WO2022240802A1

WO2022240802A1 - Solid state forms of sitravatinib salts and processes for preparation thereof

Info

Publication number: WO2022240802A1
Application number: PCT/US2022/028466
Authority: WO
Inventors: Nikolina JANTON; Helena CERIĆ
Original assignee: Teva Pharmaceuticals International Gmbh; Teva Pharmaceuticals Usa, Inc.
Priority date: 2021-05-10
Filing date: 2022-05-10
Publication date: 2022-11-17

Abstract

The present disclosure encompasses solid state forms of sitravatinib salts, processes for the preparation thereof, and pharmaceutical compositions thereof. The present disclosure includes solid state forms of sitravatinib malate, sitravatinib hydrochloride, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF SITRAVATINIB SALTS AND PROCESSES FOR PREPARATION THEREOF

FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of sitravatinib salts, processes for the preparation thereof, and pharmaceutical compositions thereof. The present disclosure includes solid state forms of sitravatinib malate, sitravatinib hydrochloride, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate, processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0002] Sitravatinib, 1 -/V-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2- yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-l-/V-(4-fluorophenyl)cyclopropane-l,l- dicarboxamidehas the following structure:

[0003] Sitravatinib belongs to a class of compounds that inhibit protein tyrosine kinase activity and thus may be useful for the treatment of cancer, such as lung cancer including non small cell lung cancer (NSCLC).

[0004] The compound is described in International Publication number WO 2009/026717 (compound 147).

[0005] International Publication number WO 2021/050580 further describes various solid state forms of sitravatinib compound.

[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 are examples of techniques that may be used to distinguish different polymorphic forms of a compound.

[0007] Different salts and solid state forms (including solvated forms and co-crystals) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms 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 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 of an active pharmaceutical ingredient may also give rise to a variety of polymorphs, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0008] Discovering new solid state forms, salts, co -crystals 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, co -crystals and salts 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, such as a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). Thus, additional solid state forms of sitravatinib and sitravatinib salts remain desirable.

SUMMARY OF THE DISCLOSURE

[0009] The present disclosure provides crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of sitravatinib, sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate or other salts of sitravatinib and their solid state forms. [0010] The present disclosure provides crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, such as for the treatment of patients with cancer.

[0011] In another aspect, the present disclosure provides pharmaceutical compositions including crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate according to the present disclosure.

[0012] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations including the described crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate or pharmaceutical compositions including the described crystalline polymorphs of above mentioned compounds and at least one pharmaceutically acceptable excipient.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or mixtures of the crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate sitravatinib tartarate, sitravatinib fumarate and/or sitravatinib succinate as defined herein and the pharmaceutical compositions or formulations of them may be used as medicaments, in embodiments for the treatment of patients with NSCLC.

[0015] The present disclosure also provides the use of crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for cancer.

BRIEF DESCRIPTION OF THE FIGURES

[0016] Figure 1 shows a characteristic X-Ray powder diffraction (XRPD) of Sitravatinib hydrochloride form A.

[0017] Figure 2 shows a charaOcteristic XRPD of crystalline form of Sitravatinib malate form A. [0018] Figure 3 shows a characteristic XRPD of an amorphous sitravatinib malate.

[0019] Figure 4 shows a characteristic XRPD of crystalline form of Sitravatinib malate form B. [0020] Figure 5 shows a characteristic XRPD of crystalline form of Sitravatinib malate form C. [0021] Figure 6 shows a characteristic XRPD of crystalline form of Sitravatinib malate form D. [0022] Figure 7 shows a characteristic XRPD of crystalline form of Sitravatinib malate form E. [0023] Figure 8 shows a characteristic XRPD of crystalline form of Sitravatinib malate form F. [0024] Figure 9 shows a characteristic XRPD of crystalline form of Sitravatinib tartarate form A. [0025] Figure 10 shows a characteristic XRPD of crystalline form of Sitravatinib succinate form A.

[0026] Figure 11 shows a characteristic XRPD of crystalline form of Sitravatinib fumarate form A.

[0027] Figure 12 shows a ¹³C solid state NMR spectrum of Sitravatinib malate form A (200-0 ppm).

[0028] Figure 13 shows a ¹³C solid state NMR spectrum of Sitravatinib malate Form C (200-0 ppm).

[0029] Figure 14 shows a ¹³C solid state NMR spectrum of Sitravatinib Fumarate form A (200-0 ppm).

[0030] Figure 15 shows a ¹³C solid state NMR spectrum of Sitravatinib hydrochloride form A (200-0 ppm).

[0031] Figure 16 shows a ¹³C solid state NMR spectrum of Sitravatinib tartarate form A (200-0 ppm).

DETAILED DESCRIPTION

[0032] The present disclosure encompasses solid state forms of sitravatinib hydrochloride, sitravatinib malate (particularly sitravatinib L-malate), sitravatinib tartarate (particularly sitravatinib L-tartarate), sitravatinib fumarate and sitravatinib succinate, including crystalline polymorphs of sitravatinib hydrochloride form A, sitravatinib malate (particularly sitravatinib L- malate) forms A-F, sitravatinib tartarate (particularly sitravatinib L-tartarate) form A, sitravatinib fumarate form A and sitravatinib succinate form A, processes for preparation thereof, and pharmaceutical compositions thereof.

[0033] Solid state properties of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate, sitravatinib succinate and crystalline polymorphs thereof can be influenced by controlling the conditions under which they are obtained in solid form. [0034] 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, about 0.5% (w/w) or less or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Such forms include, for example, other crystalline forms of sitravatinib and/or salts thereof and/or amorphous Thus, crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate 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 polymorphs respectively. In some embodiments of the disclosure, the described crystalline polymorphs of sitravatinib compounds mentioned above may contain from about 0.5% to about 20% (w/w) or 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 sitravatinib or salts thereof. [0035] Depending on other crystalline polymorphs with which a comparison is made, the crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate of the present disclosure 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. Particularly, a crystalline polymorph of sitravatinib malate, sitravatinib hydrochloride and sitravatinib fumarate as described in any aspect or embodiment of the present disclosure may be stable, for example to grinding. Crystalline sitravatinib malate form A as described in any aspect or embodiment of the present disclosure, may be especially stable to conditions of grinding. Crystalline sitravatinib malate form A, crystalline fumarate form A, crystalline tartarate form A and crystalline succinate form A as described in any aspect or embodiment of the present disclosure, may also have improved solubility. [0036] 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 sitravatinib hydrochloride, sitravatinib malate or sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate 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 above mentioned sitravatinib compounds characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0037] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of the present disclosure relates to a crystalline form which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would typically not contain more than 1% (w/w), of either water or organic solvents as measured, for example, by TGA or by Karl Fischer analysis.

[0038] As used herein, "sitravatinib hydrochloride" refers to a salt of sitravatinib and hydrochloric acid, wherein the molar ratio between sitravatinib and hydrochloric acid is between about 1 : 1 to about 1:3, preferably about 1:1.

[0039] As used herein, "sitravatinib malate" refers to a salt of sitravatinib and malic acid or other complexes (co-crystals) including sitravatinib and malic acid (particularly amorphous form, and any of crystalline Forms A, B, C, D, E, or F), wherein the malic acid is L-malic acid, D-malic acid or mixtures thereof (including racemic mixtures i.e., D, L-malic acid). Preferably, sitravatinib malate refers to a salt of sitravatinib and malic acid or complex (co-crystal) including sitravatinib and malic acid (particularly amorphous form, and any of crystalline Forms A, B, C, D, E, or F), wherein the malic acid is L-malic acid. According to any aspect or embodiment of the present disclosure, the molar ratio of Sitravatinib to malic acid (preferably L-malic acid) is from about 1:2 to about 2:1, about 1:1.5 to about 1.5:1, about 1:1.2 to about 1.2:1, about 1:1.1 to about 1.1:1, and preferably about 1:1. Preferably the molar ratio between sitravatinib and malic acid (preferably L-malic acid) is about 1:1.

[0040] . As used herein, the term “tartaric acid” includes L-tartaric acid, D- tartaric acid, or mixtures such as a racemic mixture, i.e. D,L- tartaric acid. Thus, in any aspect or embodiment of the invention, the tartaric acid in the salt of sitravatinib with tartaric acid (including crystalline Form A) may be L- tartaric acid, D- tartaric acid or mixtures thereof, including D,L- tartaric acid. Preferably, the tartaric acid in the salt of sitravatinib with tartaric acid (including crystalline Form A) is L- tartaric acid. As used herein, " sitravatinib tartarate" refers to salt of sitravatinib and tartaric acid, wherein the molar ratio between sitravatinib and tartaric acid (preferably L- tartaric acid) is between about 1 : 1 to about 1 :2, preferably about 1:1.

[0041] As used herein, " sitravatinib succinate " refers to salt of sitravatinib and succinic acid, wherein the molar ratio between sitravatinib and succinic acid is between about 1 : 1 to about 1 :2, preferably about 1:1.

[0042] As used herein, " sitravatinib fumarate " refers to salt of sitravatinib and fumaric acid, wherein the molar ratio between sitravatinib and fumaric acid is between about 1 : 1 to about 1 :2, preferably about 1:1.

[0043] 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. In the embodiments and aspects of the invention wherein the crystalline salt is a hydrated form, the water may originate from any part of the process from added water where indicated, from residual water which may be present, or from atmospheric water vapour.

[0044] 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. Generally, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0045] 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 a 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 "v/v" 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. [0046] 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 embodiments about 16 hours.

[0047] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure may be from about 10 mbar to about 50 mbar.

[0048] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0049] As used herein, the XRPD measurements of figures 1-11, are taken using with a Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu radiation source =1.54184 A (Angstrom), typically at a temperature of 25 ± 3°C

[0050] As used herein, unless stated otherwise, ¹³C NMR reported herein are measured at 125 MHz at a magic angle spinning frequency w1_c/2p = 64 kHz, preferably at a temperature of at 293 K ± 3°C.

[0051] As used herein, water content is measured by Karl Fischer (KF) analysis.

[0052] The present disclosure includes a crystalline polymorph of sitravatinib hydrochloride, designated Form A. The crystalline Form A of sitravatinib hydrochloride may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 6.9, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta; a ¹³C solid state NMR spectrum with characteristic peaks: 169.7, 135.4, 100.7, 62.5 ± 0.2 ppm; a ¹³C solid state NMR spectrum having characteristic chemical shift differences between peaks at 169.7, 135.4, 100.7, 62.5 and a reference peak at 11.9 ± 0.2 ppm of: 157.8, 123.5, 88.8 and 50.6 ± 0.1 ppm; a ¹³C solid state NMR spectrum substantially as depicted in Figure 15, and combinations of these data.

[0053] Crystalline Form A of sitravatinib hydrochloride may be further characterized by an X- ray powder diffraction pattern having peaks at 6.9, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ±

0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.3, 15.8, 18.8, 21.4 and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0054] Crystalline Form A of sitravatinib hydrochloride may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.9, 12.3, 15.8, 16.3, 17.7, 18.8, 21.4, 23.9,

24.9 and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0055] Crystalline Form A of sitravatinib hydrochloride 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, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1; and combinations thereof.

[0056] Crystalline Form A sitravatinib hydrochloride may be anhydrous.

[0057] The above crystalline polymorph can be used to prepare other crystalline polymorphs of sitravatinib or sitravatinib salts.

[0058] The present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form A. Crystalline sitravatinib malate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ± 0.2 degrees 2-theta; a solid state ¹³C NMR spectrum having characteristic peaks at 150.2, 133.7, 69.6 and 66.2 ± 0.2 ppm; A solid state ¹³C NMR having characteristic chemical shift differences between peaks at 150.2, 133.7, 69.6, 66.2 and a reference peak at 13.4 ± 0.2 ppm of: 136.8, 120.3, 56.2 and 52.8 ± 0.1 ppm; a solid state ¹³C NMR spectrum as depicted in figure 12, and combinations of these data.

[0059] Crystalline sitravatinib malate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 12.0, 13.5,

20.3, 21.1 and 21.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0060] Crystalline Form A of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 9.5, 12.0, 13.5, 14.6, 15.3, 20.3, 21.1, 21.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0061] In embodiment crystalline Sitravatinib malate Form A may be polymorphically pure. [0062] In any embodiment of the present disclosure, crystalline sitravatinib malate Form A may be a hydrate. In any embodiment, sitravatinib malate form A may contain from about 4% to about 8%, about 4.5 to about 7.5%, about 5% to about 7%, about 5.5% to about 7%, about 6 to about 6.7% of water or about 6.52% (by weight) of water as measured by Karl-Fischer (KF). [0063] Crystalline sitravatinib malate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2; and combinations thereof.

[0064] Crystalline Sitravatinib Form A according to any aspect or embodiment of the present disclosure may be advantageously stable, for example to conditions of liquid assisted grinding, e.g. grinding with 0.02 mL of solvent such as 2-propanol on a sample of 50 gram for 2 minutes [0065] Sitravatinib malate form A may be prepared by the methods disclosed herein.

[0066] The present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form B. Crystalline sitravatinib malate Form B may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 7.0, 10.5, 11.4, 12.3 and 20.6 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0067] Crystalline sitravatinib malate Form B may be further characterized by an X-ray powder diffraction pattern having peaks at 7.0, 10.5, 11.4, 12.3 and 20.6 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 5.7, 13.7,

14.3, 16.2 and 25.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0068] Crystalline Form B of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 5.7, 7.0, 10.5, 11.4, 12.3, 13.7, 14.3, 16.2, 20.6, 25.2 degrees 2-theta ± 0.2 degrees 2-theta. [0069] Crystalline sitravatinib malate Form B may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.0,

10.5, 11.4, 12.3 and 20.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4; and combinations thereof.

[0070] In any embodiment crystalline sitravatinib malate Form B may be polymorphically pure. [0071] In any embodiment of the present disclosure, crystalline sitravatinib malate Form B may be a solvate. Specifically 1-pentanol solvate.

[0072] The present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form C. Crystalline sitravatinib malate Form C may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2- theta ± 0.2 degrees 2-theta; a solid state ¹³C NMR spectrum having characteristic peaks at 168.2,

140.5, 129.1 and 108.8 ± 0.2 ppm; A solid state ¹³C NMR having characteristic chemical shift differences between peaks at 168.2, 140.5, 129.1 and 108.8 and a reference peak at 13.0 ± 0.2 ppm of: 155.2, 127.5, 116.1 and 95.8 ± 0.1 ppm; a solid state ¹³C NMR spectrum as depicted in figure 13 and combinations of these data.

[0073] Crystalline sitravatinib malate Form C may be further characterized by an X-ray powder diffraction pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 8.9, 12.3, 13.1, 17.0 and 20.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0074] Crystalline Form C of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 8.9, 9.8, 12.3, 13.1, 14.0, 15.7, 16.3, 17.0, 18.2, 20.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0075] In embodiment crystalline Sitravatinib malate Form C may be polymorphically pure. [0076] In any embodiment of the present disclosure, crystalline sitravatinib malate Form C may be a hydrate. In any embodiment, crystalline Form C may contain from: about 3 to about 5%, about 3.5 to about 4.5%, or about 4.2% (by weight) of water, as determined by Karl -Fischer (KF).

[0077] Crystalline sitravatinib malate Form C may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5; and combinations thereof.

[0078] Crystalline sitravatinib malate Form C may be prepared by the methods disclosed herein. [0079] The present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form D. Crystalline sitravatinib malate Form D may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 8.2, 10.1, 12.3, 17.8 and 21.7 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0080] Crystalline sitravatinib malate Form D may be further characterized by an X-ray powder diffraction pattern having peaks at 8.2, 10.1, 12.3, 17.8 and 21.7 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 6.2, 13.2, 14.5, 16.1 and 20.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0081] Crystalline Form D of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 6.2, 8.2, 10.1, 12.3, 13.2, 14.5, 16.1, 17.8, 20.6 and

21.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0082] Crystalline sitravatinib malate Form D 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, 12.3, 17.8 and 21.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6; and combinations thereof.

[0083] The present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form E. Crystalline sitravatinib malate Form E may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 7; an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.6, 12.3 and 14.7 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0084] Crystalline sitravatinib malate Form E may be further characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.6, 12.3 and 14.7 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 8.4, 18.2,

19.2, 20.2 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0085] Crystalline Form E of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 5.8, 8.4, 9.2, 11.6, 12.3, 14.7, 18.2, 19.2, 20.2 and

22.7 degrees 2-theta ± 0.2 degrees 2-theta. [0086] Crystalline sitravatinib malate Form E may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.8, 9.2, 11.6, 12.3, 14.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7; and combinations thereof.

[0087] The present disclosure includes a crystalline polymorph of sitravatinib malate, designated Form F. Crystalline sitravatinib malate Form F may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at 8.8, 11.4, 12.5, 16.1 and 16.6 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0088] Crystalline sitravatinib malate Form F may be further characterized by an X-ray powder diffraction pattern having peaks at 8.8, 11.4, 12.5, 16.1, 16.6 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 7.8, 14.3, 15.5, 18.2, 20.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0089] Crystalline Form F of sitravatinib malate may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.8, 8.8, 11.4, 12.5, 14.3, 15.5, 16.1, 16.6, 18.2, 20.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0090] Crystalline sitravatinib malate Form F may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.8,

11.4, 12.5, 16.1 and 16.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 8; and combinations thereof.

[0091] Crystalline polymorph of sitravatinib malate designated Form A-F as described in any aspect or embodiment or any of the disclosure herein may be a salt of sitravatinib and malic acid, wherein the malic acid can be L-malic acid, D-malic acid, or a mixture of L-malic acid and D- malic acid (such as a racemic mixture, i.e., D, L-malic acid), and preferably a salt of sitravatinib and L-malic acid. Alternatively, crystalline polymorph of sitravatinib malate designated Form A-F may be a co-crystal or complex of sitravatinib and malic acid, wherein the malic acid can be L-malic acid, D-malic acid, or a mixture of L-malic acid and D-malic acid (such as a racemic mixture, i.e., D, L-malic acid), and preferably a co-crystal or complex of sitravatinib and L-malic acid.

[0092] The present disclosure further provides a general process for preparing a salt of Sitravatinib and malic acid, preferably a crystalline salt of Sitravatinib and malic acid, and more preferably a crystalline salt of Sitravatinib and L-malic acid. The salt of Sitravatinib and malic acid may be any form, including amorphous form, or forms A-F as described herein. The process may comprise: (i) combining Sitravatinib and malic acid, optionally L-malic acid in the presence of one or more solvents to form a mixture; (ii) optionally isolating, and (iii) optionally drying the salt.

[0093] The present disclosure particularly provides a general process for preparing a crystalline salt of Sitravatinib and malic acid, preferably Sitravatinib and L-malic acid, comprising: (i) combining Sitravatinib and malic acid, preferably L-malic acid in the presence of one or more solvents to form a mixture; (ii) optionally isolating the crystalline salt; and (iii) optionally drying the crystalline salt. Optionally, the mixture in step (i) from which the crystalline salt may be isolated is in the form of a suspension. In any embodiment of the process, the sitravatinib starting material is in a solution comprising one or more solvents, or alternatively the Sitravatinib starting material and malic acid (preferably L-malic acid), are combined with one or more polar solvents. [0094] The above described general process may be used for preparing Form A of the crystalline salt of Sitravatinib and malic acid as described in any aspect or embodiment of the disclosure. Preferably, for the preparation of Form A of the crystalline salt of Sitravatinib and malic acid (preferably L-malic acid), step (i) of the above process comprises combining a mixture of Sitravatinib in one or more polar solvents with the malic acid, preferably L-malic acid, optionally under heating and optionally cooling the mixture; or wherein step (i) comprises combining Sitravatinib and malic acid, preferably L-malic acid, and a polar solvent. The mixture of Sitravatinib in one or more polar solvents is preferably a solution. The solution may be optionally heated, typically to a temperature of about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 60°C, or about 45°C to about 55°C, or about 45°C to about 50°C. The malic acid (preferably L-malic acid) may be added to a solution of Sitravatinib in one or more polar solvents. The mixture in step (i) is heated, preferably to temperature of: about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 60°C, or about 45°C to about 55°C, or about 45°C to about 50°C. The heating may be carried out for any suitable period of time, for example about 5 minutes to about 3 hours, about 10 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes. The mixture can be cooled in step (i), optionally to a temperature of: about 5°C to about 30°C, about 10°C to about 30°C, about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C, prior to isolation of the salt. The cooling may be optionally stirred, for example for a period of about 1 hour to about 72 hours, about 3 hours to about 48 hours, about 5 hours to about 36 hours, about 6 hours to about 24 hours, about 8 hours to about 10 hours. Preferably, for the preparation of Form A of the salt of Sitravatinib and malic acid, particularly Sitravatinib L-malate, the polar solvent comprises, consists of, or consists essentially of an alcohol or a ketone, or a combination thereof; preferably a C1-3 alcohol or a C3-6 ketone, or a combination thereof; more preferably methanol, acetone, or methyl ethyl ketone, or a combination thereof; and particularly methanol, acetone, methyl ethyl ketone, or a combination of methanol and acetone or methanol and methyl ethyl ketone. The salt may be isolated by any suitable procedure and may be optionally dried.

[0095] The above described general process may be used for preparing Form C of the crystalline salt of Sitravatinib and malic acid as described in any aspect or embodiment of the disclosure. Preferably, for the preparation of Form C of the crystalline salt of Sitravatinib and malic acid (preferably L-malic acid), step (i) may comprise combining the Sitravatinib starting material and malic acid, optionally L-malic acid, with one or more polar solvents, (ii) optionally heating, and (iii) optionally cooling the mixture. The mixture may be heated to a temperature of about 40°C to about 90°C, about 45°C to about 80°C, about 50°C to about 70°C, or about 55°C to about 65°C, or about 60°C. The heating may be carried out for any suitable period of time, particularly for a period of about 5 minutes to about 3 hours, about 10 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes to obtain a suspension. The mixture in step (i) can be cooled, optionally to a temperature of: about 5°C to about 30°C, about 10°C to about 30, about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C. A further quantity of the polar solvent may be added. Optionally, the mixture may be stirred for a suitable period of time, typically about 1 hour to about 72 hours, about 3 hours to about 48 hours, about 5 hours to about 36 hours, about 6 hours to about 24 hours, about 8 hours to about 10 hours. Preferably, for the preparation of Form C of the salt of Sitravatinib and malic acid, particularly Sitravatinib L- malate, the polar solvent comprises, consists of, or consists essentially of an alcohol, preferably a Ci-3 alcohol, and more preferably methanol.

[0096] In any aspect or embodiment of the process as described herein, step (ii) comprises isolating the salt from the mixture, optionally by filtration, decantation or centrifuge, optionally by filtration. The amorphous salt of Sitravatinib and malic acid may be prepared by evaporation (e.g. by heating at about 40°C to about 80°C, about 40°C, to about 60°C, about 45°C, to about 55°C, or about 50°C) of the solvent or solvents (preferably wherein the solvent comprises a mixture of acetone/water, optionally in a volume ratio of about 5: 1 to about 1:5, about 5: 1 to about 1 :2, about 4: 1 to about 1:1, about 4: 1 to about 2: 1, or about 3 : 1) from a solution of Sitravatinib and malic acid (preferably L-malic acid), preferably under reduced pressure for a suitable period of time.

[0097] In any aspect or embodiment of the process as described herein, the molar ratio of Sitravatinib to malic acid, optionally L-malic acid, is from about 1:2 to about 2:1, about 1:1.5 to about 1.5:1, about 1:1.2 to about 1.2:1, about 1:1.1 to about 1.1:1, and preferably about 1:1. [0098] Preferably, in any aspect or embodiment of the process as described herein, the malic acid is L-malic acid.

[0099] According to any aspect or embodiment of the process as described herein the drying in step (iii) may be carried out under reduced pressure, preferably at a temperature of: about 40°C to about 90°C, about 45°C to about 80°C, about 50°C to about 70°C, or about 55°C to about 65°C, or about 60°C, for any suitable period of time, preferably for a period of: about 2 to about 12 hours, about 4 to about 8 hours, or about 6 hours, or to reach a constant mass. Alternatively, the drying may be carried out at room temperature for a suitable period of time.

[0100] According to any aspect or embodiment, the process as described herein may further comprise a step of combining the salt of Sitravatinib and malic acid with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0101] The present disclosure includes a crystalline polymorph of sitravatinib tartarate, designated Form A. Crystalline sitravatinib tartarate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 9; an X-ray powder diffraction pattern having peaks at 5.9, 9.3, 12.5, 15.0 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta; a ¹³C solid state NMR spectrum with characteristic peaks: 177.6, 129.4, 74.5, 59.9 ± 0.2 ppm; a ¹³C solid state NMR spectrum having characteristic chemical shift differences between peaks at 177.6, 129.4, 74.5, 59.9 and a reference peak at 14.1 ± 0.2 ppm of: 163.5, 115.3, 60.4 and 45.8 ± 0.1 ppm; a ¹³C solid state NMR spectrum substantially as depicted in Figure 16, and combinations of these data.

[0102] Crystalline sitravatinib tartarate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 5.9, 9.3, 12.5, 15.0 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from

4.2, 8.3, 17.7, 20.9 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0103] Crystalline Form A of sitravatinib tartarate may alternatively be characterized by an X- ray powder diffraction pattern having peaks at 4.2, 5.9, 8.3, 9.3, 12.5, 15.0, 17.2, 17.7, 20.9 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0104] Crystalline sitravatinib tartarate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.9,

9.3, 12.5, 15.0 and 17.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 9; and combinations thereof.

[0105] Crystalline polymorph of sitravatinib tartarate Form A as described in any aspect or embodiment or any of the disclosure herein may be a salt of sitravatinib and tartaric acid, wherein the tartaric acid can be L-tartaric acid, D-tartaric acid, or a mixture of L-tartaric acid and D-tartaric acid (such as a racemic mixture, i.e., D, L-tartaric acid), and preferably a salt of sitravatinib and L-tartaric acid. Alternatively, crystalline polymorph of sitravatinib tartarate designated Form A may be a co-crystal or complex of sitravatinib and tartaric acid, wherein the tartaric acid can be L-tartaric acid, D- tartaric acid, or a mixture of L-tartaric acid and D-tartaric acid (such as a racemic mixture, i.e., D, L-tartaric acid), and preferably a co-crystal or complex of sitravatinib and L-tartaric acid.

[0106] The present disclosure includes a crystalline polymorph of sitravatinib succinate, designated Form A. Crystalline sitravatinib succinate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 10; an X-ray powder diffraction pattern having peaks at 6.2, 7.6, 9.8, 11.3 and 12.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0107] Crystalline sitravatinib succinate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 6.2, 7.6, 9.8, 11.3 and 12.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 10.5, 17.3, 20.5, 21.3 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0108] Crystalline Form A of sitravatinib succinate may alternatively be characterized by an X- ray powder diffraction pattern having peaks at 6.2, 7.6, 9.8, 10.5, 11.3 12.4, 17.3, 20.5, 21.3 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta. [0109] Crystalline sitravatinib succinate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.2, 7.6, 9.8, 11.3 and 12.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 10; and combinations thereof.

[0110] The present disclosure includes a crystalline polymorph of sitravatinib fumarate, designated Form A. Crystalline sitravatinib fumarate Form A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 11; an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta; a solid state ¹³C NMR spectrum having characteristic peaks at 172.2, 146.5, 133.8, 99.4± 0.2 ppm; 172.2, 146.5, 133.8, 99.4 and a reference peak at 13.9 ± 0.2 ppm of: 158.3, 132.6, 119.9 and 85.5 ± 0.1 ppm; a solid state ¹³C NMR spectrum as depicted in figure 14; and combinations of these data.

[0111] Crystalline sitravatinib fumarate Form A may be further characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 14.5, 17.1, 18.0, 19.3 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0112] Crystalline Form A of sitravatinib fumarate may alternatively be characterized by an X- ray powder diffraction pattern having peaks at 5.8, 9.2, 11.7, 12.5, 14.5, 17.1, 18.0, 19.3, 20.8 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0113] In embodiment crystalline Sitravatinib fumarate Form A may be polymorphically pure. [0114] In any embodiment of the present disclosure, crystalline sitravatinib fumarate Form A may be a hydrate. In any embodiment, crystalline sitravatinib fumarate Form A may contain about 4 to about 6, about 4.5 to about 5.5, or about 5 % (by weight) of water determined by Karl- Fischer (KF).

[0115] Crystalline sitravatinib fumarate Form A may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 11; and combinations thereof.

[0116] In any aspect or embodiment of the present disclosure, any of the solid state forms of Sitravatinib salts, such as malate, tartrate, succinate, and fumarate, may be polymorphically pure, e.g. the form may be substantially free of any other solid state forms of the subject Sitravatinib salt. Thus, for example according to any aspect or embodiment of the present disclosure a solid state form of Sitravatinib malate may be polymorphically pure, and may be substantially free of any other solid state forms of the subject Sitravatinib salt, i.e. Sitravatinib malate (for example Sitravatinib L-malate may be polymorphically pure and may be substantially free of any other solid state forms of Sitravatinib L-malate). In any aspect or embodiment of the present disclosure, any of the solid state forms of the Sitravatinib salts, may contain: 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, about 0.5% (w/w) or less, about 0.2% (w/w) or less, about 0.1% (w/w) or less, or about 0%, of any other solid state forms of the subject compound, preferably as measured by XRPD. Thus, any of the disclosed crystalline forms of the Sitravatinib salts described herein may be substantially free of any other solid state forms of the subject Sitravatinib salt, and may 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 solid state form of the Sitravatinib salt.

[0117] The present disclosure also encompasses the use of crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, tartarate, succinate and fumarate of the present disclosure for the preparation of pharmaceutical compositions thereof.

[0118] 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 sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate of the present disclosure with at least one pharmaceutically acceptable excipient.

[0119] Pharmaceutical formulations of the present invention contain the solid state form of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate and sitravatinib succinate 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.

[0120] 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®), microfme 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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. [0125] 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 invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0126] 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.

[0127] In liquid pharmaceutical compositions of the present invention, sitravatinib hydrochloride and sitravatinib malate and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin. [0128] 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.

[0129] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel 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, and xanthan gum.

[0130] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0131] 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.

[0132] 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.

[0133] The solid compositions of the present invention include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, 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.

[0134] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0135] The dosage form of the present invention can be a capsule containing the composition, in embodiments a powdered or granulated solid composition of the present disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[0136] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[0141] A pharmaceutical formulation of sitravatinib compounds of this disclosure can be administered. The compounds of this disclosure may be formulated for administration to a mammal, in embodiments a human, by injection sitravatinib compounds of this disclosure can be formulated, for example, as a viscous liquid solution or suspension, in embodiments 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. See, e.g., Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0142] The crystalline polymorphs of sitravatinib hydrochloride, sitravatinib malate, sitravatinib tartarate, sitravatinib fumarate, sitravatinib succinate and the pharmaceutical compositions and/or formulations thereof of the present disclosure can be used as medicaments, in embodiments of patients with cancer diseases including lung cancer.

[0143] The present disclosure also provides methods of treating lung cancer diseases by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of sitravatinib compounds of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.

[0144] Having thus described the disclosure with reference to exemplary 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

[0145] The sample was powdered in a mortar and pestle and applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with a Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 A (Angstrom), X’Celerator (2.022° degrees 2theta) detector. Scanning parameters: angle range: 3-40 degrees 2theta, step size 0.0167, time per step 37 s, continuous scan.

Solid state nuclear magnetic resonance ("ssNMR") method [0146] Solid state NMR analysis was done at Joint Laboratory of Solid State NMR Spectroscopy in Prague, Czech Republic. The spectra was measured at 11.7 T using a Bruker Avance III HD 500 US/WB NMR spectrometer (Karlsruhe, Germany, 2013). The ¹³C CP/MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 11 kHz. The recycle delay was 8 s and the cross-polarization contact time was 2 ms. The strength of spin-locking fields B1(¹³C) expressed in frequency units co 1/2p=gB1 was 64 kHz.

[0147] The ¹³C NMR scale was referenced to a-glycine (176.03 ppm). Frictional heating of the spinning samples was offset by active cooling, and the temperature calibration was performed with Pb(N03)2.

[0148] The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Dn 1 /2was less than 3.5 Hz at 250 ms of acquisition time).

Karl-Fischer titration ("KF")

[0149] Water content was determined by coulometric KF titration on Metrohm 831 KF Coulometer.

Preparation of starting materials

[0150] Sitravatinib used for the below examples can be prepared according to any procedure known from the literature for example as appear in International Publication No. WO 2009/026717. Example 1 Preparation of Sitravatinib hydrochloride Form A

[0151] Sitravatinib (80 mg) was dissolved in methanol/methyl tert-butyl ether (18 mL; 1 : 1 v/v) by heating to about 50°C. Hydrochloric acid, 37% (0.018 mL) was added in one portion and the reaction mixture was stirred for 30 minutes after which crystallization occurred. The heating was discontinued and the suspension was left to cool down to room temperature and then was stirred for 12 hours. The solid was filtered and analyzed by XRPD and identified as Sitravatinib hydrochloride form A (Figure 1).

Example 2. Preparation of Sitravatinib malate Form A

[0152] Sitravatinib (2.1 grams) was dissolved in methanol/acetone (40 mL, 1 : 1 v/v) by heating to about 50°C. L-Malic acid (89 mg) was added to the solution in one portion. The obtained suspension was stirred for 30 minutes at about 50°C, then was left to cool down to room temperature, and then was stirred overnight. The solid was filtered and dried in a vacuum oven at 60°C for 6 hours. Obtained product was analyzed by XRPD and identified as crystalline form A of sitravatinib malate (Figure 2).

Example 3. Preparation of Amorphous Sitravatinib malate

[0153] Sitravatinib (0.5 grams) and /.-malic acid (0.11 grams) were dissolved in acetone/water (27 mL, 3:1 v/v) at room temperature, solvent was further removed by vacuum evaporation (10 mbar) at 50°C for 2 hours. Obtained solid was left to dry at room temperature for 24 hours. Analysis by X-ray powder diffraction method shows Amorphous sitravatinib malate. The XRPD pattern is presented in Figure 3.

Example 4. Preparation of Sitravatinib malate Form B

[0154] 2-pentanol (lmL) was added to sitravatinib malate (0.02 grams). The suspension was heated to about 119°C until complete dissolution. Crystallization flask was sealed and left to cool down to room temperature. Spontaneously after reaching room temperature, crystallization occurred. The obtained solid was vacuum filtered over the black ribbon and analyzed by XRPD. Sitravatinib malate form B was obtained. An XRPD pattern is shown in Figure 4. The same procedure can be repeated with 1-pentanol.

Example 5. Preparation of Sitravatinib malate Form B

[0155] 1 -butanol (6 mL) was added to sitravatinib malate (0.02 grams). The suspension was heated to about 119°C until complete dissolution. Crystallization flask was sealed and left to cool down to room temperature. 24 hours after reaching room temperature, crystallization occurred. The obtained solid was vacuum filtered over the black ribbon and analyzed by XRPD. Sitravatinib malate form B was obtained.

Example 6. Preparation of Sitravatinib malate Form B

[0156] 1 -propanol (6 ml) was added to sitravatinib malate (0.02 grams). The suspension was heated to about 97°C until complete dissolution. Crystallization flask was sealed and left to cool down to room temperature. 24 hours after reaching room temperature, crystallization occurred. The obtained solid was vacuum filtered over the black ribbon and analyzed by XRPD. Sitravatinib malate form B was obtained.

Example 7. Preparation of Sitravatinib malate Form C

[0157] Methanol (20 mL) was added to sitravatinib (1.0 gram) and Z-malic acid (0.64 gram) in a 50 mL round bottomed flask (equipped with condenser and magnetic stirrer). The suspension was heated to about 60°C until complete dissolution. After additional stirring at about 60°C for 10 minutes, crystallization occurred. The suspension was left to cool to room temperature for about 30 minutes. Methanol (20 mL) was added and the suspension was stirred over night at room temperature. The obtained solid was vacuum filtered over the black ribbon at 60°C for 6 hours and analyzed by XRPD. Sitravatinib malate form C was obtained. An XRPD pattern is shown in Figure 5.

Example 7 A. Preparation of Sitravatinib malate Form C

[0158] Methanol (20 mL) was added to sitravatinib (1.0 gram) and Z-malic acid (0.64 gram) in a 50 mL round bottomed flask (equipped with condenser and magnetic stirrer). The suspension was heated to about 60°C until complete dissolution. After additional stirring at about 60°C for 10 minutes, crystallization occurred. The suspension was left to cool to room temperature for about 30 minutes. Methanol (20 mL) was added and the suspension was stirred over night at room temperature. The obtained solid was vacuum filtered over the black ribbon, dried in a vacuum oven at 60°C for 6 hours and analyzed by XRPD. Sitravatinib malate form C was obtained. An XRPD pattern is shown in Figure 5.

Example 8. Preparation of Sitravatinib malate Form D

[0159] Sitravatinib malate form C (0.1 grams) was placed in ‘Anton Paar TTK 450’ chamber on Philips X'Pert PRO X-ray powder diffractometer. The sample was heated up to 100°C by heating rate 5°C/min and analysed by XRPD. Sitravatinib malate form D as in Figure 6 was obtained.

Example 9. Preparation of Sitravatinib malate Form E

[0160] Sitravatinib malate form C (0.6 grams) was suspended in toluene (20 mL) at 110°C and stirred for 5 hours. Solid was isolated by vacuum filtration and analysed by XRPD. Sitravatinib malate form E was obtained. An XRPD pattern is shown in Figure 7.

Example 10. Preparation of Sitravatinib malate Form F

[0161] 1,2-propylene carbonate (2 mL) was added to sitravatinib malate form A (0.02 grams). The suspension was heated to about 200°C until complete dissolution. Crystallization flask was sealed and left to cool down to room temperature. During cooling, crystallization occurred. The obtained solid was vacuum filtered and analyzed by XRPD. Sitravatinib malate form F was obtained. An XRPD pattern is shown in Figure 8.

Example 11. Preparation of Sitravatinib tartarate form A

[0162] Sitravatinib (0.93 grams) was stirred in 96% ethanol (25 mL) at room temperature until clear solution was obtained. (2R,3R)-2,3-dihydroxysuccinic acid (0.35 grams) was added in one portion to the solution and precipitation immediately occurred. The obtained suspension was stirred at room temperature for 16 hours after which it was isolated by vacuum filtration. Product was dried at 60°C for 6 hours under vacuum and analyzed by XRPD. Sitravatinib tartarate form A was obtained. An XRPD pattern is shown in Figure 9.

Example 12. Preparation of Sitravatinib succinate form A

[0163] Butanedioic acid (0.49 grams) was suspended in methanol (10 mL) and heated at about 50°C until complete dissolution. Sitravatinib hydrate (1.0 grams) was added in one portion to the acid solution at 50°C and precipitation immediately occurred. The obtained suspension was stirred at room temperature for 16 hours after which it was isolated by vacuum filtration. Product was dried at 75°C for 4 hours under vacuum and analyzed by XRPD. Sitravatinib succinate form A was obtained. An XRPD pattern is shown in Figure 10. Example 13. Preparation of Sitravatinib fumarate form A

[0164] Sitravatinib (1.0 grams) and (2E)-But-2-enedioic acid (0.46 grams) were dissolved in methanol (10 mL) at room temperature with stirring until clear solution was obtained. Precipitation occurred after few seconds. The obtained suspension was stirred at room temperature for 16 hours and then isolated by vacuum filtration. The obtained product was dried at 60°C for 6 hours under vacuum and analyzed by XRPD. Sitravatinib fumarate form A was obtained. An XRPD pattern is shown in Figure 11.

Example 14. Preparation of Sitravatinib malate form A

[0165] Sitravatinib (1.0 g) was dissolved in MEK (25 mL) by heating to 45-50°C. Z-Malic acid (256 mg) was added to the solution. The obtained suspension was stirred for 30 minutes at about 45°C, then cooled to room temperature and stirred overnight. The solid was filtered and dried in a vacuum oven at 60°C for 6 hours. Obtained product was analyzed by XRPD. Sitravatinib malate form A was obtained.

Claims

1. Crystalline salt of Sitravatinib and malic acid, optionally wherein the crystalline salt is of Sitravatinib and L-malic acid.

2. A crystalline salt according to claim 1 which is a hydrate.

3. A crystalline salt according to claim 1 or claim 2 designated form A, which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ± 0.2 degrees 2-theta; b. an XRPD pattern having peaks at 6.0, 8.5, 9.5, 14.6 and 15.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.0, 13.5, 20.3, 21.1 and 21.9 degrees two theta ± 0.2 degrees two theta; c. an X-ray powder diffraction pattern having peaks at 6.0, 8.5, 9.5, 12.0, 13.5, 14.6, 15.3, 20.3, 21.1, 21.9 degrees 2-theta ± 0.2 degrees 2-theta; d. an XRPD pattern substantially as depicted in Figure 2; e. a solid state ¹³C NMR spectrum having characteristic peaks at 150.2, 133.7, 69.6 and 66.2 ppm ± 0.2 ppm; f. a solid state ¹³C NMR spectrum substantially as depicted in Figure 11; and g. a solid state ¹³C NMR spectrum having the following chemical shift differences between peaks at 150.2, 133.7, 69.6 and 66.2 ppm and a reference peak at 13.4 ppm ± 0.2 ppm of: 136.8, 120.3, 56.2 and 52.8 ppm ± 0.1 ppm;

4. A crystalline salt according to any one of claims 1-3 which is a hydrate, optionally containing water in an amount of: about 4 to about 8 wt%, about 4.5 to about 7.5 wt%, about 5 wt% to about 7 wt%, about 5.5% to about 7%, or about 6 to about 6.7%.

5. A crystalline salt according to any one of claims 2-4, 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 the salt of Sitravatinib and malic acid, and/or 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 an amorphous salt of Sitravatinib and malic acid. A crystalline salt of Sitravatinib and L-malic acid according to any one of claims 2-5, 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 a salt of Sitravatinib and L-malic acid, and/or 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 an amorphous salt of Sitravatinib and malic acid. A crystalline salt according to claim 1 or claim 2 designated form C which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta; b. an XRPD pattern having peaks at 9.8, 14.0, 15.7, 16.3 and 18.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 8.9, 12.3, 13.1, 17.0 and 20.6 degrees two theta ± 0.2 degrees two theta; c. an X-ray powder diffraction pattern having peaks at 8.9, 9.8, 12.3, 13.1, 14.0,

15.7, 16.3, 17.0, 18.2, 20.6 degrees 2-theta ± 0.2 degrees 2-theta; d. an XRPD pattern substantially as depicted in Figure 5; e. a solid state ¹³C NMR spectrum having characteristic peaks at 168.2, 140.5, 129.1 and 108.8 ppm ± 0.2 ppm; f. a solid state ¹³C NMR spectrum substantially as depicted in Figure 13; and g. a solid state ¹³C NMR spectrum having the following chemical shift differences between peaks at 168.2, 140.5, 129.1, 108.8 and a reference peak at 13.0 ppm ± 0.2 ppm of: 155.2, 127.5, 116.1 and 95.8 ppm ± 0.1 ppm. A crystalline salt according to claim 1 or claim 7 which is a hydrate, optionally containing water in an amount of: about 2 to about 6 wt%, about 2.5 to about 5.5 wt%, or about 3 wt% to about 5 wt%. A crystalline salt according to any of claims 7-8, 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 the salt of Sitravatinib and malic acid, and/or 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 an amorphous salt of Sitravatinib and malic acid. A crystalline salt of Sitravatinib and L-malic acid according to any one of claims 7-9, 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 a salt of Sitravatinib and L-malic acid, and/or 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 an amorphous salt of Sitravatinib and L-malic acid. A process for the preparation of a crystalline salt according to any one of claims 1-10 comprising:

(i) combining Sitravatinib and malic acid, optionally L-malic acid, in the presence of one or more solvents to form a mixture;

(ii) optionally isolating the crystalline salt; and

(iii) optionally drying the crystalline salt. A process according to claim 11 wherein the mixture in step (i) is a suspension. A process according to claim 11 or claim 12, wherein the Sitravatinib starting material is in a solution comprising one or more solvents, or wherein the Sitravatinib starting material and malic acid, optionally L-malic acid, are combined with one or more polar solvents. A process according to any of claims 11-13, optionally wherein the crystalline salt of Sitravatinib and malic acid is Form A, wherein step (i) comprises combining a mixture of Sitravatinib in one or more polar solvents with the malic acid, optionally L-malic acid, optionally under heating and optionally cooling the mixture; or wherein step (i) comprises combining Sitravatinib and malic acid, optionally L-malic acid, and a polar solvent. A process according to claim 14 wherein the mixture of Sitravatinib in one or more polar solvents is a solution, wherein the solution is optionally heated, optionally wherein the solution is heated to a temperature of about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 60°C, or about 45°C to about 55°C, or about 45°C to about 50°C. A process according to any of Claims 11-15, wherein the malic acid, optionally L-malic acid, is added to the solution of Sitravatinib in one or more polar solvents. A process according to any of claims 11-16 wherein the mixture in step (i) is heated, preferably to temperature of: about 30°C to about 80°C, about 35°C to about 70°C, about 40°C to about 60°C, or about 45°C to about 55°C, or about 45°C to about 50°C. A process according to claim 17, wherein the heating is carried out for a period of about 5 minutes to about 3 hours, about 10 minutes to about 2 hours, about 15 minutes to about 1 hour, or about 30 minutes. A process according to any of claims 11-18, wherein step (i) comprises cooling the mixture, optionally to a temperature of: about 5°C to about 30°C, about 10°C to about 30°C, about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C. A process according to any of Claims 11-19, wherein the polar solvent comprises an alcohol or a ketone, or a combination thereof; preferably a C1-3 alcohol or a C3-6 ketone, or a combination thereof; more preferably methanol, acetone, or methyl ethyl ketone, or a combination thereof; and particularly methanol, acetone, methyl ethyl ketone, or a combination of methanol and acetone or methanol and methyl ethyl ketone. A process according to any of claims 11-20, optionally wherein the crystalline salt of Sitravatinib and malic acid is Form C, and step (i) comprises combining the Sitravatinib starting material and malic acid, optionally L-malic acid, with one or more polar solvents, optionally heating and optionally cooling the mixture. A process according to claim 21 wherein the heating is to a temperature of about 40°C to about 90°C, about 45°C to about 80°C, about 50°C to about 70°C, or about 55°C to about 65°C, or about 60°C. A process according to any of claims 21-22, wherein step (i) comprises cooling the mixture, optionally to a temperature of: about 5°C to about 30°C, about 10°C to about 30, about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C. A process according to any of claims 21-23, wherein a further quantity of the polar solvent is added, and optionally wherein the mixture is stirred for a period of: about 1 hour to about 72 hours, about 3 hours to about 48 hours, about 5 hours to about 36 hours, about 6 hours to about 24 hours, or about 8 hours to about 10 hours. A process according to any of Claims 21-24, wherein the polar solvent comprises an alcohol, preferably a C1-3 alcohol, and more preferably methanol. A process according to any of claims 11-25, wherein step (ii) comprises isolating the crystalline salt from the mixture, optionally by filtration, decantation or centrifuge, optionally by filtration. A process according to any of claims 11-26, wherein the molar ratio of Sitravatinib to malic acid, optionally L-malic acid, is from about 1 :2 to about 2:1, about 1 : 1.5 to about 1.5:1, about 1:1.2 to about 1.2:1, about 1:1.1 to about 1.1:1, and preferably about 1:1. A process according to any of claims 11-27, wherein the malic acid is L-malic acid. A process according to any of claims 11-28, wherein the drying in step (iii) is carried out under reduced pressure, preferably at a temperature of: about 40°C to about 90°C, about 45°C to about 80°C, about 50°C to about 70°C, or about 55°C to about 65°C, or about 60°C, preferably for a period of: about 2 to about 12 hours, about 4 to about 8 hours, or about 6 hours. A process according to any of claims 11-29, further comprising combining the crystalline salt of Sitravatinib and malic acid with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition. Amorphous salt of Sitravatinib and malic acid. Crystalline salt of Sitravatinib and fumaric acid. A crystalline salt according to claim 32 designated form A which is characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta; b. an XRPD pattern having peaks at 5.8, 9.2, 11.7, 12.5 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 14.5, 17.1, 18.0, 19.3 and 23.9 degrees two theta ± 0.2 degrees two theta; c. an X-ray powder diffraction pattern having peaks at 5.8, 9.2, 11.7, 12.5, 14.5,

17.1, 18.0, 19.3, 20.8 and 23.9 degrees 2-theta ± 0.2 degrees 2-theta; d. an XRPD pattern substantially as depicted in Figure 11; e. a solid state ¹³C NMR spectrum having characteristic peaks at 172.2, 146.5, 133.8 and 99.4 ppm ± 0.2 ppm; f. a solid state ¹³C NMR spectrum substantially as depicted in Figure 17; and g. a solid state ¹³C NMR spectrum having the following chemical shift differences between peaks at 172.2, 146.5, 133.8, 99.4 and a reference peak at 13.9 ppm ± 0.2 ppm of: 158.3, 132.6, 119.9 and 85.5 ppm ± 0.1 ppm. A crystalline salt according to any one of claims 32-33 which is a hydrate, optionally containing water in an amount of: about 3 to about 7 wt%, about 3.5 to about 6.5 wt%, or about 4 wt% to about 6 wt%. A crystalline salt according to any of claims 32-34 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 crystalline forms of the salt of Sitravatinib and fumaric acid, and/or 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 an amorphous salt of Sitravatinib and fumaric acid. Crystalline Sitravatinib hydrochloride. Crystalline Sitravatinib hydrochloride according to claim 36, designated Form A, which is characterized by data selected from one or more of the following:

(i) an X-ray powder diffraction pattern having peaks at 6.9, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta;

(ii) an X-ray powder diffraction pattern having peaks at 6.9, 16.3, 17.7, 23.9 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.3, 15.8, 18.8, 21.4 and 27.1 degrees 2-theta ± 0.2 degrees 2-theta;

(iii) an X-ray powder diffraction pattern having peaks at 6.9, 12.3, 15.8, 16.3, 17.7, 18.8, 21.4, 23.9, 24.9 and 27.1 degrees 2-theta± 0.2 degrees 2-theta; and

(iv) an X-ray powder diffraction pattern substantially as depicted in Figure 1;

(v) a solid state ¹³C NMR spectrum having characteristic peaks at : 169.7, 135.4, 100.7, 62.5 ± 0.2 ppm;

(vi) a solid state ¹³C NMR spectrum substantially as depicted in Figure 15; and (vii) a solid state ¹³C NMR spectrum having the following chemical shift differences between peaks at 169.7, 135.4, 100.7, 62.5 and a reference peak at at 11.9 ± 0.2 ppm of: 157.8, 123.5, 88.8 and 50.6 ± 0.1 ppm. Crystalline Form A of Sitravatinib hydrochloride according to claim 36 or claim 37, which is anhydrous. A pharmaceutical composition comprising a salt according to any of 1-10 or Claims 31- 38 and at least one pharmaceutically acceptable excipient. A process for preparing the pharmaceutical composition according to Claim 39, comprising combining a salt according to any of Claims 1-10 or Claims 31-38, with at least one pharmaceutically acceptable excipient. A salt according to any of Claims 1-10 or Claims 31-38, or a pharmaceutical composition according to Claim 39, for use as a medicament. A salt according to any of Claims 1-10 or Claims 31-38, or a pharmaceutical composition according to Claim 39, for use in the treatment of cancer. A method of treating cancer comprising administering a therapeutically effective amount of a salt according to any of Claims 1-10 or Claims 31-38, or a pharmaceutical composition according to Claim 39, to a subject in need of the treatment. Use of a salt according to any of Claims 1-10 or Claims 31-38, in the preparation of another solid state form of Sitravatinib or salt thereof. A process for preparing a solid state form of Sitravatinib or salt thereof comprising preparing any one or a combination of a salt according to any one of Claims 1-10 or Claims 31-38, and converting it to another a solid state form thereof.