may be dissolved in a first solvent.
  • suitable first solvents include alcohol solvents, ketone solvents, aprotic solvents, and mixtures thereof.
  • suitable alcohol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3- pentanol, 2-methyl- 1 -propanol, 2-methyl- 1 -butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl- 1 -propanol, and mixtures thereof.
  • suitable ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, and mixtures thereof.
  • aprotic polar solvent examples include, but are not limited to, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylacetamide (DMA), and mixtures thereof. In some embodiments, a mixture of DMSO and water is also suitable.
  • DMF N,N- dimethylformamide
  • DMSO dimethylsulfoxide
  • DMA ⁇ , ⁇ -dimethylacetamide
  • a mixture of DMSO and water is also suitable.
  • dissolution of betrixaban may be facilitated by heating the mixture of betrixaban and first solvent, for example, to a temperature of about 40 °C to about reflux.
  • a temperature of about 50 °C to about 80 °C which may be about 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, or between any of the aforementioned temperatures, including the ranges of about 50 °C - 55 °C, 50 °C - 60 °C, 50 °C - 65 °C, 50 °C - 70 °C, 50 °C - 75 °C, 50 °C - 80 °C, 55 °C - 60 °C, 55 °C - 65 °C, 55 °C - 70 °C, 55 °C - 75 °C, 55 °C - 80 °C, 60 °C - 65 °C,
  • the solution obtained may then be cooled to less than about 20 °C - 40 °C, which may be about 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, or between any of the aforementioned temperatures, including the ranges of about 20 °C - 25 °C, 20 °C - 30 °C, 20 °C - 35 °C, 20 °C - 40 °C, 25 °C - 30 °C, 25 °C - 35 °C, 25 °C - 40 °C, 30 °C - 35 °C, 30 °C - 40 °C, and 35 °C - 40 °C. In some embodiments, cooling to a temperature of about 25 °C to about 30 °C is used.
  • a second solvent may be added.
  • suitable second solvents include water, ether solvents, hydrocarbon solvents, and mixtures thereof.
  • water is used as a second solvent.
  • suitable ether solvents include, but are not limited to, methyl tert-butyl ether, isopropyl ether, and mixtures thereof.
  • suitable hydrocarbon solvents include, but are not limited to, toluene, heptane, hexane, and mixtures thereof.
  • the solution is maintained at about room temperature while stirring.
  • the temperature is maintained at a temperature of about 25 °C to about 30 °C, which may be about 25 °C, 26 °C, 27 °C, 28 °C, 29 °C, 30 °C or between any of the aforementioned temperatures, including the ranges of about 25 °C - 26 °C, 25 °C -27°C, 25 °C - 28 °C, 25 °C - 29 °C, 26 °C - 27 °C, 26 °C - 28 °C, 26 °C - 29 °C, 26 °C - 30 °C, 27 °C - 28 °C, 27 °C - 29 °C, 27 °C - 30 °C, 28 °C - 29 °C, 28 °C - 30 °C, and 29 °C - 30 °C, for about 2 - 5 hours
  • this aforementioned stirring step may result in the formation of amorphous betrixaban base.
  • Solid amorphous betrixaban base may then be isolated. Isolation may be carried out by methods well known in the art, for example, by isolation of the solid by filtration. The solid may be further processed, for example, by drying.
  • each disclosed form of betrixaban including all solvates, salts, bases both crystalline and amorphous, as well as disclosed solid dispersions thereof (e.g., betrixaban base form-Mi, form-M2, form-M3, form-M4, form-M5, amorphous, betrixaban maleate form-Mi, form-M2, form-M3, and amorphous, as well as solid dispersion of amorphous betrixaban maleate) may be useful in the formulation of a pharmaceutical dosage form as well as useful for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.
  • VTE venous thromboembolism
  • Particularly useful dosage forms include oral dosage forms, for example, a tablet or capsule.
  • Tablets or capsules may contain one or more inactive ingredients, including, for example, triglycerides, hard fat, lecithin, and mixtures thereof.
  • That tablet or capsule in some embodiments, may be coated with a film that includes gelatin, glycerol, titanium dioxide, and artificial colorings such as red ferric oxide, yellow ferric oxide, and inks, such as black ink.
  • Example 1 Preparation of amorphous betrixaban maleate
  • Betrixaban maleate (6 g) was dissolved in methanol (120 ml) at 60 - 65 °C. The solution was filtered to remove any undissolved particulate. The clear solution was completely distilled off under vacuum at 60 - 65 °C on a Buchi rotary evaporator resulting in a foamy solid. The solid obtained was identified as amorphous betrixaban maleate.
  • Example 2 Preparation of amorphous betrixaban maleate
  • Betrixaban maleate 100 mg was suspended in methanol (5 ml) and heated at 55 - 60 °C to obtain a clear solution. The solvent was removed completely from the resulting clear solution under vacuum using a rotary evaporator with bath temperature maintained at 45 °C. The residue obtained was then cooled to 25 - 30 °C, methyl t-butyl ether (5 ml) was added, and the mixture was stirred for 15 - 30 minutes. The mixture was filtered and the obtained solid was dried under vacuum at 35 °C for 3 hours. The solid obtained was identified as amorphous betrixaban maleate.
  • Example 3 Preparation of amorphous betrixaban maleate
  • Betrixaban maleate (3 g) was dissolved in methanol (45 ml) at 60 - 65 °C. The solution was filtered to remove any undissolved particles. The clear solution was distilled under vacuum by downward distillation at bath temperature of 60 - 65 °C to obtain a foamy solid. The temperature of the foamy solid was reduced to -20 °C and a mixture was of pre-cooled anisole (9 ml) and methyl tert-butyl ether (27 ml) was added over 10 - 15 minutes. The mixture was stirred for 1 - 2 hours at -20 °C. The reaction mass was filtered under nitrogen atmosphere and dried at 30 °C for 15 hours to yield amorphous betrixaban maleate.
  • Example 4 Preparation of an amorphous solid dispersion of betrixaban maleate with PLASDONE S-630 (50% w/w)
  • Example 5 Preparation of an amorphous solid dispersion of betrixaban maleate with PLASDONE S-630 (50% w/w)
  • Example 6 Preparation of an amorphous solid dispersion of betrixaban maleate with PLASDONE S-630 (50% w/w) Betrixaban maleate (100 mg) and PLASDONE S-630 (100 mg) were suspended in methanol (5 ml) and the suspension was heated at 50 - 55 °C to obtain clear solution. The solvent was removed completely from the resulting clear solution under vacuum using a rotary evaporator with bath temperature maintained at 45 °C. The residue obtained was cooled to 25 - 30 °C, methyl t-butyl ether (5 ml) was added, and the mixture was stirred for 15 - 30 minutes. The mixture was filtered and the obtained solid was dried under vacuum at 35 °C for 3 hours to obtain an amorphous solid dispersion of betrixaban maleate with PLASDONE S-630, which was identified as amorphous.
  • Example 7 Preparation of an amorphous solid dispersion of betrixaban maleate with Povidone K30 (50% w/w)
  • Betrixaban maleate (4 g) and Povidone K30 (PVP-K30) (4 g) were dissolved in methanol (60 ml) at 55 - 60 °C.
  • the solution was filtered through Hyflo to remove any undissolved particulate and the clear solution was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-290) with a solution feed rate of 5 ml/minutes and an inlet temperature at 75 °C to yield an amorphous solid dispersion of betrixaban maleate with Povidone K30.
  • Example 8 Preparation of an amorphous solid dispersion of betrixaban maleate with Povidone K30 (50% w/w)
  • Betrixaban maleate (100 mg) and Povidone K30 (100 mg) were suspended in methanol (5 ml) and heated at 55 - 60 °C to obtain clear solution. The solvent was removed completely from the resulting clear solution, under vacuum using a rotary evaporator with bath temperature maintained at 45 °C. The residue obtained was cooled to 25 - 30 °C, methyl t-butyl ether (5 ml) was added, and the mixture was stirred for 15 - 30 minutes. The mixture was filtered and the obtained solid was dried under vacuum at 35 °C for 3 hours to obtain an amorphous solid dispersion of betrixaban maleate with Povidone K30, which was identified as amorphous.
  • Example 9 Preparation of an amorphous solid dispersion of betrixaban maleate with HPMC (50% w/w)
  • Betrixaban (5 g) and maleic acid (2.75 g) were suspended in ethanol (115 ml) and water (28.5 ml) at 25 - 30 °C and maintained under stirring for 1 hour.
  • Tetrahydrofuran (90 ml) was added to the resulted suspension and the mixture was stirred for 30 minutes to get a clear solution.
  • the reaction mixture was then filtered to remove any dissolved particulate.
  • the clear solution was then subjected to vacuum distillation at 45 - 50 °C and concentrated to about 30 ml. Then water (9 ml) was added into the concentrated reaction mass and the solvent was again distilled off yield a volume of about 30 ml.
  • Example 12 Preparation of crystalline betrixaban maleate form-Mi Betrixaban maleate (3 g) was dissolved in methanol (45 ml) at 60 - 65 °C. The solution was filtered to remove any undissolved particles. The clear filtrate was distilled under vacuum by downward distillation at a bath temperature of 60 - 65 °C. The mixture was then cooled to -20 °C and a mixture of pre-cooled anisole (9 ml) and methyl tert-butyl ether (27 ml) was added over 10 - 15 minutes. Water (100 ⁇ ) was then added (100 ⁇ .) and the mixture was stirred for 1 - 2 hours at -20 °C. The product obtained was filtered under nitrogen atmosphere and dried at 30 °C for 15 hours to yield crystalline betrixaban maleate form-Mi.
  • Example 13 Preparation of crystalline betrixaban maleate form-Mi
  • Betrixaban maleate (3 g) was dissolved in methanol (15 ml) and tetrahydrofuran (15 ml) at 60 - 65 °C. The solution was filtered to remove any undissolved particles. The clear filtrate was distilled under vacuum at 50 - 55 °C using a rotary evaporator. The reaction mass was cooled to -20 °C and a mixture of pre-cooled anisole (15 ml) and methyl tert-butyl ether (90 ml) was added over 10 - 15 minutes maintaining the temperature at -15 - 20 °C. The mixture was stirred at same temperature for 30 minutes. Water (100 ⁇ .) was then added and the mixture was stirred for 3 hours at -20 °C. The product obtained was filtered under nitrogen atmosphere and dried at 35 °C for 20 hours to yield crystalline betrixaban maleate form-Mi.
  • Example 14 Preparation of crystalline betrixaban maleate form-M2 Betrixaban maleate (0.5 g) was dissolved in methanol (20 ml) at 55 °C then cooled to 25 - 30 °C. Cyclohexane (10 ml) was added to the clear solution. The clear solution was filtered to remove any undissolved particulate, pre-frozen to -50 °C to -60 °C, then lyophilized in a laboratory freeze dryer (Model Labocon: LFD-BT-104) with vacuum pressure below 10 Pa and a condenser temperature of -80 °C to yield crystalline betrixaban maleate form-M2.
  • Example 15 Preparation of crystalline betrixaban maleate form-M2
  • Betrixaban maleate 250 mg was dissolved in methanol (5 ml) at 60 °C. The solution was filtered at 60 °C to remove any undissolved particulate and maintained under stirring at 30 °C for 15 minutes. Cyclohexane (2.5 ml) was added to the reaction mass and which was slowly cooled to 10 - 20 °C while stirring for 15 minutes. The mixture was seeded with betrixaban maleate form-M2 (20 mg) while stirring was maintained 15 minutes. Cyclohexane (2.5 ml) was added and the solution continued to be stirred for 2 hours at 10 - 20 °C. The mixture was filtered and the solid obtained was washed with cyclohexane (1 ml) and suck-dried to yield crystalline betrixaban maleate form-M2.
  • Betrixaban maleate (5 g) was dissolved in formic acid (10 ml) at 30 - 35 °C and the solution was cooled to 0 - 5 °C.
  • Tert-butyl methyl ether 50 ml was added to the reaction mass, maintaining this temperature and stirred for 1 - 2 hours. The temperature was then raised to 20 - 25 °C and stirred for 15 hours.
  • Tert-butyl methyl ether (50 ml) was added and the reaction mixture was stirred at 20 - 25 °C for 2 hours.
  • the reaction mixture was filtered and the solid obtained was washed with tert-butyl methyl ether (10 ml) and dried under vacuum for 6 hours at 30 °C to yield crystalline betrixaban maleate form-M3.
  • Betrixaban maleate (5 g) was dissolved in formic acid (10 ml) at 25 - 30 °C. The solution was filtered to remove any undissolved particulate. The clear solution was taken into a round bottomed flask and methyl tert-butyl ether (50 ml) was slowly added under agitation over a period of 30 - 45 minutes at 25 - 30 °C then stirred at same temperature for 1 - 2 hours. A second lot of methyl tert-butyl ether (50 ml) was added to the reaction mass over a period of 30 - 45 minutes at 25 - 30 °C and the mixture was stirred for 15 hours at 25 - 30 °C.
  • Betrixaban (1.0 g) was suspended in anisole (10 ml). The reaction mixture was heated to 50 ⁇ 5 °C and the resulting suspension was maintained under stirring for 24 hours. The mixture was filtered and the obtained solid was dried under vacuum at 50 °C for 24 hours to yield crystalline betrixaban base form-M 1.
  • Betrixaban (50 mg) was suspended in acetone (5 ml). The reaction mixture was heated to 50 ⁇ 5 °C and the resulting suspension was subjected to slow evaporation at 25 ⁇ 5 °C for 24 hours. The solution was filtered and the solid obtained was suck-dried to obtained crystalline betrixaban base form-M2.
  • Betrixaban 500 mg was suspended in acetone (50 ml). The reaction mixture was heated to 50 ⁇ 5 °C and the resulting suspension was maintained under stirring at 25 ⁇ 5 °C for 16 hours. The solution was filtered and the product obtained was suck-dried to yield crystalline betrixaban base form-M3.
  • Betrixaban (50 mg) was dissolved in DMSO (1 ml) at 70 °C. The reaction mixture was cooled to 25 - 30 °C and maintained under stirring for 6 days. Water (2 ml) was added and the reaction mass was stirred at 25 - 30 °C for 3 hours. The solution was filtered and the product obtained was washed with water (5 ml) then dried under vacuum at 25 - 30 °C for 12 hours to yield amorphous betrixaban.
  • Betrixaban (100 mg) was dissolved in DMSO (2 ml) at 70 °C. The reaction mixture was cooled to 25 - 30 °C. Water (4 ml) was added and the reaction mass was stirred at 25 - 30 °C for 3 hours. The mixture was filtered and the obtained solid was dried under vacuum at 25 - 30 °C for 12 hours to yield amorphous betrixaban.

Abstract

L'invention concerne une forme polymorphe du maléate de bétrixaban et sur son procédé de préparation. L'invention concerne également une dispersion solide du polymorphe de maléate de bétrixaban avec des excipients pharmaceutiquement acceptables et leurs procédés de préparation. L'invention concerne également des formes polymorphes de base de bétrixaban et des procédés de préparation de celles-ci.
PCT/IN2017/050466 2016-10-13 2017-10-12 Polymorphes et dispersion solide de betrixaban et leurs procédés de préparation WO2018069936A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN108570003A (zh) * 2018-06-01 2018-09-25 浙江宏元药业股份有限公司 一种贝曲西班马来酸盐的一水无定形及其制备方法
EP3463352A4 (fr) * 2016-06-02 2019-10-30 Dr. Reddy S Laboratories Limited Polymorphes de betrixaban et de son sel maléate

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