WO2024023796A1

WO2024023796A1 - Polymorphs, co-crystals and solvates of fruquintinib, processes for the preparation and use thereof

Info

Publication number: WO2024023796A1
Application number: PCT/IB2023/057714
Authority: WO
Inventors: Thierry Bonnaud; Jethro BEAMISH-COOK
Original assignee: Macfarlan Smith Limited
Priority date: 2022-07-29
Filing date: 2023-07-28
Publication date: 2024-02-01
Also published as: GB202211142D0

Abstract

Anhydrous fruquintinib as amorphous or crystalline (Form 1) solids, co-crystals of fruquintinib and organic acids as crystalline solids and solvates of co-crystals of fruquintinib and organic acids as crystalline solids and processes for preparing thereof are described and characterized herein.

Description

P101769 July 2022 Polymorphs, Co-Crystals and Solvates of Fruquintinib, Processes for the Preparation and Use Thereof The present invention relates to polymorphs of fruquintinib, namely a new anhydrous polymorph of fruquintinib as amorphous or crystalline (Form 1) solids, and four novel co- crystals of fruquintinib and selected organic acids as crystalline solids and novel acetonitrile solvates of the co-crystals of fruquintinib and selected organic acids as crystalline solids that are prepared from the invented anhydrous fruquintinib, to processes for the preparation of the new anhydrous polymorph of fruquintinib as an amorphous solid and the 4 novel co-crystals of fruquintinib prepared from the amorphous fruquintinib, as amorphous or crystalline (Form 1) solids, and to pharmaceutical compositions comprising the polymorphs and solvates of fruquintinib. Background Fruquintinib has the IUPAC name of 6-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide and has the structure:

Fruquintinib is an orally available, small molecule inhibitor of vascular endothelial growth factor receptors (VEGFRs), with potential anti-angiogenic and antineoplastic activities. Upon oral administration, fruquintinib inhibits VEGF-induced phosphorylation of VEGFRs 1, 2, and 3 which may result in the inhibition of migration, proliferation and survival of endothelial cells, micro-vessel formation, the inhibition of tumor cell proliferation, and tumor cell death. Expression of VEGFRs may be upregulated in a variety of tumor cell types. Fruquitinib is used to treat cancers in human subjects. Currently, it has been approved for the treatment of metastatic colorectal cancer (mCRC) in patients who have failed at least two prior systemic antineoplastic therapies in China and is presently on expedited approval in the US FDA as of 2020. 1 P101769 July 2022 The ability of a compound to exist in at least one crystal structure or solid-state form is known as polymorphism. Many compounds may exist as polymorph crystals and those compounds may also exist in a solid amorphous state. Until polymorphism of a compound is discovered, it is highly unpredictable (1) whether a particular compound will exhibit polymorphism, (2) how to make any such unknown polymorphs, and (3) what the properties, such as stability, will be of any such unknown polymorphs. See, e.g., J. Bernstein "Polymorphism in Molecular Crystals", Oxford University Press, (2002). US Pat. No. 10,519,142 discloses and claims polymorphic forms of fruquintinib. Fruquintinib, (6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3- carboxamide), can exist in different crystalline forms, and can form solvates with certain solvents. The existence of various polymorphic forms of the compound of Formula A was explored. Based on these studies and disclosure, the invention discloses polymorphs which are designated Form I, Form II, Form III, Form IV, Form VII, and Form VIII respectively. In particular, Form I is an anhydrous form (Hutch Form I). Alternative polymorphic forms of fruquintinib (amorphous, anhydrous forms) are still of great commercial interest, because the properties of any solid material depend on the structure, as well as on the nature of the compound itself, different solid-state forms of a compound can and often do exhibit different physical and chemical properties. Differences in chemical properties can be determined through a variety of analytical techniques to be used to characterize, analyze, and compare. And those differences in chemical properties may ultimately be used to differentiate among different solid-state forms that may be discovered to exist. Furthermore, differences in physical properties, such as solubility and bioavailability, of solid-state forms can be important when formulating a pharmaceutical compound. As such, novel crystalline and amorphous solid- state forms of pharmaceutical compounds, such as the compound of Formula A, can be important in the development of such compounds. Inventors have discovered a new anhydrous form of fruquintinib as amorphous or crystalline (Form 1) solids, in addition to four novel co-crystals of fruquintinib with organic acids selected from: citric acid, adipic acid, fumaric acid and succinic acid and acetonitrile solvates of fruquintinib with selected organic acids. According to one embodiment of the, a novel anhydrous polymorph of fruquintinib as an amorphous solid or a crystalline solid (Form 1) is disclosed, In a separate embodiment, the amorphous solid or a crystalline solid (Form 1) is used to prepare 4 novel co-crystals of fruquintinib with selected organic acids and to prepare solvates of the co-crystals of fruquintinib with selected organic acid. 2 P101769 July 2022 Definitions The follow abbreviations are defined herein in Table 1. Table 1 Table of Abbreviations Abbreviations Meaning 1H NMR Proton Nuclear Magnetic Resonance

3 P101769 July 2022 The term “about” or “approximately” means an acceptable error for a particular value as determined by a person of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3 or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In certain embodiments and with reference to X- ray powder diffraction two-theta peaks, the terms “about” or “approximately” means within ± 0.2 ^o 2θ. The term “ambient temperature” means one or more room temperatures between about 15 ^oC to about 30 ^oC, such as about 15 ^oC to about 25 ^oC. The term “consisting” is closed and excludes additional, unrecited elements or method steps in the claimed invention. The term “consisting essentially of” is semi-closed and occupies a middle ground between “consisting” and “comprising”. “Consisting essentially of” does not exclude additional, unrecited elements or method steps which do not materially affect the essential characteristic(s) of the claimed invention. The term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps in the claimed invention. The term is synonymous with “including but not limited to”. The term “comprising” encompasses three alternatives, namely (i) “comprising”, (ii) “consisting”, and (iii) “consisting essentially of”. The term “crystalline” and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, means that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995). The term “pharmaceutical composition” is intended to encompass a pharmaceutically effective amount of a new anhydrous polymorph of fruquintinib as an amorphous solid and 4 novel co- crystals of fruquintinib prepared from the amorphous fruquintinib of the invention and a pharmaceutically acceptable excipient. As used herein, the term “pharmaceutical compositions” includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations. 4 P101769 July 2022 The term “excipient” refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients may be natural or synthetic substances formulated alongside the active ingredient of a medication, included for the purpose of bulking-up formulations that contain potent active ingredients (thus often referred to as "bulking agents," "fillers," or "diluents"), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life. The term “patient” refers to an animal, preferably a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. Further, a patient may not have exhibited any symptoms of the disorder, disease or condition to be treated and/prevented, but has been deemed by a physician, clinician or other medical professional to be at risk for developing said disorder, disease or condition. The terms “treat”, “treating” and “treatment” refer to the therapeutic attempt at eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more therapeutic agents to a patient with such a disease or disorder. In some embodiments, the terms refer to the administration of the crystalline salt provided herein, with or without other additional active agents, after the onset of symptoms of a disease. Brief Description of the Figures Certain aspects of the embodiments described herein may be more clearly understood by reference to the drawings, which are intended to illustrate but not limit, the invention, and wherein: Figure 1 shows a representative XRPD pattern of an invented anhydrous form of fruquintinib (Form 1) as a polycrystalline solid. Figure 2 is a representative TGA analysis of an invented anhydrous form of fruquintinib (Form 1) from Preparation 3. Figure 3 is a representative ¹H NMR spectrum of an invented anhydrous form of fruquintinib (Form 1) from Preparation

5 P101769 July 2022 Figure 4 is a HPLC chromatogram and purity analysis of an invented anhydrous form of fruquintinib (Form 1) from Preparation 2. Figure 5 is an XRPD overlay of an invented anhydrous form of Fruquintinib as an amorphous solid before and after static storage for 7 days at 40 °C / 75% RH (open vial) showing conversion to an anhydrous form of fruquintinib as a polycrystalline solid. Figure 6 is a representative XRPD pattern of a co-crystal of fruquintinib with citric acid. Figure 7 is a representative XRPD pattern of a co-crystal of fruquintinib with fumaric acid. Figure 8 is a representative XRPD pattern of a co-crystal of fruquintinib with fumaric acid as an acetonitrile solvate. Figure 9 is a representative XRPD pattern of a co-crystal of fruquintinib with adipic acid. Figure 10 is a representative XRPD pattern of a co-crystal of fruquintinib with succinic acid. Figure 11 is a representative XRPD pattern of a co-crystal of fruquintinib with succinic acid as an acetonitrile solvate. Detailed Description of the Invention According to one embodiment of the, a novel anhydrous polymorph of fruquintinib as an amorphous solid was discovered. A crystalline anhydrous form of fruquintinib is described in US Pat. No. 10,519, 142 (Hutch Form I. Figure 1 shows a representative XRPD pattern of an invented anhydrous form of fruquintinib as a polycrystalline solid (Form 1). In certain embodiments and depending on time, temperature and humidity, the crystalline anhydrous form of fruquintinib (Form 1) was stable. The characteristic XRPD 2-theta peaks anhydrous form of fruquintinib (Form 1) are summarized in Table 1. Figure 2 is a representative TGA analysis of an anhydrous form of fruquintinib (Form 1) from Preparation 3. Figure 3 is a representative ¹H NMR spectrum of an anhydrous form of fruquintinib (Form 1) from Preparation 3. Figure 4 is a HPLC chromatogram and purity analysis of an anhydrous form of fruquintinib (Form 1) from Preparation 2. 6 P101769 July 2022 Table 1 Pos. [°2θ] Rel. Int. [%] Pos. [°2θ] Rel. Int. [%] 9.3 3.9 21.5 8.5

Form Fruquintinib (Invented Form 1) T_GA ^{Weight loss of 0.8% between 110‐170 °C.} ^ol

g p v , p u y u of fruquintinib was unexpectedly discovered. Fruquintinib was dissolved in THF/H2O with heating and stirring to give a clear solution after a period of time. The solution was dispensed into vials to give 20 mg of material per vial. Each sample was flash frozen in dry ice/acetone then lyophilised for an extended time period of hours using a freeze dryer. The invented amorphous anhydrous form of fruquintinib as an amorphous solid may be useful as an active ingredient in pharmaceutical formulations. In certain embodiments and depending on time, temperature and humidity, the anhydrous form converts to the polycrystalline Form 1 of fruquitinib. Figure 5 is an XRPD overlay of an anhydrous form of fruquintinib as an amorphous solid before and after static storage for 7 days at 40 °C / 75% RH (open vial) showing conversion from an anhydrous form of fruquintinib to a polycrystalline solid form of fruquintinib (Form 1). 7 P101769 July 2022 Co-crystal of fruquintinib with citric acid According to a separate embodiment, inventors discovered fruquintinib as a co-crystal with citric acid using the invented anhydrous form (amorphous or crystalline Form 1) of fruquintinib. The crystalline solid can be prepared in a well-defined and consistently reproducible co-crystal form with citric acid. In certain embodiments and depending on time, temperature and humidity, the co-crystal form was stable. The invented co-crystal of fruquintinib and citric acid as a crystalline solid may be useful as an active ingredient in pharmaceutical formulations. Figure 6 shows a representative XRPD pattern of a co-crystal of fruquintinib with citric acid. The characteristic XRD 2-theta peaks for the co-crystal of fruquintinib with citric acid are summarized in Table 2. Table 2 Pos. [°2θ] Rel. Int. [%] Pos. [°2θ] Rel. Int. [%] 6.2 32.2 20.0 5.7

The crystalline form described herein was characterised using a number of methods known to the skilled person in the art, including single crystal X-ray diffraction, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, nuclear magnetic resonance (NMR) spectroscopy (including solution and solid-state NMR). The chemical purity was determined by standard analytical methods, such as thin layer chromatography (TLC), gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS). 8 P101769 July 2022 Co-crystal of fruquintinib with fumaric acid According to a separate embodiment, inventors discovered fruquintinib as a co-crystal with fumaric acid using the invented anhydrous form (amorphous or crystalline Form 1) of fruquintinib. The crystalline solid can be prepared in a well-defined and consistently reproducible co-crystal form with fumaric acid. In certain embodiments and depending on time, temperature and humidity, the co-crystal form was stable. The invented co-crystal of fruquintinib and fumaric acid as a crystalline solid may be useful as an active ingredient in pharmaceutical formulations. Figure 7 shows a representative XRPD pattern of a co-crystal of fruquintinib with fumaric acid. The characteristic XRD 2-theta peaks for the co-crystal of fruquintinib with fumaric acid are summarized in Table 3. Table 3 Pos. [°2θ] Rel. Int. [%] Pos. [°2θ] Rel. Int. [%] 4.5 14.6 21.0 29.4

o-c ys a o uqu w u v According to a separate embodiment, inventors discovered fruquintinib as a co-crystal with fumaric acid as acetonitrile solvate using the invented anhydrous form (amorphous or crystalline Form 1) of fruquintinib. The crystalline solid can be prepared in a well-defined and consistently reproducible co-crystal form with fumaric acid. In certain embodiments and depending on time, temperature and humidity, the co-crystal form was stable. The invented co-crystal of fruquintinib and fumaric acid as a crystalline solid may be useful as an active ingredient in pharmaceutical formulations. Figure 8 shows a representative XRPD pattern of a co-crystal of fruquintinib with fumaric acid as an acetonitrile solvate. The characteristic XRD 2-theta peaks for the co-crystal of fruquintinib with fumaric acid are summarized in Table 4. 9 P101769 July 2022 Table 4 Pos. [°2θ] Rel. Int. [%] Pos. [°2θ] Rel. Int. [%] 6.3 8.4 20.4 8.1

Co-crystal of fruquintinib with adipic acid According to a separate embodiment, inventors discovered fruquintinib as a co-crystal with adipic acid using the invented anhydrous form (anhydrous or crystalline Form 1) of fruquintinib. The crystalline solid can be prepared in a well-defined and consistently reproducible co-crystal form with adipic acid. In certain embodiments and depending on time, temperature and humidity, the co-crystal form was stable. The invented co-crystal of fruquintinib and adipic acid as a crystalline solid may be useful as an active ingredient in pharmaceutical formulations. Figure 9 shows a representative XRPD pattern of a co-crystal of fruquintinib with adipic acid. The characteristic XRD 2-theta peaks for the co-crystal of fruquintinib with adipic acid are summarized in Table 5. 10 P101769 July 2022 Table 5 Pos. [°2θ] Rel. Int. [%] Pos. [°2θ] Rel. Int. [%] 6.3 79.6 18.2 7.4

Co-crystal of fruquintinib with succinic acid According to a separate embodiment, inventors discovered fruquintinib as a co-crystal with succinic acid using the invented anhydrous form (anhydrous or crystalline Form 1) of fruquintinib. The crystalline solid can be prepared in a well-defined and consistently reproducible co-crystal form with succinic acid. In certain embodiments and depending on time, temperature and humidity, the co-crystal form was stable. The invented co-crystal of fruquintinib and succinic acid as a crystalline solid may be useful as an active ingredient in pharmaceutical formulations. Figure 10 shows a representative XRPD pattern of a co-crystal of fruquintinib with succinic acid. The characteristic XRD 2-theta (2ɵ) peaks for the co-crystal of fruquintinib with succinic acid are summarized in Table 6. Table 6 Pos. [°2θ] Rel. Int. [%] Pos. [°2θ] Rel. Int. [%]

11 P101769 July 2022 Co-crystal of fruquintinib with succinic acid as an Acetonitrile Solvate According to a separate embodiment, inventors discovered fruquintinib as a co-crystal with succinic acid as an acetonitrile solvate using the invented anhydrous form (anhydrous or crystalline Form 1) of fruquintinib. The crystalline solid can be prepared in a well-defined and consistently reproducible co-crystal form with succinic acid. In certain embodiments and depending on time, temperature and humidity, the co-crystal is stable. The invented co-crystal of fruquintinib and succinic acid as a crystalline solid may be useful as an active ingredient in pharmaceutical formulations. Figure 11 shows a representative XRPD pattern of a co-crystal of fruquintinib with succinic acid as an acetonitrile solvate. The characteristic XRD 2-theta peaks for the co-crystal of fruquintinib with succinic acid are summarized in Table 7. Table 7 Pos. [°2θ] Rel. Int. [%] Pos. [°2θ] Rel. Int. [%] 63 42 21 8 104

Fruquintinib as a free base is sparingly soluble in water and soluble in weakly acidic media. The polycrystalline (Form 1) and co-crystals of fruquintinib with citric, fumaric, adipic and succinic acid respectively, of the present invention were demonstrated to have significantly enhanced solubility in very acidic media, such as simulated gastric fluid, compared with fruquintinib, and other conventional forms of fruquintinib (e.g. Hutch Form I). The invented anhydrous form of fruquintinib as a crystalline solid (Form 1) as described herein was prepared by a process comprising the steps of: 12 P101769 July 2022 (a) contacting anhydrous fruquintinib with one or more organic solvents, water or mixtures thereof, and heating to form a solution; (b) flash freezing then lyophilising the solids using a freeze dryer; (c) allowing the solids to slowly warm to ambient temperature for an extended period of time. The invented anhydrous form of fruquintinib as an amorphous solid as described herein was prepared by a process comprising the steps of: (a) contacting anhydrous fruquintinib with one or more organic solvents, water or mixtures thereof, to form a solution; (b) heating the solution with stirring; and (c) flash freezing then lyophilising the solids for 18 hours on a freeze dryer. The co-crystal forms of fruquintinib with organic acids selected from citric acid, fumaric acid, adipic acid and succinic acid as described above was prepared by a process comprising the steps of: (a) contacting anhydrous fruquintinib as an amorphous solid with one or more organic solvents, water, or a mixture thereof, to form a solution; (b) adding an organic acid to the solution of fruquintinib; and (c) recovering the co-crystal of fruquintinib and the organic acid as a crystalline solid. The acid (as a solid or acidic solution) may be added to the reaction mixture in a single portion. Alternatively, the acid may be added portion-wise (e.g. dropwise if an acidic solution is utilised). The period of time over which the acid is added to the reaction mixture is not particularly limiting and may be from about 1 minute to about 60 minutes. The period of time for which the mixture of acid and solvent is treated at the desired temperature before addition to the fruquintinib solution is not particularly limiting. In one embodiment, the period of time may be from about 1 minute to about 24 hours. When the acid is added to the reaction mixture as a solution, the total quantity of solvent used in the process will be the combined volumes used to dissolve the fruquintinib, as well as that used to dissolve the acid. After the addition of the acid, the reaction mixture may be treated for a period of time at ambient temperature or less as described above in connection with step (a). The reaction mixture may be stirred. 13 P101769 July 2022 Alternatively, the reaction mixture may be treated for a period of time at one or more temperatures greater than ambient i.e. greater than 30 ^oC and below the boiling point of the reaction mixture as described above in connection with step (a). The reaction mixture may be stirred. Additional solvent may be added to aid the dissolution or suspension of the reaction mixture. The reaction mixture may be left for a further period of time, e.g. about 1 minute to about 24 hours. Howsoever the amorphous solids of anhydrous fruquintinib or co-crystals of fruquintinib and an organic acid are recovered, the separated product may be washed with solvent (e.g. as described above) and dried. Drying may be performed using known methods, for example, at temperatures in the range of about 10 ^oC to about 60 ^oC, such as about 20 ^oC to about 40 ^oC, for example, ambient temperature under vacuum (for example about 1 mbar to about 30 mbar, such as about 25 mbar) for about 1 hour to about 24 hours, such as about 6 hours. Alternatively or in combination with another drying method, the crystalline or amorphous fruquintinib product may be left to dry under ambient temperature naturally i.e. without the active application of vacuum. It is preferred that the drying conditions are maintained below the point at which the salt decomposes and so when the salt is known to decompose within the temperature or pressure ranges given above, the drying conditions should be maintained below the decomposition temperature or vacuum pressure. Steps (a) to (c) may be carried out one or more times (e.g. 1, 2, 3, 4 or 5 times). Alternatively or in addition, when steps (a) to (c) are carried out more than once (e.g. 2, 3, 4 or 5 times), the solution or suspension formed in step (b) may be optionally seeded with crystalline or amorphous fruquintinib product (which was previously prepared and isolated by a method described herein). The fruquintinib products in anhydrous form (crystalline or amorphous) or as solvates or as co- crystals or as solvates of co-crystals may be optionally recrystallised from a solvent as described above in connection with step (a). The crystalline or amorphous products may be dissolved in the solvent and treated for a period of time at one or more temperatures greater than ambient i.e. greater than 30 ^oC and below the boiling point of the reaction mixture as described above in connection with step (a) (e.g. at about 50 to about 60 ^oC). The solution may then be cooled (e.g. to about 5 ^oC) and the recrystallised salt may be recovered, optionally washed and dried as described above. 14 P101769 July 2022 Pharmaceutical compositions comprising anhydrous fruquintinib (as an amorphous or crystalline solid), methods of treatment comprising anhydrous fruquintinib as an amorphous solid and uses thereof In another aspect, the present invention provides a pharmaceutical composition comprising the invented anhydrous form fruquintinib (as an amorphous or crystalline, Form 1) as described herein and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is an oral dosage form, such as a tablet, capsule, syrup, or dissolution film which may dissolve when placed e.g. under the tongue. Pharmaceutical compositions comprising co-crystals of fruquintinib and an organic acid (including solvates), methods of treatment comprising the co-crystal, and uses thereof In another aspect, the present invention provides a pharmaceutical composition comprising a co-crystal of fruquintinib and an organic acid as described herein and at least one pharmaceutically acceptable excipient. In a separate embodiment the pharmaceutical composition comprises a co-crystal solvate with an organic acid) and at least one pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is an oral dosage form, such as a tablet, capsule, syrup, or dissolution film which may dissolve when placed e.g. under the tongue. In another aspect, the present invention provides a method for treating metastatic colorectal cancer (mCRC) in a human subject comprising administering a therapeutically effective amount of anhydrous fruquintinib as an amorphous solid as described herein to the patient. In another aspect, the present invention provides a method for treating metastatic colorectal cancer (mCRC) in a human subject comprising administering a therapeutically effective amount of comprising a co-crystal of fruquintinib and an organic acid as described herein to the patient. In another aspect, the present invention provides anhydrous fruquintinib as an amorphous solid as described herein for use in treating mCRC. In another aspect, the present invention provides a co-crystal of fruquintinib and an organic acid as described herein for use in treating mCRC. Embodiments and/or optional features of the invention have been described above. Any aspect of the invention may be combined with any other aspect of the invention, unless the context demands otherwise. Any of the embodiments or optional features of any aspect may be combined, singly or in combination, with any aspect of the invention, unless the context demands otherwise. 15 P101769 July 2022 The invention will now be described further by reference to the following examples, which are intended to illustrate but not limit, the scope of the invention. Examples Abbreviations API active pharmaceutical ingredient EtOH ethanol rpm revolutions per minute RH relative humidity RT room temperature SCXRD single crystal X-ray diffraction Instrument and Methodology Details XRPD Bruker AXS D8 Advance XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a θ-2θ goniometer fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively. Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane. The details of the standard data collection method are: ^ Angular range: 2 to 42° 2θ ^ Step size: 0.05° 2θ ^ Collection time: 0.5 s/step (total collection time: 6.40 min) The instrument is performance checked weekly using NIST1976 corundum to the peak position of 35.149 ± 0.01° 2θ. Differential Scanning Calorimetry (DSC) DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan. 16 P101769 July 2022 The sample was heated at 10 °C/min from 25 °C to 250 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample. The instrument control software was Advantage for Q Series and Thermal Advantage and the data were analysed using Universal Analysis or TRIOS. Thermo-Gravimetric Analysis (TGA) TGA data were collected on a TA Instruments Discovery TGA, equipped with a 25 position auto- sampler. Typically, 5 – 10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C min^-1 from ambient temperature to 350 °C. A nitrogen purge at 25 mL min^-1 was maintained over the sample. The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis. Nuclear Magnetic Resonance (NMR) ¹H NMR spectra were collected on a Bruker 400 MHz instrument equipped with an auto-sampler and controlled by a Avance NEO nanobay console. Samples were prepared in DMSO-d₆ solvent. Automated experiments were acquired using ICON-NMR configuration within Topspin software, using standard Bruker-loaded experiments (¹H). Off-line analysis was performed using ACD Spectrus Processor. Chemical Purity Determination by High Performance Liquid Chromatography (HPLC) Purity analysis was performed on an Agilent HP1100/Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software. The full method details are provided below (Table 8): Table 8 HPLC method for chemical purity determinations Parameter Value

17 P101769 July 2022 100 x 4.6 mm Column Temperature (°C) 25 T

Static Stability Experiments Solid material was placed into open vials at elevated storage conditions, unless otherwise stated. These conditions were achieved using saturated salt solutions at specific temperatures within sealed containers. Storage containers were pre-equilibrated prior to input of samples (Table 9). Table 9 Salt solutions used to produce static storage conditions Condition Saturated Salt Solution Temperature (°C)

Freeze Dryer Samples were freeze dried using a Telstar Lyoquest laboratory freeze dryer with a condenser temperature of -55 °C using a pressure below 10 mbar. Solutions to be freeze dried were filtered through a 0.45 µm PVDF before flash-freezing using dry ice/ acetone. The frozen samples were then connected to the freeze dryer and freeze-dried for 17 18 P101769 July 2022 hours. Direct contact of the sample vessel with the surrounding ambient environment provided heat energy required for freeze drying. Crystalline anhydrous fruquintinib (Form 1) Example 1 Procedure 1 Fruquintinib (25 mg) was dissolved in THF/H₂O 7:3 v/v (2.5 mL, 100 vol) at 50 °C with 400 rpm stirring. The resultant solution was flash frozen in dry ice/acetone then lyophilised on a freeze dryer for 18 hours to produce a white powder which was confirmed amorphous by XRPD (Figure 1). After leaving the sample uncapped at ambient for 2 days, crystalline Form 1 was produced. Procedure 2 Fruquintinib (25 mg) was dissolved in THF/H₂O 7:3 v/v (2.5 mL, 100 vol) at 50 °C with 400 rpm stirring. The resultant solution was flash frozen in dry ice/acetone then lyophilised on a freeze dryer for 18 hours to produce a white powder which was confirmed amorphous by XRPD (Figure 5). After storing the sample at 40 °C / 75% RH (open vial) for 7 days, crystalline Form 1 (Figures 1 and 5) was produced. Procedure 3 Fruquintinib (400 mg) was dissolved in THF/H₂O 7:3 v/v (44 mL, 110 vol) at 50 °C with 400 rpm stirring. The resultant solution was flash frozen in dry ice/acetone then lyophilised on a freeze dryer overnight (ca. 18 hours) to produce a white powder which was confirmed amorphous by XRPD. The powder was heated to 100 °C for 30 minutes to give crystalline anhydrous fruquintinib Form 1. Crystallinity of the sample was improved by washing with MeOH (6 mL) then filtering with a Buchner funnel and negative pressure. Procedure 4 Fruquintinib (20 mg) was dissolved in THF/H₂O 7:3 v/v (2 mL, 100 vol) at 60 °C with 500 rpm stirring. The resultant solution was flash frozen in dry ice/acetone then lyophilised on a freeze dryer overnight (ca. 18 hours) to produce a white powder. TBME (400 µL) was then added to the solid at 5 °C and was then stirred at 5 °C for 2 hours to produce crystalline anhydrous fruquintinib Form 1, as confirmed by XRPD (Figure 1). The sample was isolated using filter frit and negative pressure. Anhydrous fruquintinib as amorphous solids Example 2 Procedure 5 Amorphous preparation Fruquintinib (520 mg) was dissolved in THF/H2O (100 vol. 52 mL) at 70 °C with 500 rpm stirring to give a clear solution after 10 minutes. The solution was dispensed into vials to give 20 mg of material per vial. Each sample was flash frozen in dry ice/acetone then 19 P101769 July 2022 lyophilised for 18 hours on a freeze dryer. The amorphous form was characterized by XRPD (see Figure 5) and ¹HNMR. Co-crystal of fruquintinib and citric acid as crystalline solids Example 3 Procedure 6 Fruquintinib (Form 1, 520 mg) was dissolved in THF/H₂O (100 vol. 52 mL) at 70 °C with 500 rpm stirring to give a clear solution after 10 minutes. The solution was dispensed into vials to give 20 mg of material per vial. Each sample was flash frozen in dry ice/acetone then lyophilised for 18 hours on a freeze dryer. The amorphous form was characterized by XRPD (Figure 6) and ¹HNMR. Procedure 7 Fruquintinib (amorphous, 20 mg, 0.05 mmol) was added along with citric acid (10.99 mg, 1.1 mol eq) and acetonitrile (660 µL, 33 vol) into a vial. The sample was then stirred at RT for 6 days to produce a white suspension which was filtered using filter cartridge and frit to give a white solid. The solid was analysed by XRPD (Figure 6) and ¹H NMR.

Co-crystal of fruquintinib and fumaric acid as crystalline solids Example 4 Procedure 8 Fruquintinib (amorphous, 20 mg, 0.05 mmol) was added along with fumaric acid (8.43 mg, 1.2 mol eq) and acetonitrile (660 µL, 33 vol). The sample was then stirred at RT for 6 days to produce a white suspension which was filtered using filter cartridge and frit to give a white solid. The solid was analysed by XRPD (Figure 7) and ¹H NMR. Co-crystal of fruquintinib and succinic acid as acetonitrile solvate as crystalline solids Example 5 Procedure 9 Fruquintinib (50 mg) along with fumaric acid (7.5 mg) to a vial. Acetonitrile (50 vol., 2.5 mL) was added, and the sample was stirred at RT for 24 hours. The resultant suspension was isolated using polyethylene filter frit and cartridge and negative pressure. The solid was analysed by XRPD (Figure 8) and ¹H NMR. Co-crystal of fruquintinib and adipic acid as crystalline solids Example 6 Procedure 10 20 P101769 July 2022 Fruquintinib (amorphous, 20 mg, 0.05 mmol) was added along with adipic acid (8.43 mg, 1.1 mol eq) and acetonitrile (660 µL, 33 vol). The sample was then stirred at RT for 6 days to produce a white suspension which was filtered using filter cartridge and frit to give a white solid. The solid was analysed by XRPD (Figure 9) and ¹H NMR. Procedure 11 Fruquintinib (Form 1, 50 mg, 0.13 mmol) was dissolved in MeOH/DCM 1:1 v/v (40 vol, 2 mL) by stirring at RT for 10 minutes. Adipic acid (19 mg, 0.13 mmol, 1 mol eq) was added and stirred for 10 mins at RT form a clear solution. The sample was then cooled to 5 °C and stirred for 1 hour to produce a white suspension. The suspension was filtered using frit and cartridge to give a white solid. The solid was analysed by XRPD (Figure 9) and ¹H NMR. Procedure 12 Fruquintinib (Form 1, 1.00 g) was dissolved in DCM/MeOH 1:1 v/v (40 vol, 40 mL). Adipic acid (1 mol eq, 377 mg) was added, then the mixture was stirred until a clear solution formed. The vessel was then uncapped, and the solvent left to evaporate overnight (18 hours). The resultant white powder was dried under vacuum for 4 hours in an oven at room temperature. To remove excess coformer the following procedure was followed: MeOH (10 vol, 10 mL) was added to the solid described previously (1.00 g) with the resultant suspension stirred at RT for 1 hour. The suspension was then filtered using negative pressure and Whatman Grade 1 filter paper. The solid was then dried in a vacuum oven set to 50 °C overnight to give a white powder. The solid was analysed by XRPD (Figure 9) and ¹H NMR.

Co-crystal of fruquintinib and succinic acid as crystalline solids Example 7 Procedure 13 Fruquintinib (amorphous, 20 mg, 0.05 mmol) was added along with succinic acid (5.82 mg, 1.0 mol eq) and acetonitrile (660 µL, 33 vol). The sample was then stirred at RT for 6 days to produce a white suspension which was filtered using filter cartridge and frit to give a white solid. The solid was analysed by XRPD (Figure 10) and ¹H NMR. Co-crystal of fruquintinib and succinic acid as Acetonitrile Solvate as crystalline solids Example 8 Procedure 14 Fruquintinib (50 mg) along with succinic acid (7.5 mg) to a vial. Acetonitrile (50 vol., 2.5 mL) was added, and the sample was stirred at RT for 24 hours. The resultant suspension was isolated using polyethylene filter frit and cartridge and negative pressure. The solid was analysed by XRPD (Figure 11) and ¹H NMR.

21 P101769 July 2022 Claims 1. Anhydrous fruquintinib as a crystalline solid. 2. The anhydrous fruquintinib of claim 1, wherein the crystalline form (Form 1) exhibits an X-ray powder diffraction pattern (XRPD) comprising one or more peaks selected from the group consisting of: about 9.3, 9.9, 10.7, 11.2, 11.8, 13.1, 14.5, 15.0, 17.5, 18.4, 18.7 and 19.2 degrees two-theta ± 0.2 degrees two-theta. 3. The anhydrous fruquintinib of claim 1, wherein the crystalline form (Form 1) exhibits a weight loss of 0.8% between 110-170 °C and decomposition beginning 270 °C from a thermogravimetric analysis TGA. 4. The anhydrous fruquintinib of claim 1, wherein the crystalline form (Form 1) exhibits an endotherm peak (139 J/g) with onset 245.5 °C from differential scanning calorimetry DSC. 5. The anhydrous fruquintinib of claim 1, comprising the steps of: (a) contacting anhydrous fruquintinib with one or more organic solvents, water or mixtures thereof, with heating to form a solution; (b) flash freezing, then lyophilising the solids using a freeze dryer; (c) allowing the solids to slowly warm to ambient temperature for an extended period of time. 6. Anhydrous fruquintinib as an amorphous solid. 7. The anhydrous fruquintinib of claim 6 as an amorphous solid, exhibiting an XRPD pattern as shown in Figure 5. 8. The anhydrous fruquintinib of claim 7 as an amorphous solid, as prepared by a process comprising the steps of: (a) contacting fruquintinib with one or more organic solvents, water or mixtures thereof, to form a solution; (b) heating the solution with stirring; and (c) flash freezing then lyophilising the solids for 18 hours on a freeze dryer. 9. The process according to claim 5, wherein fruquintinib as amorphous solids or seeded with crystalline solids of anhydrous fruquintinib Form 1. 22 P101769 July 2022 10. A co-crystal of fruquintinib and citric acid. 11. The co-crystal of fruquintinib and citric acid of claim 10, wherein the crystalline solid exhibits an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.2, 9.0, 10.2, 10.5, 12.1, 12.5, 13.3, 13.9, 15.0, 17.1, 18.1, 18.8 and 19.6 degrees two-theta ± 0.2 degrees two-theta. 12. A co-crystal of fruquintinib and fumaric acid. 13. The co-crystal of fruquintinib and fumaric acid of claim 12, wherein the crystalline solid Exhibits an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 4.5, 8.3, 9.2, 13.8, 16.2, 17.3, 17.7, 19.4, 21.0, 22.5, and 23.0 degrees two-theta ± 0.2 degrees two-theta. 14. A co-crystal of fruquintinib and fumaric acid as an acetonitrile solvate. 15. The co-crystal of fruquintinib and fumaric acid as an acetonitrile solvate of claim 14, wherein the crystalline solid exhibits an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.3, 8.0, 11.3, 11.6, 12.6, 14.1, 15.2, 17.0, 18.1, 18.9 and 19.7 degrees two-theta ± 0.2 degrees two-theta. 16. A co-crystal of fruquintinib and adipic acid. 17. The co-crystal of fruquintinib and adipic acid of claim 16, wherein the crystalline solid exhibits an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.3, 8.0, 11.4, 12.7, 13.8, 14.2, 15.1, 16.2, 16.9, 18.2, 19.4 and 20.6 degrees two-theta ± 0.2 degrees two-theta. 18. A co-crystal of fruquintinib and succinic acid. 19. The co-crystal of fruquintinib and succinic acid of claim 18, wherein the crystalline solid exhibits an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 8.2, 10.6, 12.5, 12.8, 13.5, and 14.6 degrees two-theta ± 0.2 degrees two-theta. 20. A co-crystal of fruquintinib and succinic acid as an acetonitrile solvate. 21. The co-crystal of fruquintinib and succinic acid as an acetonitrile solvate of claim 20, 23 P101769 July 2022 wherein the crystalline solid exhibits an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.3, 8.0, 11.2, 11.6, 12.6, 14.1, 15.3, 17.1, 18.1, 18.9, 19.7 and 20.4 degrees two-theta ± 0.2 degrees two-theta. 22. A co-crystal of fruquintinib with an organic acid selected from: citric acid, fumaric acid, adipic acid and succinic acid, as prepared by a process comprising the steps of: (a) contacting anhydrous fruquintinib, as amorphous or crystalline solids, with one or more organic solvents, water, or a mixture thereof, to form a solution; (b) adding an organic acid to the solution of fruquintinib; and (c) recovering the co-crystal of fruquintinib and the organic acid as a crystalline solid. 23. A co-crystal of fruquintinib with an organic acid, as a solvate selected from: citric acid, fumaric acid, adipic acid and succinic acid, as prepared by a process comprising the steps of: (a) contacting anhydrous fruquintinib, as amorphous or crystalline solids, with one or more organic solvents, water, or a mixture thereof, to form a solution; (b) adding an organic acid to the solution of fruquintinib; and (c) recrystallizing the crystalline solids with an organic solvent that functions as a solvating agent; and (d) recovering a solvate of the co-crystal of fruquintinib and the organic acid as a crystalline solid. 24. A pharmaceutical composition comprising anhydrous fruquintinib and at least one pharmaceutically acceptable excipient. 25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition Further comprising anhydrous fruquintinib, as amorphous or crystalline solids, further comprises an oral dosage form selected from: a tablet, capsule, syrup, or dissolution film which may dissolve when placed under the tongue. 26. A pharmaceutical composition comprising a co-crystal of fruquintinib and an organic acid and a pharmaceutically acceptable excipient. 27. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition further comprises a solvate of the co-crystal of fruquintinib and an organic acid. 28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition 24 P101769 July 2022 comprising a co-crystal of fruquintinib and an organic acid, wherein the pharmaceutical composition further comprises an oral dosage form selected from: a tablet, capsule, syrup, or dissolution film which may dissolve when placed under the tongue. 29. A method for treating metastatic colorectal cancer (mCRC) in a human subject comprising the step of: administering a therapeutically effective amount of anhydrous fruquintinib as amorphous or crystalline solids solid to the human subject. 30. A method for treating metastatic colorectal cancer (mCRC) in a human subject comprising the step of: administering a therapeutically effective amount of a co-crystal of anhydrous fruquintinib and an organic acid as a crystalline solid to the human subject. 25

Claims

Claims 1. Anhydrous fruquintinib as a crystalline solid. 2. The anhydrous fruquintinib of claim 1, wherein the crystalline form (Form 1) exhibits an X‐ray powder diffraction pattern (XRPD) comprising one or more peaks selected from the group consisting of: about 9.3, 9.9, 10.7, 11.2, 11.8, 13.1, 14.5, 15.0, 17.5, 18.4, 18.7 and 19.2 degrees two‐theta ± 0.

2 degrees two‐theta.

3. The anhydrous fruquintinib of claim 1, wherein the crystalline form (Form 1) exhibits a weight loss of 0.8% between 110‐170 °C and decomposition beginning 270 °C from a thermogravimetric analysis TGA.

4. The anhydrous fruquintinib of claim 1, wherein the crystalline form (Form 1) exhibits an endotherm peak (139 J/g) with onset 245.5 °C from differential scanning calorimetry DSC.

5. The anhydrous fruquintinib of claim 1, comprising the steps of: (a) contacting anhydrous fruquintinib with one or more organic solvents, water or mixtures thereof, with heating to form a solution; (b) flash freezing, then lyophilising the solids using a freeze dryer; (c) allowing the solids to slowly warm to ambient temperature for an extended period of time.

6. Anhydrous fruquintinib as an amorphous solid.

7. The anhydrous fruquintinib of claim 6 as an amorphous solid, exhibiting an XRPD pattern as shown in Figure 5.

8. The anhydrous fruquintinib of claim 7 as an amorphous solid, as prepared by a process comprising the steps of: (a) contacting fruquintinib with one or more organic solvents, water or mixtures thereof, to form a solution; (b) heating the solution with stirring; and (c) flash freezing then lyophilising the solids for 18 hours on a freeze dryer.

9. The process according to claim 5, wherein fruquintinib as amorphous solids or seeded with crystalline solids of anhydrous fruquintinib Form 1.

10. A co‐crystal of fruquintinib and citric acid.

11. The co‐crystal of fruquintinib and citric acid of claim 10, wherein the crystalline solid exhibits an X‐ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.2, 9.0, 10.2, 10.5, 12.1, 12.5, 13.3, 13.9, 15.0, 17.1, 18.1, 18.8 and 19.6 degrees two‐theta ± 0.2 degrees two‐theta.

12. A co‐crystal of fruquintinib and fumaric acid. 13. The co‐crystal of fruquintinib and fumaric acid of claim 12, wherein the crystalline solid Exhibits an X‐ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 4.5, 8.3, 9.2,

13.8, 16.2, 17.3, 17.7, 19.4, 21.0, 22.5, and 23.0 degrees two‐theta ± 0.2 degrees two‐theta. 14. A co‐crystal of fruquintinib and fumaric acid as an acetonitrile solvate. 15. The co‐crystal of fruquintinib and fumaric acid as an acetonitrile solvate of claim 14, wherein the crystalline solid exhibits an X‐ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.3, 8.0, 11.3, 11.6, 12.6,

14.1,

15.2, 17.0, 18.1, 18.9 and 19.7 degrees two‐theta ± 0.2 degrees two‐theta.

16. A co‐crystal of fruquintinib and adipic acid.

17. The co‐crystal of fruquintinib and adipic acid of claim 16, wherein the crystalline solid exhibits an X‐ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.3, 8.0, 11.4, 12.7, 13.8, 14.2, 15.1, 16.2, 16.9,

18.2,

19.4 and 20.6 degrees two‐theta ± 0.2 degrees two‐theta. 18. A co‐crystal of fruquintinib and succinic acid. 19. The co‐crystal of fruquintinib and succinic acid of claim 18, wherein the crystalline solid exhibits an X‐ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 8.2, 10.6, 12.5, 12.8, 13.5, and 14.6 degrees two‐theta ± 0.2 degrees two‐theta.

20. A co‐crystal of fruquintinib and succinic acid as an acetonitrile solvate.

21. The co‐crystal of fruquintinib and succinic acid as an acetonitrile solvate of claim 20, wherein the crystalline solid exhibits an X‐ray powder diffraction pattern comprising one or more peaks selected from the group consisting of: about 6.3, 8.0, 11.2, 11.6, 12.6, 14.1, 15.3, 17.1, 18.1, 18.9, 19.7 and 20.4 degrees two‐theta ± 0.2 degrees two‐theta.

22. A co‐crystal of fruquintinib with an organic acid selected from: citric acid, fumaric acid, adipic acid and succinic acid, as prepared by a process comprising the steps of: (a) contacting anhydrous fruquintinib, as amorphous or crystalline solids, with one or more organic solvents, water, or a mixture thereof, to form a solution; (b) adding an organic acid to the solution of fruquintinib; and (c) recovering the co‐crystal of fruquintinib and the organic acid as a crystalline solid.

23. A co‐crystal of fruquintinib with an organic acid, as a solvate selected from: citric acid, fumaric acid, adipic acid and succinic acid, as prepared by a process comprising the steps of: (a) contacting anhydrous fruquintinib, as amorphous or crystalline solids, with one or more organic solvents, water, or a mixture thereof, to form a solution; (b) adding an organic acid to the solution of fruquintinib; and (c) recrystallizing the crystalline solids with an organic solvent that functions as a solvating agent; and (d) recovering a solvate of the co‐crystal of fruquintinib and the organic acid as a crystalline solid.

24. A pharmaceutical composition comprising anhydrous fruquintinib and at least one pharmaceutically acceptable excipient.

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition Further comprising anhydrous fruquintinib, as amorphous or crystalline solids, further comprises an oral dosage form selected from: a tablet, capsule, syrup, or dissolution film which may dissolve when placed under the tongue.

26. A pharmaceutical composition comprising a co‐crystal of fruquintinib and an organic acid and a pharmaceutically acceptable excipient.

27. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition further comprises a solvate of the co‐crystal of fruquintinib and an organic acid.

28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition comprising a co‐crystal of fruquintinib and an organic acid, wherein the pharmaceutical composition further comprises an oral dosage form selected from: a tablet, capsule, syrup, or dissolution film which may dissolve when placed under the tongue.

29. A method for treating metastatic colorectal cancer (mCRC) in a human subject comprising the step of: administering a therapeutically effective amount of anhydrous fruquintinib as amorphous or crystalline solids solid to the human subject.

30. A method for treating metastatic colorectal cancer (mCRC) in a human subject comprising the step of: administering a therapeutically effective amount of a co‐crystal of anhydrous fruquintinib and an organic acid as a crystalline solid to the human subject.