WO2025224678A1

WO2025224678A1 - Solid state forms of milvexian and process for preparation thereof

Info

Publication number: WO2025224678A1
Application number: PCT/IB2025/054297
Authority: WO
Inventors: Anantha Rajmohan MUTHUSAMY; Meenakshi Sundaram SOMASUNDARAM; Chanchal Singh; Babita KAUSHIK
Original assignee: Assia Chemical Industries Ltd
Current assignee: Assia Chemical Industries Ltd
Priority date: 2024-04-25
Filing date: 2025-04-24
Publication date: 2025-10-30
Anticipated expiration: 2026-10-25

Abstract

The present disclosure relates to Milvexian solid state forms, in embodiments crystalline polymorphs of Milvexian, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Description

SOLID STATE FORMS OF MILVEXIAN AND PROCESS FOR PREPARATION THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, Indian Provisional Patent Application No. 202411032896 filed on April 25, 2024, and Indian Provisional Patent Application No. 202411069962 filed on September 16, 2024. The entire disclosures of the foregoing applications are incorporated by reference herein.

FIELD OF THE DISCLOSURE

[0002] The present disclosure encompasses solid state forms of Milvexian, in embodiments crystalline polymorphs of Milvexian, processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0003] Milvexian, (6R, 105)- 10-[4-[5-chloro-2-(4-chloro- 1 H- 1 ,2,3 -triazol- 1 -yl)phenyl]-6- oxo- 1 (6J7)-pyrimidinyl]- 1 -(difluoromethyl)- 1 ,4,7, 8,9, 10-hexahydro-6-methyl- 11,15- Metheno-15J/-pyrazolo[4,3-Z>][l,7]diazacyclotetradecin-5(6J7)-one, has the following structure:

[0004] Milvexian is a Factor Xia inhibitor developed for the prevention of blood clots in patients undergoing surgery and for the prevention of stroke. Milvexian is also investigated for the treatment or prevention of thromoboembolic disorders, and is also under clinical investigation for the treatment or prevention of acute coronary syndrome and atrial fibrillation. [0005] The compound is described in International Publication Nos. WO 2015116886 and WO 2016053455. International Publication No. WO 2020210629 describes an amorphous solid dispersion composition of Milvexian in one or more polymers. International Publication No. WO 2021207659 describes crystalline forms of Milvexian. International Publication No. WO 2022081473 describes a synthetic process for preparation of Milvexian and an acetone solvate thereof.

[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (¹³C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0007] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0008] Discovering new salts, solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemi cal/phy si cal stability). For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Milvexian and of Milvexian. SUMMARY OF THE DISCLOSURE

[0009] The present disclosure provides crystalline polymorphs of Milvexian, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Milvexian, other Milvexian salts and cocrystals and their solid state forms.

[0010] The present disclosure also provides uses of the said solid state forms of Milvexian in the preparation of other solid state forms of Milvexian, Milvexian or other salts or co-crystals and their solid state forms thereof.

[0011] The present disclosure provides crystalline polymorphs of Milvexian for use in medicine, including for the prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation.

[0012] The present disclosure also encompasses the use of crystalline polymorphs of Milvexian of the present disclosure for the preparation of pharmaceutical compositions and/or formulations, particularly pharmaceutical compositions or formulations for oral administration. [0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Milvexian according to the present disclosure. Pharmaceutical compositions according to any aspect of the present disclosure may include oral dosage forms.

[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Milvexian with at least one pharmaceutically acceptable excipient. Particularly, the pharmaceutical compositions may comprise pharmaceutically acceptable excipient suitable for preparing an oral dosage form.

[0015] The crystalline polymorph of Milvexian as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Milvexian may be used as medicaments, such as for prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation.

[0016] The present disclosure also provides methods of prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Milvexian of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject in need for prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation, or otherwise in need of the treatment.

[0017] The present disclosure also provides uses of crystalline polymorphs of Milvexian of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., for prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation. The medicament may be administered as an oral dosage form.

[0018] According to any aspect or embodiment of the present disclosure, pharmaceutical compositions or formulations for the prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation, are preferably in the form of oral dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of crystalline Milvexian form Ml.

[0020] Figure 2 shows a characteristic XRPD of crystalline Milvexian form M2.

[0021] Figure 3 shows a characteristic XRPD of crystalline Milvexian form M3.

[0022] Figure 4 shows a characteristic XRPD of crystalline Milvexian form M4.

[0023] Figure 5 shows a characteristic XRPD of crystalline Milvexian form M5.

[0024] Figure 6 shows a characteristic XRPD of crystalline Milvexian form M6.

[0025] Figure 7 shows a characteristic XRPD of crystalline Milvexian form M7.

[0026] Figure 8 shows a characteristic XRPD of crystalline Milvexian form M8.

[0027] Figure 9 shows a characteristic XRPD of crystalline Milvexian form M9.

[0028] Figure 10 shows a characteristic XRPD of crystalline Milvexian form M10.

[0029] Figure 11 shows a characteristic XRPD of crystalline Milvexian form Ml 1.

[0030] Figure 12 shows a characteristic XRPD of crystalline Milvexian form M12.

[0031] Figure 13 shows a characteristic XRPD of crystalline Milvexian form Ml 3.

[0032] Figure 14 shows a characteristic XRPD of crystalline Milvexian form M14.

[0033] Figure 15 shows a characteristic XRPD of crystalline Milvexian form Ml 5.

[0034] Figure 16 shows a characteristic XRPD of crystalline Milvexian form Ml 6. [0035] Figure 17 shows a characteristic XRPD of crystalline Milvexian form Ml 7.

[0036] Figure 18 shows a characteristic XRPD of crystalline Milvexian form Ml 8.

[0037] Figure 19 shows a characteristic XRPD of crystalline Milvexian form Ml 9.

[0038] Figure 20 shows a characteristic XRPD of crystalline Milvexian form M20.

[0039] Figure 21 shows a XRPD of crystalline Milvexian form B, according to International Publication No. WO 2021207659.

[0040] Figure 22 shows a XRPD of crystalline Milvexian acetone solvate, according to International Publication No. WO 2022081473.

[0041] Figure 23a shows a solid state ¹³C NMR spectrum of crystalline Milvexian form Ml (full scan).

[0042] Figure 23b shows a solid state ¹³C NMR spectrum of crystalline Milvexian form Ml (0-100 ppm).

[0043] Figure 23c shows a solid state ¹³C NMR spectrum of crystalline Milvexian form Ml (100-250 ppm).

DETAILED DESCRIPTION OF THE DISCLOSURE

[0044] The present disclosure encompasses solid state forms of Milvexian, including crystalline polymorphs of Milvexian, processes for preparation thereof, and pharmaceutical compositions thereof.

[0045] Solid state properties of Milvexian and crystalline polymorphs thereof can be influenced by controlling the conditions under which Milvexian and crystalline polymorphs thereof are obtained in solid form.

[0046] The solid-state form may be referred to herein as “Milvexian Form Name” or “Crystalline Form Name of Milvexian” or “Crystalline Milvexian Form Name” or “Crystalline polymorph Name of Milvexian” or “Crystalline Milvexian polymorph Name” or “Milvexian polymorph Name” . For example, crystalline Form Ml of Milvexian may be interchangeably referred to herein as Milvexian Form Ml or as Crystalline Milvexian Form Ml or as Crystalline polymorph Ml of Milvexian or as Crystalline Milvexian polymorph Ml or Milvexian polymorph Ml.

[0047] A solid-state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Milvexian or of Milvexian complexes described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Milvexian or of Milvexian complexes. In some embodiments of the disclosure, the described crystalline polymorph of Milvexian or of Milvexian complexes may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Milvexian or of Milvexian complexes.

[0048] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein in this context, the expression “substantially free of any other compounds” will be understood to mean that the pure compound contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other compound as measured, for example, by HPLC. Thus, pure or purified Milvexian or of Milvexian salt, such as Milvexian described herein as substantially free of any compounds would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject Milvexian or of Milvexian salt, such as Milvexian. In some embodiments of the disclosure, the described pure or purified Milvexian or of Milvexian salt, such as Milvexian may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other compounds.

[0049] In specific embodiments, the above described pure or purified Milvexian may relate to enantiomeric purity, i.e. pure or purified Milvexian refers to Milvexian that is substantially free of enantiomers of Milvexian.

[0050] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Milvexian of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density. [0051] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Milvexian referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Milvexian or of Milvexian salt, such as Milvexian, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0052] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Milvexian or of Milvexian salt, such as Milvexian, relates to a crystalline form of Milvexian or Milvexian, which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, unless otherwise indicated, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.

[0053] The term “solvate,” as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a “hydrate.” The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0054] Co-Crystal” or “Co-crystal” as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. In some embodiments, the co-crystal includes two molecules which are in natural state. [0055] As used herein, the term “isolated” in reference to crystalline polymorph of Milvexian of the present disclosure corresponds to a crystalline polymorph of Milvexian or of Milvexian complex that is physically separated from the reaction mixture in which it is formed. [0056] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.54187 A . XRPD peaks reported herein are measured using CuK a radiation, = 1.54187 A, typically at a temperature of 25 ± 3 °C.

[0057] As used herein, unless stated otherwise, ^l3C ,\ MR reported herein are measured at 280 K ± 3 K at a magic angle spinning frequency ror/2rc ^:=: 11 kHz, preferably at a temperature of at 280 K ± 3 K. Preferably, the ¹³C scale is referenced to a-glycine (176.03 ppm for ¹³C).

[0058] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.

[0059] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term “N/N” may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0060] A process or step may be referred to herein as being carried out “overnight ” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0061] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0062] As used herein and unless indicated otherwise, the term “ambient conditions” refer to atmospheric pressure and a temperature of 22-24 °C [0063] As used herein and unless indicated otherwise, the term Crystalline Milvexian Form B refers to Crystalline Milvexian Form B as described in WO 2021207659. Specifically, Crystalline Milvexian Form B can be characterized by a group of characteristic peaks from the list: 5.3±0.2, 9.0±0.2, 9.5±0.2, 10.6±0.2, 11.2±0.2, 13.9±0.2, 14.4±0.2, 14.7±0.2, 16.0±0.2, 16.8±0.2, 17.4±0.2, 18.3±0.2, 19.3±0.2, 20.2±0.2, 20.9±0.2, 21.3±0.2, 23.0±0.2, 23.8±0.2, 25.8±0.2, and 26.1±0.2 degrees 2-theta; or by an XRPD pattern substantially as depicted in Figure 5A of WO 2021207659 (reproduced here as Figure 21).

[0064] As used herein and unless indicated otherwise, the term Crystalline Milvexian acetone solvate refers to Crystalline Milvexian acetone solvate as described in WO 2022081473. Specifically, Crystalline acetone solvate can be characterized by a group of characteristic peaks from the list: 20.0 ± 0.2, 21.3 ± 0.2, 21.6 ± 0.2, and 23.9 ± 0.2. degrees 2- theta; or by an XRPD pattern substantially as depicted in Figure 1 of WO 2022081473 (reproduced here as Figure 22).

[0065] The present disclosure includes a crystalline polymorph of Milvexian, designated Form Ml. Crystalline Form Ml may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 9.2, 12.3, 13.3, 16.6 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 1; or by a solid state ¹³C NMR spectrum having peaks at about 17.8, 32.9, 52.7, 115.4, 150.0, and 171.3 ppm ± 0.2 ppm; or by a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from a peak at 58.4 ppm ± 2 ppm: 40.6, 25.5, 5.7, 57, 91.6, and 112.9 ppm ± 0.1 ppm; or by a solid state ¹³C NMR spectrum having chemical shift difference from a peak at 17.8 ppm ± 1 ppm of 40.6 ppm ± 0.1 ppm; or by a solid state ¹³C NMR spectrum as depicted in any one of Figures 23a 23b or 23c; or by combinations thereof. Crystalline Form Ml may be further by an XRPD pattern having characteristic peaks at 9.2, 12.3, 13.3, 16.6 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 18.6, 19.6, 20.0 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0066] Crystalline Form Ml may be described by an XRPD pattern having characteristic peaks at 9.2, 12.3, 13.3, 16.6, 18.6, 19.6, 20.0, 22.2 and 23.5 degrees 2-theta ± 0.2 degrees 2- theta.

[0067] Crystalline Form Ml according to any aspect or embodiment may be described by an XRPD pattern having characteristic peaks at 4.5, 7.3, 9.2, 10.1, 10.9, 12.0, 12.3, 13.3, 13.9,

14.3, 14.7, 15.1, 15.3, 16.6, 17.3, 17.6, 18.6, 19.6, 20.0, 20.6, 21.4, 22.2, 23.0, 23.5, 24.5, 25.8,

28.4, 29.9 and 30.6 degrees 2-theta ± 0.2 degrees 2-theta. [0068] According to any aspect or embodiment, crystalline Form Ml of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta. Alternatively, crystalline Form Ml of Milvexian may be characterized by an XRPD pattern having the characteristic XRPD peaks as described in any aspect or embodiment herein, and wherein the XRPD pattern also has an absence of peaks at 5.0 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, according to any aspect or embodiment, crystalline Form Ml of Milvexian characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and further characterized by an XRPD pattern having an absence of peaks at any one, two, or three of the following options (a), (b) and (c): (a) either: (i) 5.0 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta, or (ii) 5.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta; (b) 7.8 to 8.0 degrees 2-theta ± 0.2 degrees 2- theta; and (c) 15.8 to 16.1 degrees 2-theta ± 0.2 degrees 2-theta. Thus, according to any aspect or embodiment, crystalline Form Ml of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a-i) alone, or (a-ii) alone; or (b) alone; or (c) alone; or (a-i) and (b) in combination; or (a-ii) and (b) in combination; or (a-i) and (c) in combination, or (a-ii) and (c) in combination; or (a- i), (b) and (c) in combination; or (a-ii), (b) and (c) in combination.

[0069] According to any aspect or embodiment of the present disclosure, crystalline Form Ml of Milvexian is preferably isolated.

[0070] In certain embodiments, Crystalline Form Ml of Milvexian may be an anhydrous form.

[0071] Crystalline Form Ml of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.2, 12.3, 13.3, 16.6 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0072] According to any aspect or embodiment of the disclosure, crystalline Form Ml of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[0073] Depending on which other crystalline polymorphs a comparison is made, the crystalline Milvexian form Ml of the present disclosure may have advantageous properties as described above. Particularly, crystalline form Ml of Milvexian stable under various stress conditions, such as heating to a temperature of up to about 100 °C, exposure to a relative humidity of from about 20% to about 100% for a period of at least about 7 days, dry grinding and solvent drop grinding using water, ethanol or isopropanol.

[0074] In addition, form Ml has advantageous solubility for example when compared to other known forms, such as amorphous form, acetone solvate form and form B.

[0075] The present disclosure comprises a process for preparing crystalline Milvexian form Ml.

[0076] In one embodiment, the present disclosure comprises a process for preparing crystalline Milvexian form Ml comprising crystallizing Milvexian form Ml from a solution comprising Dimethylformamide (“DMF”) and n-heptane. Specifically, the process includes dissolving Milvexian in DMF, and maintaining the obtained solution in an atmosphere of n- heptane. First, Milvexian is dissolved in DMF, and to aid dissolution it can be done while heating, for example to a temperature of from about 55 °C to about 65 °C, particularly 60 °C. After complete dissolution, the solution can be cooled, for example to room temperature. The cooled solution is than maintained under n-heptane vapor diffusion, for example by maintaining the solution in a closed container which contains n-heptane; until crystalline form is obtained. The solid may be isolated, for example by filtration, and optionally dried, for example, under vacuum (e.g. using a vacuum tray dryer), optionally at about 30 °C to about 60 °C, about 45 °C to about 55 °C or about 50 °C. The drying may be carried out for any suitable period of time, such as about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 3 hours, or about 2 hours.

[0077] In another embodiment, the present disclosure comprises a further process for preparing crystalline Milvexian form Ml comprising crystallizing Milvexian form Ml from acetonitrile. Specifically, the process includes dissolving Milvexian in acetonitrile, and adding a seed of crystalline Milvexian form Ml . First, Milvexian is dissolved in acetonitrile, and to aid dissolution it can be done while heating, for example to a temperature of about from 35 °C to about 45 °C, particularly 40 °C. After complete dissolution, the solution can be cooled, for example to a temperature of from about 0 °C to about 5 °C. Then, a seed of crystalline Milvexian form Ml may be added to the cooled solution and the solution is maintained until crystallization occurs and a solid is formed. The mixture may be optionally stirred at a temperature of from about 0 °C to about 5 °C for a period of time, for example from 30 minutes to about 6 hours, or about 1 hour to about 3 hours, or about 2 hours. The obtained crystalline form can then be filtered and dried, for example by vacuum tray dryer, at temperature of from about 55 °C to about 65 °C, particularly 60 °C, for sufficient amount of time. [0078] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M2. Crystalline Form M2 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 8.2, 10.1, 17.5, 20.1 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 2; or by combinations thereof. Crystalline Form M2 may be further by an XRPD pattern having characteristic peaks at 8.2, 10.1, 17.5, 20.1 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 7.2, 18.6, 19.5 and 24.0 degrees 2- theta ± 0.2 degrees 2-theta.

[0079] Crystalline Form M2 may be described by an XRPD pattern having characteristic peaks at 7.2, 8.2, 10.1, 17.5, 18.6, 19.5, 20.1, 21.4 and 24.0 degrees 2-theta ± 0.2 degrees 2- theta.

[0080] According to any aspect or embodiment, crystalline Form M2 of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta. According to any aspect or embodiment, crystalline Form M2 of Milvexian may be characterized by an XRPD pattern having the characteristic XRPD peaks as described in any aspect or embodiment herein, and wherein the XRPD pattern also has an absence of peaks at: 4.0 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks in the area from 5.5 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, crystalline Form M2 of Milvexian may be characterized by an XRPD pattern having the characteristic XRPD peaks as described in any aspect or embodiment herein, and wherein the XRPD pattern also has an absence of peaks at 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0081] According to any aspect or embodiment, crystalline Form M2 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 8.7 to 9.1 degrees 2-theta ± 0.2 degrees 2-theta. Optionally, according to any aspect or embodiment, crystalline Form M2 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any embodiment herein, and wherein the XRPD pattern also has an absence of peaks: at 5.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta and at 8.7 to 9.4 degrees 2-theta ± 0.2 degrees 2-theta.

[0082] Thus, crystalline Form M2 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at any one, two or three of options (a), (b) or (c): (a) 4.0 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta; (b) one of: (i) 5.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, or (ii) at 5.5 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta; and (c) 8.7 to 9.1 degrees 2-theta ± 0.2 degrees 2-theta. Thus, according to any aspect or embodiment, crystalline Form M2 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a) alone; or (b-i) alone; or (b-ii) alone, or (c) alone; or (a) and (b-i) in combination; or (a) and (b-ii) in combination; or (a) and (c) in combination, or (b-i) and (c) in combination; or (b-ii) and (c) in combination; or (a), (b-i) and (c) in combination; or (a), (b-ii) and (c) in combination.

[0083] According to any aspect or embodiment of the present disclosure, crystalline Form M2 of Milvexian is preferably isolated.

[0084] In certain embodiments, Crystalline Form M2 of Milvexian may be an isopropanol solvate.

[0085] Crystalline Form M2 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.2, 10.1, 17.5, 20.1 and 21.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0086] According to any aspect or embodiment of the disclosure, crystalline Form M2 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[0087] Crystalline Form M2 of Milvexian may be prepared by stirring Milvexian (preferably Form Ml) in isopropyl alcohol. The mixture may be stirred at room temperature for a suitable period of time (preferably about 8 hours to about 72 hours, about 12 hours to about 48 hours, about 20 hours to about 36 hours, or about 24 hours). The solid may be isolated, for example by filtration, and optionally dried, for example, under vacuum, preferably at a temperature of: about 20 °C to about 50 °C, about 25 °C to about 40 °C, or about 30 °C, for a suitable period of time (particularly about 10 to about 60 minutes, or about 20 to about 30 minutes). The solid may be further dried, preferably under vacuum (e.g. using a vacuum tray dryer), optionally at about 30 °C to about 60 °C, about 45 °C to about 55 °C or about 50 °C. The drying may be carried out for any suitable period of time, such as about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 3 hours, or about 2 hours.

[0088] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M3. Crystalline Form M3 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.8, 14.8, 18.2, 19.6, and 20.8 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 3; or by combinations thereof. Crystalline Form M3 may be further by an XRPD pattern having characteristic peaks at 7.8, 14.8, 18.2, 19.6, and 20.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 6.7, 17.0, 21.8 and 23.3 degrees 2- theta ± 0.2 degrees 2-theta.

[0089] Crystalline Form M3 may be described by an XRPD pattern having characteristic peaks at 6.7, 7.8, 14.8, 17.0, 18.2, 19.6, 20.8, 21.8, 23.3 and 24.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0090] According to any aspect or embodiment, crystalline Form M3 of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta.

[0091] According to any aspect or embodiment of the present disclosure, crystalline Form M3 of Milvexian is preferably isolated.

[0092] In certain embodiments, Crystalline Form M3 of Milvexian may be a 1,2- Dimethoxy ethane solvate hydrate.

[0093] Crystalline Form M3 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.8, 14.8, 18.2, 19.6, and 20.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0094] According to any aspect or embodiment of the disclosure, crystalline Form M3 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[0095] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M4. Crystalline Form M4 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 8.0, 17.1, 20.5, 21.1 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 4; or by combinations thereof. Crystalline Form M4 may be further by an XRPD pattern having characteristic peaks at 8.0, 17.1, 20.5, 21.1 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 9.9, 23.5, 25.0 and 30.4 degrees 2- theta ± 0.2 degrees 2-theta.

[0096] Crystalline Form M4 may be described by an XRPD pattern having characteristic peaks at 8.0, 9.9, 17.1, 20.5, 21.1, 23.5, 25.0, 26.5 and 30.4 degrees 2-theta ± 0.2 degrees 2- theta. [0097] According to any aspect or embodiment, crystalline Form M4 of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta.

[0098] According to any aspect or embodiment of the present disclosure, crystalline Form M4 of Milvexian is preferably isolated.

[0099] In certain embodiments, Crystalline Form M4 of Milvexian may be an anisole solvate.

[00100] Crystalline Form M4 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.0, 17.1, 20.5, 21.1 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.

[00101] According to any aspect or embodiment of the disclosure, crystalline Form M4 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00102] Crystalline Form M4 of Milvexian may be prepared by a process comprising crystallizing Milvexian (preferably Milvexian Form Ml as described in any aspect or embodiment herein) from anisole. The process may comprise stirring Milvexian (preferably Form Ml) in anisole for a suitable period of time, and optionally isolating and optionally drying the resulting product. Preferably a mixture of Milvexian in anisole may be stirred at about room temperature, optionally for a period of about 2 to about 60 hours, or about 8 to about 45 hours, or about 12 to about 36 hours, or about 18 to about 30 hours, or about 24 hours. The solid may be isolated, for example by filtration, and optionally dried, for example, under vacuum (e.g. using a vacuum tray dryer), optionally at about 30 °C to about 60 °C, about 45 °C to about 55 °C or about 50 °C. The drying may be carried out for any suitable period of time, such as about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 3 hours, or about 2 hours.

[00103] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M5. Crystalline Form M5 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 8.0, 16.1, 20.0, 23.8, and 26.4 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 5; or by combinations thereof. Crystalline Form M5 may be further by an XRPD pattern having characteristic peaks at 8.0, 16.1, 20.0, 23.8, and 26.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 17.2, 18.3, 19.3 and 21.0 degrees 2- theta ± 0.2 degrees 2-theta.

[00104] Crystalline Form M5 may be described by an XRPD pattern having characteristic peaks at 8.0, 16.1, 17.2, 18.3, 19.3, 20.0, 21.0, 23.8, and 26.4 degrees 2-theta ± 0.2 degrees 2- theta.

[00105] According to any aspect or embodiment, crystalline Form M5 of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta.

[00106] According to any aspect or embodiment of the present disclosure, crystalline Form M5 of Milvexian is preferably isolated.

[00107] In certain embodiments, Crystalline Form M5 of Milvexian may be an ethyl acetate solvate.

[00108] Crystalline Form M5 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.0, 16.1, 20.0, 23.8, and 26.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5, and combinations thereof.

[00109] According to any aspect or embodiment of the disclosure, crystalline Form M5 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00110] Crystalline Form M5 of Milvexian may be prepared by a process comprising crystallisation of Milvexian from ethyl acetate. The process may comprise obtaining a solution of Milvexian in ethyl acetate, optionally with heating (for example to a temperature of about 40 °C to about 70 °C, about 55 °C to about 65 °C, or preferably about 60 °C). The heated solution may be cooled (for example to about 40 °C to about 60 °C, or about 45 °C to about 55 °C, or preferably about 50 °C). The mixture may be subjected to cooling-heating cycles, wherein the cooling is to about -40 °C to about -10 °C, or about -40 °C to about -20 °C, or preferably about -30 °C), and wherein the heating is to about 40 °C to about 60 °C, or about 45 °C to about 55 °C, or preferably about 50 °C). The cooling-heating cycles may be carried out a number of times (e.g. 3, 4, 5, 6, 7 or 8 times, or 4 to 6 times, or preferably 5 times). At each cooling and heating step, the mixture may be held at the cooling or heating temperature for about 30 minutes to about 2 hours, or about 45 minutes to about 1.5 hours, or preferably about 1 hour). The cooling rate may about 1 °C/min to about 5 °C/min. about 1 °C/min to about 3 °C/min, or preferably about 2 °C/min). The heating rate may about 1 °C/min to about 5 °C/min. about 1 °C/min to about 3 °C/min, or preferably about 2 °C/min). Preferably, the cooling cycle is to a temperature of about -30 °C and held for about 1 hour, and the heating cycle is to about 50 °C and held for about 1 hour, and the cooling-heating cycle is carried out 5 times. The resulting mixture is brought to about room temperature and the solid is preferably isolated, preferably by filtration. The solid is preferably dried under vacuum (e.g. using a vacuum tray dryer), optionally at about 30 °C to about 60 °C, about 45 °C to about 55 °C or about 50 °C. The drying may be carried out for any suitable period of time, such as about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 3 hours, or about 2 hours.

[00111] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M6. Crystalline Form M6 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.8, 9.7, 19.8, 20.6 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 6; or by combinations thereof. Crystalline Form M6 may be further characterized by an XRPD pattern having characteristic peaks at 7.8, 9.7, 19.8, 20.6 and 26.0 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three or four additional peaks at 6.9, 15.7, 19.3 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta.

[00112] Crystalline Form M6 may be described by an XRPD pattern having characteristic peaks at 6.9, 7.8, 9.7, 15.7, 19.3, 19.8, 20.6, 23.4 and 26.0 degrees 2-theta ± 0.2 degrees 2- theta.

[00113] According to any aspect or embodiment, crystalline Form M6 of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta, or an absence of peaks in the area from 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form M6 of Milvexian may be characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 8.3 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta. Thus, crystalline Form M6 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at one or both of options (a) and (b): (a) one of (i) 5.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, or 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta; and (b) 8.3 to 9.2 degrees 2-theta ± 0.2 degrees 2-theta. Thus, according to any aspect or embodiment, crystalline Form M6 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a-i) alone; (a-ii) alone; or (b) alone; or (a-i) and (b) in combination; or (a-ii) and (b) in combination.

[00114] According to any aspect or embodiment of the present disclosure, crystalline Form M6 of Milvexian is preferably isolated.

[00115] In certain embodiments, Crystalline Form M6 of Milvexian may be an Isopropyl acetate solvate.

[00116] Crystalline Form M6 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.8, 9.7, 19.8, 20.6 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.

[00117] According to any aspect or embodiment of the disclosure, crystalline Form M6 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00118] Crystalline Form M6 of Milvexian may be prepared by a process comprising crystallising Milvexian (preferably Milvexian Form Ml as described in any aspect or embodiment herein) from isopropyl acetate. The process may comprise stirring Milvexian (preferably Form Ml) in isopropyl acetate for a suitable period of time, and optionally isolating and optionally drying the resulting product. Preferably a mixture of Milvexian in anisole may be stirred at about room temperature, optionally for a period of about 2 to about 60 hours, or about 8 to about 45 hours, or about 12 to about 36 hours, or about 18 to about 30 hours, or about 24 hours. The solid may be isolated, for example by filtration, and optionally dried, for example, under vacuum (e.g. using a vacuum tray dryer), optionally at about 30 °C to about 60 °C, about 45 °C to about 55 °C or about 50 °C. The drying may be carried out for any suitable period of time, such as about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 3 hours, or about 2 hours.

[00119] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M7. Crystalline Form M7 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.9, 9.7, 18.0, 19.4, and 20.4 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure7; or by combinations thereof. Crystalline Form M7 may be further by an XRPD pattern having characteristic peaks at 7.9, 9.7, 18.0, 19.4, and 20.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 6.9, 14.8, 15.7 and 23.6 degrees 2-theta ± 0.2 degrees 2- theta. [00120] Crystalline Form M7 may be described by an XRPD pattern having characteristic peaks at 6.9, 7.9, 9.7, 14.8, 15.7, 18.0, 19.4, 20.4 and 23.6 degrees 2-theta ± 0.2 degrees 2- theta.

[00121] According to any aspect or embodiment, crystalline Form M7 of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta.

[00122] According to any aspect or embodiment of the present disclosure, crystalline Form M7 of Milvexian is preferably isolated.

[00123] In certain embodiments, Crystalline Form M7 of Milvexian may be a t-butyl acetate solvate.

[00124] Crystalline Form M7 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.9, 9.7, 18.0, 19.4, and 20.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7, and combinations thereof.

[00125] According to any aspect or embodiment of the disclosure, crystalline Form M7 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00126] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M8. Crystalline Form M8 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 9.5, 11.3, 17.5, 18.5 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 8; or by combinations thereof. Crystalline Form M8 may be further by an XRPD pattern having characteristic peaks at 9.5, 11.3, 17.5, 18.5 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks at 21.6, 24.3 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00127] Crystalline Form M8 may be described by an XRPD pattern having characteristic peaks at 9.5, 11.3, 17.5, 18.5, 21.6, 23.7, 24.3 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00128] According to any aspect or embodiment, crystalline Form M8 of Milvexian may be further characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at the area from 5.0 to 6.5 degrees 2- theta ± 0.2 degrees 2-theta, or an absence of peaks in the area from 5.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta. [00129] According to any aspect or embodiment of the present disclosure, crystalline Form M8 of Milvexian is preferably isolated.

[00130] In certain embodiments, Crystalline Form M8 of Milvexian may be a solvate- hydrate form, particularly a dimethyl carbonate solvate-hydrate form. In specific embodiments, Crystalline Form M8 of Milvexian may be a dimethyl carbonate monosolvate-monohydrate form.

[00131] Crystalline Form M8 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.5, 11.3, 17.5, 18.5 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 8, and combinations thereof.

[00132] According to any aspect or embodiment of the disclosure, crystalline Form M8 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00133] Crystalline Milvexian form M8 may be prepared by a process comprising crystallizing Milvexian from a solution comprising dimethylcarbonate (“DMC”) and n- heptane. Preferably, the process comprises maintaining a solution of Milvexian in DMC in an atmosphere of n-heptane. Particularly, Milvexian may be is dissolved in DMC, optionally with heating (optionally to a temperature of from about 55 °C to about 65 °C, particularly 60 °C), to aid dissolution. The solution may be cooled, for example to room temperature. The cooled solution may be maintained under n-heptane vapor diffusion, for example by maintaining the solution in a closed container which contains n-heptane; until crystalline form is obtained. The solid may be isolated, for example by filtration, and optionally dried, for example, under vacuum (e.g. using a vacuum tray dryer), optionally at about 30 °C to about 60 °C, about 45 °C to about 55 °C or about 50 °C. The drying may be carried out for any suitable period of time, such as about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 3 hours, or about 2 hours.

[00134] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M9. Crystalline Form M9 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.3, 15.6, 18.3, 19.7 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 9; or by combinations thereof. Crystalline Form M9 may be further by an XRPD pattern having characteristic peaks at 7.3, 15.6, 18.3, 19.7 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 10.6, 17.3 and 25.6 degrees 2-theta ± 0.2 degrees 2-theta. [00135] Crystalline Form M9 may be described by an XRPD pattern having characteristic peaks at 7.3, 10.6, 15.6, 17.3, 18.3, 19.7, 25.6 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00136] According to any aspect or embodiment, crystalline Form M9 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has: an absence of peaks at 4.0 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta, or an absence of peaks in the area from 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta. According to any aspect or embodiment, crystalline Form M9 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 16.1 to 16.8 degrees 2-theta ± 0.2 degrees 2-theta. Thus, crystalline Form M9 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at one or both of options (a) and (b): (a) one of (i) 4.0 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta, or (ii) 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, and (b) 16.1 to 16.8 degrees 2-theta ± 0.2 degrees 2-theta. Thus, according to any aspect or embodiment, crystalline Form M9 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a-i) alone; or (a-ii) alone; or (a-i) and (b) in combination; or (a-ii) and (b) in combination.

[00137] According to any aspect or embodiment of the present disclosure, crystalline Form M9 of Milvexian is preferably isolated.

[00138] In certain embodiments, Crystalline Form M9 of Milvexian may be a solvate form, particularly a dimethyl carbonate solvate form. In specific embodiments, Crystalline Form M9 of Milvexian may be a dimethyl carbonate monosolvate-monohydrate form.

[00139] Crystalline Form M9 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.3, 15.6, 18.3, 19.7 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 9, and combinations thereof.

[00140] According to any aspect or embodiment of the disclosure, crystalline Form M9 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00141] Crystalline Milvexian form M9 may be prepared by a process comprising crystallizing Milvexian from a solution comprising dimethylcarbonate (“DMC”) and water. Preferably, the process comprises maintaining a solution of Milvexian in DMC in an atmosphere of water. Particularly, Milvexian may be is dissolved in DMC, optionally with heating (optionally to a temperature of from about 55 °C to about 65 °C, particularly 60 °C), to aid dissolution. The solution may be cooled, for example to room temperature. The cooled solution may be maintained under water vapor diffusion, for example by maintaining the solution in a closed container which contains water; until crystalline form is obtained. The solid may be isolated, for example by filtration, and optionally dried, for example, under vacuum (e.g. using a vacuum tray dryer), optionally at about 30 °C to about 60 °C, about 45 °C to about 55 °C or about 50 °C. The drying may be carried out for any suitable period of time, such as about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 3 hours, or about 2 hours.

[00142] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M10. Crystalline Form M10 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.1, 17.0, 18.7, 20.8 and 24.1 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 10; or by combinations thereof. Crystalline Form M10 may be further by an XRPD pattern having characteristic peaks at 7.1, 17.0, 18.7, 20.8 and 24.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 10.4, 15.9 and 23.2 degrees 2-theta ± 0.2 degrees 2-theta.

[00143] Crystalline Form M10 may be described by an XRPD pattern having characteristic peaks at 7.1, 10.4, 15.9, 17.0, 18.7, 20.8, 23.2 and 24.1 degrees 2-theta ± 0.2 degrees 2-theta. [00144] According to any aspect or embodiment, crystalline Form M10 of Milvexian may be characterized by an XRPD pattern as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 4.0 to 5.0 degrees 2-theta ± 0.2 degrees 2-theta, or an absence of peaks at 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta.

[00145] According to any aspect or embodiment of the present disclosure, crystalline Form M10 of Milvexian is preferably isolated.

[00146] In certain embodiments, Crystalline Form M10 of Milvexian may be a solvate form, particularly a 1,4-dioxane solvate form. In specific embodiments, Crystalline Form M10 of Milvexian may be a 1,4-dioxane monosolvate form.

[00147] Crystalline Form M10 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.1, 17.0, 18.7, 20.8 and 24.1 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 10, and combinations thereof. [00148] According to any aspect or embodiment of the disclosure, crystalline Form MIO of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00149] The present disclosure includes a crystalline polymorph of Milvexian, designated Form Ml 1. Crystalline Form Ml 1 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 8.2, 10.1, 16.5, 17.6 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 11; or by combinations thereof. Crystalline Form Mi l may be further by an XRPD pattern having characteristic peaks at 8.2, 10.1, 16.5, 17.6 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 22.5, 23.9 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00150] Crystalline Form Ml 1 may be described by an XRPD pattern having characteristic peaks at 8.2, 10.1, 16.5, 17.6, 21.6, 22.5, 23.9 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00151] According to any aspect or embodiment, crystalline Form Mi l of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 4.0 to 5.5 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks in the area from 5.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta. According to any aspect or embodiment, crystalline Form Ml 1 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks: at 10.6 to 11.2 degrees 2-theta ± 0.2 degrees 2-theta, or at 12.6 to 13.4 degrees 2-theta ± 0.2 degrees 2- theta. Thus, according to any aspect or embodiment, crystalline Form Mi l of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at any one, two or three of (a), (b) and (c): (a) at one of: (i) 4.0 to 5.5 degrees 2-theta ± 0.2 degrees 2-theta, (ii) 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, or (iii) 5.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta; (b) 10.6 to 11.2 degrees 2-theta ± 0.2 degrees 2-theta, and (c) 12.6 to 13.4 degrees 2-theta ± 0.2 degrees 2-theta. Thus, according to any aspect or embodiment, crystalline Form Mi l of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a-i) alone; or (a-ii) alone; or (a-iii) alone, (b) alone, or (c) alone; or (a-i) and (b) in combination; or (a-ii) and (b) in combination; or (a-iii) and (b) in combination; or (a-i) and (c) in combination; or (a-ii) and (c) in combination; or (a-iii) and (c) in combination; or (b) and (c) in combination; or (a-i), (b) and (c) in combination; or (a-ii), (b) and (c) in combination; or (a-iii), (b) and (c) in combination.

[00152] According to any aspect or embodiment of the present disclosure, crystalline Form Ml 1 of Milvexian is preferably isolated.

[00153] In certain embodiments, Crystalline Form Mi l of Milvexian may be a dichloromethane solvate.

[00154] Crystalline Form Mi l of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.2, 10.1, 16.5, 17.6 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 11, and combinations thereof.

[00155] According to any aspect or embodiment of the disclosure, crystalline Form Ml 1 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00156] Crystalline Form Mi l of Milvexian may be prepared by distillation of a dichloromethane solution of Milvexian. Preferably, the distillation is carried out under reduced pressure, and optionally with heating (optionally to a temperature of about 40 °C to about 70 °C, about 50 °C to about 70 °C, about 55 °C to about 65 °C, or preferably about 60 °C). The distillation may be carried out for a sufficient period of time (optionally about 1 to about 8 hours, about 2 to about 6 hours, about 2 to about 5 hours, or about 4 hours).

[00157] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M12. Crystalline Form M12 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 8.5, 8.7, 17.9, 21.8 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 12; or by combinations thereof. Crystalline Form M12 may be further by an XRPD pattern having characteristic peaks at 8.5, 8.7, 17.9, 21.8 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 13.3, 16.6 and 19.9 degrees 2-theta ± 0.2 degrees 2-theta.

[00158] Crystalline Form M12 may be described by an XRPD pattern having characteristic peaks at 8.5, 8.7, 13.3, 16.6, 17.9, 19.9, 21.8 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta.

[00159] According to any aspect or embodiment of the present disclosure, crystalline Form M12 of Milvexian is preferably isolated.

[00160] In certain embodiments, Crystalline Form M12 of Milvexian may be a valerolactone solvate. [00161] Crystalline Form M12 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.5, 8.7, 17.9, 21.8 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 12, and combinations thereof.

[00162] According to any aspect or embodiment, crystalline Form M12 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 4.5 to 5.5 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 9.5 to 10.5 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 11.5 to 12.5 degrees 2-theta ± 0.2 degrees 2-theta.

[00163] According to any aspect or embodiment of the disclosure, crystalline Form M12 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00164] Crystalline Form M12 of Milvexian may be prepared by distillation of a valerolactone solution of Milvexian. Preferably, the distillation is carried out under reduced pressure, and optionally with heating (optionally to a temperature of about 40 °C to about 70 °C, about 50 °C to about 70 °C, about 55 °C to about 65 °C, or preferably about 60 °C). The distillation may be carried out for a sufficient period of time (optionally about 1 to about 8 hours, about 2 to about 6 hours, about 2 to about 5 hours, or about 4 hours).

[00165] The present disclosure includes a crystalline polymorph of Milvexian, designated Form Ml 3. Crystalline Form Ml 3 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.9 9.8, 15.9, 17.0 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 13; or by combinations thereof. Crystalline Form Ml 3 may be further by an XRPD pattern having characteristic peaks at 7.9 , 9.8, 15.9, 17.0 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 15.1, 18.1 and 28.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00166] Crystalline Form M13 may be described by an XRPD pattern having characteristic peaks at 7.9, 9.8, 15.9, 17.0 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00167] According to any aspect or embodiment of the present disclosure, crystalline Form Ml 3 of Milvexian is preferably isolated.

[00168] In certain embodiments, Crystalline Form M13 of Milvexian may be a propyl acetate solvate. [00169] Crystalline Form M13 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.9, , 9.8, 15.9, 17.0 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 13, and combinations thereof.

[00170] According to any aspect or embodiment, crystalline Form M13 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 4.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta.

[00171] According to any aspect or embodiment of the disclosure, crystalline Form M13 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00172] Crystalline form Ml 3 of Milvexian may be prepared by crystallisation of Milvexian from a mixture of propyl acetate and toluene. Preferably, toluene and a solution of Milvexian in propyl acetate are combined, more preferably the combining is by the addition of the solution of Milvexian in propyl acetate to toluene. The solution of Milvexian in propyl acetate may be prepared by dissolving Milvexian in propyl acetate with heating, preferably to a temperature of: about 40 °C to about 80 °C, about 50 °C to about 70 °C, about 55 °C to about 65 °C, or about 60 °C. The solution may be filtered prior to combining with toluene. The solution is preferably added dropwise to the toluene. Preferably the toluene is pre-cooled, more preferably to a temperature of: about -10 °C to about 10 °C, or about -5 °C to about 5 °C, or about 0 °C to about 5 °C. The resulting mixture may be stirred, optionally at room temperature, and optionally for a period of about 8 hours to about 72 hours, about 12 hours to about 48 hours, or about 24 hours. The solid may be isolated by filtration, and dried under vacuum filtration for a suitable period of time (preferably about 5 minutes to about 30 minutes or about 10 to about 15 minutes).

[00173] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M14. Crystalline Form M14 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 8.7, 11.7, 12.9, 28.3 and 30.3 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 14; or by combinations thereof. Crystalline Form M14 may be further by an XRPD pattern having characteristic peaks at 8.7, 11.7, 12.9, 28.3 and 30.3degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 15.4, 20.6 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta. [00174] Crystalline Form M14 may be described by an XRPD pattern having characteristic peaks at 8.7, 11.7, 12.9, 15.4, 20.6, 22.8 28.3 and 30.3 degrees 2-theta ± 0.2 degrees 2-theta.

[00175] According to any aspect or embodiment, crystalline Form M14 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 4.0 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta; and/or 5.5 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta.

[00176] According to any aspect or embodiment of the present disclosure, crystalline Form M14 of Milvexian is preferably isolated.

[00177] In certain embodiments, Crystalline Form M14 of Milvexian may be a nitromethane solvate.

[00178] Crystalline Form M14 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.7, 11.7, 12.9, 28.3 and 30.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 14, and combinations thereof.

[00179] According to any aspect or embodiment of the disclosure, crystalline Form M14 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00180] The present disclosure includes a crystalline polymorph of Milvexian, designated Form Ml 5. Crystalline Form Ml 5 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 8.3, 10.1, 16.6, 25.0 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 15; or by combinations thereof. Crystalline Form Ml 5 may be further by an XRPD pattern having characteristic peaks at 8.3, 10.1, 16.6, 25.0 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 29.9, 31.2 and 33.6 degrees 2-theta ± 0.2 degrees 2-theta.

[00181] Crystalline Form Ml 5 may be described by an XRPD pattern having characteristic peaks at 8.3, 10.1, 16.6, 25.0, 29.0, 29.9, 31.2 and 33.6 degrees 2-theta ± 0.2 degrees 2-theta.

[00182] According to any aspect or embodiment, crystalline Form Ml 5 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks: at 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, or at 4.2 to 5.5 degrees 2-theta ± 0.2 degrees 2-theta; and/or an absence of peaks at 10.5 to 11.5 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 12.8 to 13.5 degrees 2-theta ± 0.2 degrees 2-theta; and/or an absence of peaks at 17.9 to 18.5 degrees 2-theta ± 0.2 degrees 2-theta. Thus, crystalline Form M15 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at any one, two, three or four of options (a), (b), (c) and (d): (a) one of: (i) 4.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, or (ii) 4.2 to 5.5 degrees 2-theta ± 0.2 degrees 2-theta; (b) 10.5 to 11.5 degrees 2-theta ± 0.2 degrees 2-theta; (c) 12.8 to 13.5 degrees 2-theta ± 0.2 degrees 2-theta; and (d) 17.9 to 18.5 degrees 2-theta ± 0.2 degrees 2-theta. Thus, according to any aspect or embodiment, crystalline Form Ml 5 of Milvexian may characterized by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a-i) alone; or (a-ii) alone, or (b) alone; or (c) alone, or (d) alone; or (a-i) and (b) in combination; or (a-ii) and (b) in combination; or (a-i) and (c) in combination; or (a- ii) and (c) in combination; or (a-i) and (d) in combination; or (a-ii) and (d) in combination; or

(b) and (c) in combination; or (b) and (d) in combination; or (c) and (d) in combination; or (a- i), (b) and (c) in combination; or (a-ii), (b) and (c) in combination; or (a-i), (b) and (d) in combination; or (a-ii), (b) and (d) in combination; or (b), (c) and (d) in combination; or (a-i),

(c) and (d) in combination; or (a-ii), (c) and (d) in combination; or (a-i), (b), (c), and (d) in combination; or (a-ii), (b), (c), and (d) in combination.

[00183] According to any aspect or embodiment of the present disclosure, crystalline Form Ml 5 of Milvexian is preferably isolated.

[00184] In certain embodiments, Crystalline Form Ml 5 of Milvexian may be an acetone solvate.

[00185] Crystalline Form Ml 5 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.3, 10.1, 16.6, 25.0 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 15, and combinations thereof.

[00186] According to any aspect or embodiment of the disclosure, crystalline Form M15 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00187] Crystalline Form Ml 5 of Milvexian may be prepared by crystallization of Milvexian from acetone. Preferably the process comprises evaporation of a solution of Milvexian in acetone. Preferably the process comprises allowing a solution of Milvexian to evaporate at a temperature of: about 20 °C to about 30 °C, about 22 °C to about 28 °C, or about 25 °C, optionally for: about 10 to about 36 hours, about 18 to about 28 hours, or about 24 hours. The solid may be isolated, for example by filtration, and optionally dried, for example, under suction filtration, preferably at a temperature of about 20 °C to about 30 °C, about 22 °C to about 28 °C, or about 25 °C, for a suitable period of time (preferably about 5 to about 60 minutes, about 10 to about 40 minutes, or about 15 minutes.

[00188] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M16. Crystalline Form M16 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 3.9, 6.3, 12.5, 16.0 and 22.5 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 16; or by combinations thereof. Crystalline Form Ml 6 may be further by an XRPD pattern having characteristic peaks at 3.9, 6.3, 12.5, 16.0 and 22.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 7.4, 11.0, 18.1 and 19.0 degrees 2- theta ± 0.2 degrees 2-theta.

[00189] Crystalline Form M16 may be described by an XRPD pattern having characteristic peaks at 3.9, 6.3, 7.4, 11.0, 12.5, 16.0 18.1, 19.0 and 22.5 degrees 2-theta ± 0.2 degrees 2-theta. [00190] According to any aspect or embodiment of the present disclosure, crystalline Form Ml 6 of Milvexian is preferably isolated.

[00191] In certain embodiments, Crystalline Form M16 of Milvexian may be an acetonitrile solvate, in specific embodiments it is acetonitrile monosolvate.

[00192] Crystalline Form M16 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 3.9, 6.3, 12.5, 16.0 and 22.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 16, and combinations thereof.

[00193] According to any aspect or embodiment of the disclosure, crystalline Form M16 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00194] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M17. Crystalline Form M17 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 6.9, 17.3, 19.6, 20.9 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 17; or by combinations thereof. Crystalline Form Ml 7 may be further by an XRPD pattern having characteristic peaks at 6.9, 17.3, 19.6, 20.9 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 14.7, 18.4, 21.8 and 26.2 degrees 2- theta ± 0.2 degrees 2-theta. [00195] Crystalline Form M17 may be described by an XRPD pattern having characteristic peaks at 6.9, 14.7, 17.3, 18.4, 19.6, 20.9, 21.8, 26.2 and 26.9 degrees 2-theta ± 0.2 degrees 2- theta.

[00196] According to any aspect or embodiment of the present disclosure, crystalline Form Ml 7 of Milvexian is preferably isolated.

[00197] In certain embodiments, Crystalline Form M17 of Milvexian may be a propyl acetate hemi solvate.

[00198] Crystalline Form M17 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.9, 17.3, 19.6, 20.9 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 17, and combinations thereof.

[00199] According to any aspect or embodiment, crystalline Form M17 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at 4.0 to 4.9 degrees 2-theta ± 0.2 degrees 2-theta.

[00200] According to any aspect or embodiment of the disclosure, crystalline Form M17 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00201] Crystalline form M17 of Milvexian may be prepared by crystallization of Milvexian from a mixture of propyl acetate and propylene glycol. Preferably, propylene glycol and a solution of Milvexian in propyl acetate are combined, more preferably the combining is by the addition of the solution of Milvexian in propyl acetate to propylene glycol. The solution of Milvexian in propyl acetate may be prepared by dissolving Milvexian in propyl acetate with heating, preferably to a temperature of: about 40 °C to about 80 °C, about 50 °C to about 70 °C, about 55 °C to about 65 °C, or about 60 °C. The solution may be filtered prior to combining with toluene. The solution is preferably added dropwise to the propylene glycol. Preferably the propylene glycol is pre-cooled, more preferably to a temperature of: about -10 °C to about 10 °C, or about -5 °C to about 5 °C, or about 0 °C to about 5 °C. The resulting mixture may be stirred, optionally at room temperature, and optionally for a period of about 8 hours to about 72 hours, about 12 hours to about 48 hours, or about 24 hours. The solid may be isolated by filtration, and dried under vacuum filtration for a suitable period of time (preferably about 5 minutes to about 30 minutes or about 10 to about 15 minutes).

[00202] The present disclosure includes a crystalline polymorph of Milvexian, designated Form Ml 8. Crystalline Form Ml 8 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 7.6, 15.6, 16.6, 20.5 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 18; or by combinations thereof. Crystalline Form Ml 8 may be further by an XRPD pattern having characteristic peaks at 7.6, 15.6, 16.6, 20.5 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 9.5, 17.7 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta.

[00203] Crystalline Form Ml 8 may be described by an XRPD pattern having characteristic peaks at 7.6, 9.5, 15.6, 16.6, 17.7, 20.5, 22.9 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta.

[00204] According to any aspect or embodiment of the present disclosure, crystalline Form Ml 8 of Milvexian is preferably isolated.

[00205] In certain embodiments, Crystalline Form Ml 8 of Milvexian may be an o-xylene monosolvate hemihydrate.

[00206] Crystalline Form Ml 8 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.6, 15.6, 16.6, 20.5 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 18, and combinations thereof.

[00207] According to any aspect or embodiment of the disclosure, crystalline Form M18 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00208] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M19. Crystalline Form M19 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 5.0, 17.0, 23.5, 24.6 and 28.8 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 19; or by combinations thereof. Crystalline Form Ml 9 may be further by an XRPD pattern having characteristic peaks at 5.0, 17.0, 23.5, 24.6 and 28.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 11.5, 16.2 and 19.7 degrees 2-theta ± 0.2 degrees 2-theta.

[00209] Crystalline Form M19 may be described by an XRPD pattern having characteristic peaks at 5.0, 11.5, 16.2, 17.0, 19.7, 23.5, 24.6 and 28.8 degrees 2-theta ± 0.2 degrees 2-theta.

[00210] According to any aspect or embodiment of the present disclosure, crystalline Form Ml 9 of Milvexian is preferably isolated.

[00211] In certain embodiments, Crystalline Form M19 of Milvexian may be a diethyl ketone solvate. [00212] Crystalline Form M19 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.0, 17.0, 23.5, 24.6 and 28.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 19, and combinations thereof.

[00213] According to any aspect or embodiment of the disclosure, crystalline Form M19 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00214] The present disclosure includes a crystalline polymorph of Milvexian, designated Form M20. Crystalline Form M20 may be described by data selected from one or more of the following: an XRPD pattern having characteristic peaks at 4.7, 7.8, 12.7 and 27.4 degrees 2- theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 20; or by combinations thereof.

[00215] Crystalline Form M20 may be further characterized by an XRPD pattern having characteristic peaks at 4.7, 7.8, 12.7 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 5.6, 6.4, 10.3 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta. Alternatively, crystalline Form M20 may be characterized by an XRPD pattern having characteristic peaks at 4.7, 7.8, 12.7 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three, or four additional peaks at 5.6, 6.4, 10.3 and 19.3 degrees 2- theta ± 0.2 degrees 2-theta.

[00216] Crystalline Form M20 may be described by an XRPD pattern having characteristic peaks at 4.7, 5.6, 6.4, 7.8, 10.3 12.7, 19.3 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta.

[00217] In certain embodiments, crystalline Form M20 may be described by an XRPD pattern having characteristic peaks at 4.7, 5.6, 6.4, 7.8, 9.1, 10.3, 10.9, 12.7, 15.9, 19.3, 20.1, 21.4, 23.1, 27.4, 28.2, 29.2, 31.4, 32.2, 34.5, 36.0, 37.8 and 39.2 degrees 2-theta ± 0.2 degrees 2-theta.

[00218] According to any aspect or embodiment, crystalline Form M20 of Milvexian may be characterized by an XRPD pattern having the characteristic peaks as described in any of the embodiments herein, and wherein the XRPD pattern also has an absence of peaks at any one, two or three of options (a), (b or (c): (a) 6.9 to 7.3 degrees 2-theta ± 0.2 degrees 2-theta; (b) 14.5 to 15.1 degrees 2-theta ± 0.2 degrees 2-theta; and (c) 16.4 to 17.1 degrees 2-theta ± 0.2 degrees 2-theta. Thus, according to any aspect or embodiment, crystalline Form M20 of Milvexian may characterised by an XRPD pattern having the characteristic peaks as described in any of the above embodiments, and additionally wherein the XRPD pattern has an absence of peaks as defined in one of the following options: (a) alone; or (b) alone; or (c) alone, or (a) and (b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and (c) in combination.

[00219] According to any aspect or embodiment of the present disclosure, crystalline Form M20 of Milvexian is preferably isolated.

[00220] In certain embodiments, Crystalline Form M20 of Milvexian may be a hydrate form. In specific embodiments it is a monohydrate. Typically, the amount of water in Milvexian monohydrate form M20 is of from about 2.3% to about 3.3%, as determined for example, by KF or by TGA.

[00221] Crystalline Form M20 of Milvexian may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 4.7, 7.8, 12.7 and 27.4degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 20, and combinations thereof.

[00222] According to any aspect or embodiment of the disclosure, crystalline Form M20 of Milvexian may be polymorphically pure or may be substantially free of any other solid-state forms of Milvexian.

[00223] Crystalline form M20 of Milvexian may be prepared by crystallisation of Milvexian from a mixture of diethyl ketone and o-xylene. Preferably, o-xylene and a solution of Milvexian in diethyl ketone are combined, more preferably the combining is by the addition of o-xylene to a solution of Milvexian in diethyl ketone. The solution of Milvexian in diethyl ketone may be prepared by dissolving Milvexian in diethyl ketone with heating, preferably to a temperature of: about 40 °C to about 80 °C, about 50 °C to about 70 °C, about 55 °C to about 65 °C, or about 60 °C. The o-xylene is preferably added slowly (for example dropwise or portionwise) to the solution of Milvexian in diethyl ketone at the heated temperature. The resulting mixture may be stirred, optionally at room temperature, and optionally for a period of about 8 hours to about 72 hours, about 12 hours to about 48 hours, or about 24 hours. The stirring may be at about room temperature. The solid may be isolated by filtration, and dried under vacuum filtration for a suitable period of time (preferably about 5 minutes to about 30 minutes or about 10 to about 15 minutes).

[00224] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Milvexian, other Milvexian salts or co-crystals and their solid-state forms. Solid state forms may be crystalline polymorphs, co-crystals and complexes of Milvexian or of Milvexian salt.

[00225] The present disclosure encompasses a process for preparing other solid-state forms of Milvexian or of Milvexian salts. The process includes preparing any one of the crystalline polymorphs of Milvexian by the processes of the present disclosure. The process may further comprise converting said crystalline polymorph of Milvexian to other crystalline polymorph of Milvexian or to other Milvexian salt or co-crystal.

[00226] The present disclosure provides the above-described crystalline polymorphs of Milvexian for use in the preparation of pharmaceutical compositions comprising Milvexian or Milvexian complexes and/or crystalline polymorphs thereof.

[00227] The present disclosure also encompasses the use of crystalline polymorphs of Milvexian of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Milvexian. Particularly, the pharmaceutical compositions may be used for oral administration. The pharmaceutical compositions can be in a form of a spray-dried formulation.

[00228] The present disclosure includes processes for preparing the above-mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Milvexian of the present disclosure with at least one pharmaceutically acceptable excipient, for example spray-dried formulation with appropriate excipient/s. Particularly, the pharmaceutical compositions may comprise pharmaceutically acceptable excipient suitable for making formulations for oral administration. Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid-state forms of Milvexian or Milvexian of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes. For example, excipients may be added to assist in formation of formulation suitable for oral administration. [00229] Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[00230] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[00231] The dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[00232] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[00233] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[00234] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00235] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level. [00236] In liquid pharmaceutical compositions of the present invention, Milvexian and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[00237] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[00238] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouthfeel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[00239] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[00240] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[00241] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00242] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, intranasal and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. [00243] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00244] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.

[00245] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00246] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[00247] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00248] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00249] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00250] A pharmaceutical formulation of Milvexian can be administered. For example, it can be administrated orally. Milvexian may be formulated for administration to a mammal, in embodiments to a human. Milvexian can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent’s physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7^th ed.

[00251] The crystalline polymorphs of Milvexian and the pharmaceutical compositions and/or formulations of Milvexian of the present disclosure can be used as medicaments, in embodiments in the prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation. The medicament may preferably be administrated in oral form.

[00252] The present disclosure also provides methods of prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for the treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Milvexian of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.

[00253] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.

Powder X-ray Diffraction (“XRPD”) method

[00254] Powder X-ray Diffraction was performed on an X-Ray powder diffractometer: Bruker D8 Advance; Copper Ka radiation ( = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

[00255] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.

Measurement parameters:

Scan range: 2 - 40 degrees 2-theta;

Scan mode: continuous; Step size: 0.05 degrees;

Time per step: 0.5 s;

Sample spin: 30 rpm;

Sample holder: PMMA specimen holder ring.

Solid-state ¹³C-NMR method

[00256] The solid-state NMR spectra are measured at 11.7 T using a Bruker Avance III HD 500 US/WB NMR spectrometer (Karlsruhe, Germany, 2013) with a 4-mm probehead.

[00257] The samples (as received) were placed into the 4-mm thin-wall ZrO2 rotor. The ¹³C CP/MAS NMR spectra employing cross-polarization were acquired using the standard cross- polarization pulse scheme at spinning frequency of 11 kHz. The cross-polarization contact time was 2 ms, and the dipolar decoupling SPINAL64 was applied during the data acquisition. The spectral width was 300 ppm with the resonance offset of 100 ppm. The ¹³C scale was referenced to a-glycine (176.03 ppm for ¹³C).

[00258] The experiments were carried out with active cooling, keeping the samples at a constant temperature of 280 K ± 3 K.

EXAMPLES

Preparation of starting materials

[00259] Milvexian can be prepared according to methods known from the literature, for example International Publication Nos. WO 2015116886, WO 2016053455, WO 2020210629, WO 2021207659 and WO 2022081473.

Example 1: Preparation of Milvexian Form Ml

[00260] Milvexian (0.02g) was taken in a 1.5 mL vial and was dissolved in Dimethylformamide (0.1 ml) at temperature of about 60 °C and a clear solution was formed. The clear solution was maintained at a temperature of about 25 °C and was allowed to cool to 25 °C, over a period of about 30 minutes. The vial was put inside another 5 mL vial having 2 mL of n-heptane. The outer n-heptane vial was sealed with aluminum crimp cap with septa and maintained at temperature of about 25 °C for vapour diffusion. After 15 days, the obtained solid was filtered under suction dryer at temperature of about 25 °C for 15 minutes and was further dried under vacuum tray dryer at temperature of about 50 °C for about 2 hours. The sample was analyzed by XRPD, Form Ml was obtained. A characteristic XRPD pattern is shown in Figure 1. The obtained form Ml of this example was anhydrous form. Example 2: Preparation of Milvexian Form M2

[00261] Milvexian (Form Ml, 0.03g) was placed in a 5 mL glass vial and Isopropyl alcohol (1ml) was added, at a temperature of about 25 °C. The obtained slurry mass was stirred at temperature of about 25 °C for 24 hours. The reaction mass was filtered and dried under vacuum at a temperature of about 25-30 °C for a period of about 20-30 minutes. The obtained solid was further dried under vacuum tray dryer at a temperature of about 50 °C for about 2 hours. The obtained solid was analyzed by XRPD, Form M2 was obtained. A characteristic XRPD pattern is shown in Figure 2. The obtained Form M2 of this example was iso-propanol (“IP A”) form.

Example 3: Preparation of Milvexian Form M3

[00262] Milvexian (Form Ml, 0.1g) was placed in a 10 mL vial and dissolved in 1,2- Dimethoxyethane (0.5ml) at a temperature of about 60 °C, and a clear solution was formed. The clear solution was cooled to 25 °C over a period of about 30 minutes. Water (5ml) was added to the solution at a temperature of about 25 °C and the resulting mixture was maintained for a period of about 10-30 minutes at the same temperature. The obtained solid was filtered and suction-dried for 10-15 minutes. The solid was further dried at a temperature of about 50 °C under vacuum tray dryer for about 2 hours. The obtained dried solid was analyzed by XRPD, Form M3 was obtained. A characteristic XRPD pattern is shown in Figure 3. The obtained Form M3 of this example was 1,2-Dimethoxy ethane solvate hydrate form.

Example 4: Preparation of Milvexian Form M4

[00263] Milvexian (Form Ml, 0.03g) was placed in a 5 mL vial and anisole (1ml) was added at a temperature of about 25 °C. The obtained slurry mass was stirred at about 25 °C for a period of about 24 hours. The reaction mass was filtered and dried under vacuum at a temperature of about 25-30 °C for about 20-30 minutes. The solid was further dried under vacuum tray dryer at a temperature of about 50 °C for about 2 hours. The obtained solid was analyzed by XRPD, Form M4 was obtained. A characteristic XRPD pattern is shown in Figure 4. The obtained Form M4 of this example was anisole solvate.

Example 5: Preparation of Milvexian Form M5

[00264] Milvexian (Form Ml, 0.05g) was placed in a 5 mL glass vial and ethyl acetate (1ml) was added at a temperature of about 25 °C. The obtained reaction mixture was heated up-to a temperature of about 60 °C and a clear solution formed. Then, the solution was cooled down to about 50 °C. The clear solution was subjected to 5 cycles of cooling and heating as follows: The reaction mixture was cooled down from 50 °C to -30 °C at the rate of 2 °C per minute (total time: 40 minutes) and was maintained for about 1 hour at about -30 °C. Then the reaction mixture was heated from -30 °C to 50 °C at the rate of 2 °C per minute ramp (total time: 40 minutes) and hold at a temperature of about 50 °C for 1 Hour. After completing of the 5 cycles as described above, the final suspension was brought to a temperature of about 25 °C. The obtained solid was filtered and dried under vacuum for about 10-15 minutes at about 25 °C. The solid was further dried under vacuum tray dryer at about 50 °C for about 2 hours. The obtained solid was analyzed by XRPD, Form M5 was obtained. A characteristic XRPD pattern is shown in Figure 5. The obtained Form M5 of this example was ethyl acetate solvate.

Example 6: Preparation of Milvexian Form M6

[00265] Milvexian (Form Ml, 0.03g) was placed in a 5 mL glass vial and Isopropyl acetate (1ml) was added at a temperature of about 25 °C. The obtained slurry mass was stirred at about 25 °C for a period of about 24 hours. The reaction mass was filtered and was dried under vacuum at a temperature of about 25-30 °C for about 20-30 minutes. The solid was further dried under vacuum tray dryer at about 50 °C for about 2 hours. The solid obtained was analyzed by XRPD, Form 6 was obtained. A characteristic XRPD pattern is shown in Figure 6. The obtained Form M6 of this example was Isopropyl acetate solvate form.

Example 7: Preparation of Milvexian Form M7

[00266] Milvexian (Form Ml, 0.03g) was placed in a 5 mL glass vial tertiary butyl acetate (1 mL) at a temperature of about 25 °C. The obtained slurry mass was stirred at about 25 °C for a period of about 24 hrs. The reaction mass was filtered and dried under vacuum at a temperature of about 25-30 °C for about 20-30 minutes. The obtained solid was further dried under vacuum tray dryer at a temperature of about 50 °C for about 2 hours. The solid obtained was analyzed by XRPD, Form M7 was obtained. A characteristic XRPD pattern is shown in Figure 7. The obtained Form M7 of this example was t-butyl acetate solvate form.

Example 8: Preparation of Milvexian Form M8

[00267] Milvexian (0.02g) was placed in a 1.5 mL vial containing dimethyl carbonate (0.16 ml), and dissolved at a temperature of about 60 °C. The obtained clear solution was maintained at a temperature of about 25 °C and allowed to cool down to a temperature of about 25 °C for a period of about 30 minutes. Then the 1.5 mL vial was placed inside a 5 mL vial having 2 mL of n-heptane. The outer 5 mL vial was sealed with aluminum crimp cap and maintained at about 25 °C for vapor diffusion. After 15 days, the obtained solid was filtered under suction dryer at a temperature of about 25 °C for about 15 minutes and then it was further dried under vacuum tray dryer at about 50 °C for about 2 hours. The obtained solid was analyzed by XRD and designated as Milvexian Form M8. A characteristic XRPD pattern is shown in Figure 8. The obtained Form M8 of this example is a dimethyl carbonate monosolvate form.

Example 9: Preparation of Milvexian Form M9

[00268] Milvexian (0.02g) was placed in a 1.5 mL vial containing dimethyl carbonate (0.16ml) and dissolved at a temperature of about 60 °C. The obtained clear solution was maintained at a temperature of about 25 °C and allowed to cool down to about 25 °C for a period of about 25 minutes (and then the 1.5 mL vial was placed inside a 5 mL vial having 2 mL of water. The outer 5 mL vial was sealed with aluminum crimp cap and maintained at about 25 °C for vapor diffusion. After 15 days, the obtained solid was filtered under suction dryer at about 25 °C for about 15 minutes and then it was further dried under vacuum tray dryer at a temperature of about 50 °C for about 2 hours. The obtained solid was analyzed by XRD and designated as Milvexian Form M9. A characteristic XRPD pattern is shown in Figure 9. The obtained Form M9 of this example is a dimethyl carbonate monosolvate-monohydrate form.

Example 10: Preparation of Milvexian Form M10

[00269] Milvexian (0.02 g) was placed in a 1.5 mL vial containing 1,4-dioxane (0.5 ml) and dissolved at temperature of about 60 °C. The obtained clear solution was kept at 25 °C and allowed to cool down to 25 °C and then maintained for additional cooling at a temperature of about 0-5 °C for 1 day. After 1 days, the obtained solid was filtered under suction dryer at about 25 °C for about 15 minutes and then it was further dried under vacuum tray dryer at a temperature of about 50 °C for about 2 hours. The obtained solid was analyzed by XRD and designated as Milvexian Form M10. A characteristic XRPD pattern is shown in Figure 10. The obtained Form M10 obtained in this example is a 1,4-dioxane monosolvate.

Example 11: Preparation of Milvexian Form Mil

[00270] Milvexian (0.02 g) was placed in 5 mL glass vial containing dichloromethane (0.5 ml) and dissolved at 25 °C. The obtained clear solution was subjected to distillation under reduced pressure (below 100 mbar) at about a temperature of about 60 °C for a period of about 4 hours. The obtained solid was isolated and analyzed by XRD. The obtained solid analyzed by XRPD and designated as designated as Milvexian Form Mi l. A characteristic XRPD pattern is shown in Figure 11. The obtained Form Mi l obtained in this example is a dichloromethane solvate.

Example 12: Preparation of Milvexian Form M12

[00271] Milvexian (0.02 g) was placed in a 5 mL glass vial containing Valerolactone (0.16 ml) and dissolved at a temperature of about 25 °C. The obtained clear solution was subjected to distillation under reduced pressure (below 100 mbar) at about 60 °C for about 4 hours. The obtained solid was isolated and analyzed by XRD. The obtained solid analyzed by XRPD and designated as Milvexian Form M12. A characteristic XRPD pattern is shown in Figure 12. The obtained Form M12 obtained in this example is valerolactone solvate.

Example 13: Preparation of Milvexian Form M13

[00272] Milvexian (0.02 g) placed in 5 mL glass vial containing propyl acetate (0.5 ml) and dissolved at a temperature of about 60 °C. The obtained clear solution was filtered and added dropwise into toluene pre-cooled to a temperature of about 0 to about 5 °C and then stirred for about 1 day. After 1 day, the solid was obtained and filtered under vacuum for about 10-15 minutes. The obtained solid was isolated and analyzed by XRD. The obtained solid analyzed by XRPD and designated as Milvexian Form M13. A characteristic XRPD pattern is shown in Figure 13. The obtained Form M13 obtained in this example is a propyl acetate solvate.

Example 14: Preparation of Milvexian Form M14

[00273] Milvexian (0.02g) placed in a 5 mL vial and dissolved in nitromethane (0.33 ml) at a temperature of about 60 °C. Theo obtained clear solution was stirred for 1 day and the temperature maintained at 60 °C. After 1 day the solid was obtained and the obtained solid filtered under suction dryer at a temperature of about 25 °C for about 15 minutes. The obtained solid was analyzed by XRD and designated as Milvexian Form M14. A characteristic XRPD pattern is shown in Figure 14. The crystalline Form M14 obtained in this example is Milvexian Form M14 is a nitromethane solvate form.

Example 15: Preparation of Milvexian Form M15

[00274] Milvexian (0.02g) was placed in a 5 mL glass vial and dissolved in acetone (0.43 ml) at a temperature of about 25 °C. The obtained clear solution was left for evaporation at a temperature of about 25 °C for 1 day. After 1 day, the obtained solid was filtered under suction dryer at about 25 °C for about 15 minutes. The obtained solid analyzed by XRD and designated as Milvexian Form M15. A characteristic XRPD pattern is shown in Figure 15. The crystalline Form Ml 5 obtained in this example is acetone solvate.

Example 16: Preparation of Milvexian Form M16

[00275] Milvexian (0.02g) was placed in a 5 mL vial and dissolved in acetonitrile (0.76 ml) at a temperature of about 25 °C. The obtained clear solution was left for slow evaporation at a temperature of about 25 °C for about 1 day. After 1 day the obtained solid was filtered under suction dryer at a temperature of about 25 °C for about 15 minutes. The obtained solid analyzed by XRD and designated as Milvexian Form M16. A characteristic XRPD pattern is shown in Figure 16. The crystalline Form M16 obtained in this example is acetonitrile monosolvate.

Example 17: Preparation of Milvexian Form M17

[00276] Milvexian (0.02 g) was placed in a 5 mL glass vial and dissolved in propyl acetate (0.5 ml) at a temperature of about 60 °C. The obtained clear solution was filtered and added drop-wise into a pre cooled propylene glycol (pre-cooled to about 0 to about 5 °C) and then the clear solution was stirred for about 1 day. After 1 day a solid was obtained and filtered under vacuum for about 10-15 minutes. The obtained solid analyzed by XRPD and designated as designated as Milvexian Form M17. A characteristic XRPD pattern is shown in Figure 17. The crystalline Form M17 obtained in this example is propyl acetate hemisolvate form.

Example 18: Preparation of Milvexian Form M18

[00277] Milvexian (0.02 g) was placed in a 5 mL glass vial and dissolved in propyl acetate (0.5 ml) at a temperature of about 60 °C. The obtained clear solution was filtered and added dropwise into a pre-cooled o-xylene (pre-cooled to about 0 to about 5 °C) and the clear solution was stirred for about 1 day. After 1 day a solid was obtained and filtered under vacuum for aboutl0-15 minutes. The obtained solid was isolated and analyzed by XRD, and designated as Milvexian Form Ml 8. A characteristic XRPD pattern is shown in Figure 18. The crystalline Form Ml 8 obtained in this example is an o-xylene monosolvate hemihydrate.

Example 19: Preparation of Milvexian Form M19

[00278] Milvexian (0.02 g) was placed in a 5 mL glass vial and dissolved in diethyl ketone (0.5 ml) at a temperature of about 60 °C and a clear solution formed. Then, cyclohexane (3 ml) was added slowly to the solution at a temperature of about 60 °C. After addition of cyclohexane the reaction mass was stirred and maintained for 1 day at a temperature of about 25 °C. After 1 day a solid was obtained and filtered under vacuum for about 10-15 minutes. The obtained solid was isolated and analyzed by XRD; and designated as Milvexian Form Ml 9. A characteristic XRPD pattern is shown in Figure 19. The crystalline Form M19 obtained in this example is a diethyl ketone solvate.

Example 20: Preparation of Milvexian Form M20

[00279] Milvexian (0.02 g) was placed in a 5 mL glass vial and dissolved in diethyl ketone (0.5 ml) at a temperature of about 60 °C and a clear solution formed. Then, o-xylene (3 ml) was added slowly to the solution at a temperature of about 60 °C. After addition of o-xylene the reaction mass was stirred and maintained for 1 day at a temperature of about 25 °C. After 1 day a solid was obtained and filtered under vacuum for about 10-15 minutes. The obtained solid was isolated and analyzed by XRD, and designated as Milvexian Form M20. A characteristic XRPD pattern is shown in Figure 20. The crystalline Form M20 obtained in this example is a monohydrate.

Example 21: Preparation of Milvexian Form Ml

[00280] Milvexian (5g) was placed in a 500 ml round bottom flask containing acetonitrile (200 ml) and dissolved at a temperature of about 40 °C. The clear solution was kept at 25 °C and allowed to cool down to a temperature of about 0 °C in 1 hour. At about 0 °C a seed of crystalline form Ml was added and after 5 minutes a solid was formed. The obtained suspension maintained at a temperature of about 0 °C for a period of about 2 hours. The reaction mass was filtered and dried under vacuum at a temperature of about 25-30 °C for about 20-30 minutes. The obtained solid was further dried under air tray dryer at a temperate of about 60 °C for about 1 hour. The obtained solid was analyzed by XRD, crystalline Milvexian Form Ml obtained. The PXRD of crystalline form Ml obtained in this example is shown in Figure 21.

Example 22 - Stability Testing

Storage stability at different relative humidities

[00281] Samples of Form Ml of Milvexian were subj ected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below:

[00282] These results demonstrate that Form Ml of Milvexian is polymorphically stable after exposure to high and low relative humidity conditions for at least 7 days.

[00283] Samples of Form Ml of Milvexian were subjected to conditions of different relative humidities at different temperatures. XRPD analysis was performed on the samples after 6 months. The results are shown in Table 2 below:

Table 2 [00284] Moreover, a sample of Form Ml of Milvexian was stored at 2-8 °C for 6 months also showed no polymorphic change.

[00285] The results demonstrate that Form Ml of Milvexian is stable after exposure to high and low relative humidity at different temperatures for at least 6 months, indicating that this form has excellent storage stability.

Grinding experiments

[00286] A sample of Milvexian Form Ml was subjected to strong grinding for 2 minutes using a pestle and mortar. Samples of Milvexian Form Ml were also subjected to solvent drop grinding in water, ethanol and isopropanol. Grinding was carried out on the samples in the presence of ethanol, water or isopropanol. In these experiments, about 50-100 mg of the sample is placed in a mortar and ground with a pestle and mortar for 1 minute. The solvent, when used, as added to the crystalline material before grinding, in a volume of about 20 microlitres. XRPD analysis performed on each of the samples after the grinding experiments, confirmed no change in the starting material (Table 3):

Table 3

[00287] The results demonstrate that Form Ml of Milvexian is resistant to polymorphic changes and is highly suitable for preparing pharmaceutical formulations.

Thermal Stability

[00288] A sample of Form Ml of Milvexian was subjected to heating at 100 °C for 30 minutes in an air tray dryer (ATD). XRPD analysis of the sample confirmed no change in the starting material (Table 4):

Table 4

[00289] Accordingly, Form Ml of Milvexian is stable to high temperature, further demonstrating the stability of this solid state forms.

Claims

Claims:

1. A crystalline Milvexian form Ml, which is characterized by data selected from one or more of the following:

(a) an XRPD pattern having characteristic peaks at 9.2, 12.3, 13.3, 16.6 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta;

(b) an XRPD pattern as depicted in Figure 1;

(c) a solid state ¹³C NMR spectrum having peaks at about 17.8, 32.9, 52.7, 115.4, 150.0, and 171.3 ppm ± 0.2 ppm;

(d) a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from a peak at 58.4 ppm ± 2 ppm: 40.6, 25.5, 5.7, 57, 91.6, and 112.9 ppm ± 0.1 ppm;

(e) a solid state ¹³C NMR spectrum having chemical shift difference from a peak at 17.8 ppm ± 1 ppm of 40.6 ppm ± 0.1 ppm;

(f) a solid state ¹³C NMR spectrum as depicted in any one of Figures 23a 23b or 23c; and

(g) any combinations thereof.

2. The crystalline Milvexian form Ml according to Claim 1, which is characterised by an X-ray powder diffraction pattern having peaks at 9.2, 12.3, 13.3, 16.6 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 18.6, 19.6, 20.0 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta.

3. The crystalline Milvexian form Ml according to Claim 1 or Claim 2, which is characterized by an XRPD pattern having characteristic peaks at 9.2, 12.3, 13.3, 16.6, 18.6, 19.6, 20.0, 22.2 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Milvexian form Ml according to any of Claim 1, Claim 2, or Claim 3, which is characterized by an XRPD pattern having characteristic peaks at 4.5, 7.3, 9.2, 10.1,10.9, 12.0, 12.3, 13.3, 13.9, 14.3, 14.7, 15.1, 15.3, 16.6, 17.3, 17.6, 18.6, 19.6, 20.0, 20.6, 21.4, 22.2, 23.0, 23.5, 24.5, 25.8, 28.4, 29.9 and 30.6 degrees 2-theta ± 0.2 degrees 2-theta.

5. The crystalline Milvexian form Ml according to any of Claims 1, 2, 3, or 4, which is further characterized by an XRPD pattern having an absence of peaks at any one, two or three of (a), (b) or (c): (a) one of: (i) 5.0 to 6.5 degrees 2-theta ± 0.2 degrees 2-theta, or (ii) 5.0 to 6.8 degrees 2-theta ± 0.2 degrees 2-theta; (b) 7.8 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta; and (c) 15.8 to 16.1 degrees 2-theta ± 0.2 degrees 2-theta.

6. The crystalline Milvexian form Ml according to any preceding claim, which is isolated.

7. The crystalline Milvexian form Ml according to any preceding claim, which is an anhydrous form.

8. The crystalline Milvexian form Ml according to any preceding claim, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Milvexian.

9. The crystalline Milvexian form Ml according to any preceding claim, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Milvexian.

10. A crystalline Milvexian form M20, which is characterized by data including at least one of:

(a) an XRPD pattern having characteristic peaks at 4.7, 7.8, 12.7 and 27.4 degrees 2- theta ± 0.2 degrees 2-theta; or

(b) an XRPD pattern as depicted in Figure 20.

11. The crystalline Milvexian form M20 according to Claim 10, which is characterised by an X-ray powder diffraction pattern having peaks at 4.7, 7.8, 12.7 and 27.4 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks at 5.6, 6.4, 10.3 and 19.3 degrees 2-theta ± 0.2 degrees 2-theta.

12. The crystalline Milvexian form M20 according to Claim 10 or Claim 11, which is characterized by an XRPD pattern having characteristic peaks at 4.7, 5.6, 6.4, 7.8, 10.3 12.7, 19.3 and 27.4 degrees 2-theta ± 0.2 degrees 2-theta.

13. The crystalline Milvexian form M20 according to any of Claim 10, Claim 11, or Claim 12, which is characterized by an XRPD pattern having characteristic peaks at 4.7, 5.6, 6.4, 7.8, 9.1, 10.3, 10.9, 12.7, 15.9, 19.3, 20.1, 21.4, 23.1, 27.4, 28.2, 29.2, 31.4, 32.2, 34.5, 36.0, 37.8 and 39.2 degrees 2-theta ± 0.2 degrees 2-theta.

14. The crystalline Milvexian form M20, according to any of Claims 10, 11, 12, or 13, which is further characterized by an XRPD pattern having an absence of peaks at any one, two or three of options (a), (b or (c): (a) 6.9 to 7.3 degrees 2-theta ± 0.2 degrees 2- theta; (b) 14.5 to 15.1 degrees 2-theta ± 0.2 degrees 2-theta; and (c) 16.4 to 17.1 degrees 2-theta ± 0.2 degrees 2-theta.

15. The crystalline Milvexian form M20 according to any of Claims 10, 11, 12, 13, or 14, which is isolated.

16. The crystalline Milvexian form M20 according to any of Claims 10, 11, 12, 13, 14, or 15, which is a hydrate form, preferably a monohydrate form.

17. The crystalline Milvexian form M20 according to any of Claims 10-16, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Milvexian.

18. The crystalline Milvexian form M20 according to any of Claims 10-17, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Milvexian.

19. A crystalline Milvexian form selected from at least one of:

(a) form M4 which is characterized by an XRPD pattern having characteristic peaks at 8.0, 17.1, 20.5, 21.1 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 4;

(b) form M5 which is characterized by an XRPD pattern having characteristic peaks at 8.0, 16.1, 20.0, 23.8, and 26.4 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 5;

(c) form M6 which is characterized by an XRPD pattern having characteristic peaks at 7.8, 9.7, 19.8, 20.6 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 6;

(d) form M8 which is characterized by an XRPD pattern having characteristic peaks at 9.5, 11.3, 17.5, 18.5 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 8;

(e) form M9 which is characterized by an XRPD pattern having characteristic peaks at 7.3, 15.6, 18.3, 19.7 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 9; or

(f) form Ml 1 which is characterized by an XRPD pattern having characteristic peaks at 8.2, 10.1, 16.5, 17.6 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta, or by an XRPD pattern as depicted in Figure 11.

20. The crystalline Milvexian form according to claim 19, which is form M4, characterized by an XRPD pattern having characteristic peaks at 8.0, 17.1, 20.5, 21.1 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 9.9, 23.5, 25.0 and 30.4 degrees 2-theta ± 0.2 degrees 2-theta.

21. The crystalline Milvexian according to claim 19 or claim 20, which is form M4 and is an anisole solvate.

22. The crystalline Milvexian form according to claim 19, which is form M5, characterized by an XRPD pattern having characteristic peaks at 8.0, 16.1, 20.0, 23.8, and 26.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 17.2, 18.3, 19.3 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta.

23. The crystalline Milvexian form according to claim 19 or claim 22, which is form M5 and an ethyl acetate solvate.

24. The crystalline Milvexian form according to claim 19, which is form M6, characterized by an XRPD pattern having characteristic peaks at 7.8, 9.7, 19.8, 20.6 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks at 6.9, 15.7, 19.3 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta.

25. The rystalline Milvexian form according to claim 19 or claim 24, which is form M6 and is an isopropyl acetate solvate.

26. The crystalline Milvexian form according to claim 19, which is form M8, further characterized by an XRPD pattern having characteristic peaks at 9.5, 11.3, 17.5, 18.5 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks at 21.6, 24.3 and 25.8 degrees 2-theta ± 0.2 degrees 2-theta.

27. The rystalline Milvexian form according to claim 19 or claim 26, which is form M8 and is a dimethyl carbonate monosolvate form.

28. The crystalline Milvexian form according to claim 19, which is form M9, further characterized by an XRPD pattern having characteristic peaks at 7.3, 15.6, 18.3, 19.7 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 10.6, 17.3 and 25.6 degrees 2-theta ± 0.2 degrees 2-theta.

29. The crystalline Milvexian form according to claim 19 or claim 28, which is form M9 and is a dimethyl carbonate monosolvate-monohydrate form.

30. The crystalline Milvexian form according to claim 19, which is form Mi l, further characterized by an XRPD pattern having characteristic peaks at 8.2, 10.1, 16.5, 17.6 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks at 22.5, 23.9 and 29.8 degrees 2-theta ± 0.2 degrees 2-theta.

31. The crystalline Milvexian form according to claim 19 or claim 30, which is form Ml 1 and is a di chloromethane solvate form.

32. The crystalline Milvexian form according to any one of Claims 19-31, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Milvexian.

33. The crystalline Milvexian form according to any one of Claims 19-32, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Milvexian.

34. Use of the crystalline Milvexian form Ml or the crystalline Milvexian form M20 according to any one of Claims 1-18, or the crystalline Milvexian form according to any one of claims 19-33, for preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical composition and/or the pharmaceutical formulation is a tablet or a capsule.

35. A pharmaceutical composition comprising any one or a combination of the crystalline Milvexian form Ml or the crystalline Milvexian form M20 according to any of Claims 1-18, or the crystalline Milvexian form according to any one of claims 19-33, preferably wherein the pharmaceutical composition is a spray-dried formulation.

36. A process for preparing the pharmaceutical composition according to Claim 35, comprising combining the crystalline Milvexian form or a combination of the crystalline Milvexian forms according to any of Claims 1-33 with at least one pharmaceutically acceptable excipient.

37. The crystalline Milvexian form according to any of Claims 1-33, or a pharmaceutical composition according to Claim 35, for use as a medicament.

38. The crystalline Milvexian form according to any of Claims 1-33, or a pharmaceutical composition according to Claim 35, for use for prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation.

39. A method for prevention of blood clots in patients undergoing surgery and for the prevention of stroke, or for treatment or prevention of other thromoboembolic disorders, including acute coronary syndrome and atrial fibrillation, comprising administering a therapeutically effective amount of the crystalline Milvexian form according to any of Claims 1-33, or a pharmaceutical composition according to Claim 35, to a subject in need of the treatment.

40. Use of the crystalline Milvexian form according to any of Claims 1-33 in the preparation of another solid state form of Milvexian or Milvexian salts and crystalline forms.

1. A process for preparing a solid state form of Milvexian or Milvexian salts comprising preparing the crystalline Milvexian form according to any one of Claims 1-33, and converting the crystalline Milvexian form to another a solid state form thereof.