WO2021038204A1

WO2021038204A1 - Crystalline forms of ivosidenib

Info

Publication number: WO2021038204A1
Application number: PCT/GB2020/052016
Authority: WO
Inventors: Thierry Bonnaud; Adam Patterson
Original assignee: Johnson Matthey PLC
Current assignee: Johnson Matthey PLC
Priority date: 2019-08-29
Filing date: 2020-08-21
Publication date: 2021-03-04
Anticipated expiration: 2022-02-28
Also published as: GB201912411D0

Abstract

The present invention relates to crystalline forms of ivosidenib, in particular, ivosidenib anhydrate and molecular complexes of ivosidenib. The invention also relates to methods for the preparation of the crystalline forms, and use of the crystalline forms in the treatment of cancer, such as acute myeloid leukaemia or biliary tract cancer.

Description

Crystalline Forms of Ivosidenib

Ivosidenib free base has the lUPAC name of (2S)-A/-[(1 S)-1-(2-chlorophenyl)-2-[(3,3- difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-A/-(5-fluoropyridin-3-yl)-5-oxopyrrolidine- 2-carboxamide and has the chemical structure shown below:

US9968595 (to Agios Pharmaceuticals) describes two crystalline forms of ivosidenib, which are designated as Forms 1 and 2.

The compound ivosidenib may exist in a number of polymorphic forms and many of these forms may be undesirable for producing pharmaceutically acceptable compositions. This may be for a variety of reasons including lack of stability, high hygroscopicity, low aqueous solubility and difficulty in handing.

Definitions

The term “about”, “approximately” or “ca.” 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”, “approximately” or “ca.” means within 1 , 2, 3 or 4 standard deviations. In certain embodiments, the term “about”, “approximately”, or “ca.” 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 ± 0.2 ⁰20.

The term “ambient temperature” means one or more room temperatures between about 15 °C to about 30 °C, such as about 15 °C to about 25 °C. 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 “molecular complex” is used to denote a crystalline material composed of two or more different components which has a defined single-phase crystal structure. The components are held together by non-covalent bonding, such as hydrogen bonding, ionic bonding, van der Waals interactions, tt-p interactions, etc. The term “molecular complex” includes solvates, and co-crystals. In one embodiment, the molecular complex is a solvate. In another embodiment, the molecular complex is a co-crystal.

Without wishing to be bound by theory, it is believed that when the molecular complex is a co-crystal, the co-crystal demonstrates improved properties, such as crystallinity and bioavailability properties.

The molecular complexes may be distinguished from mixtures of ivosidenib and the selected molecular complex former, such as a PEG, by standard analytical means which are well known to those skilled in the art, for example X-ray powder diffraction (XRPD), single crystal X-ray diffraction, the comparison of XRPD overlays, or differential scanning calorimetry (DSC). The molar ratio or % w/w of the components of the molecular complex may be determined using, for example, HPLC or ¹H-NMR.

The terms “polymorph,” “polymorphic form” or related term herein, refer to a crystal form of one or more molecules of ivosidenib, or ivosidenib molecular complex thereof that can exist in two or more forms, as a result different arrangements or conformations of the molecule(s) in the crystal lattice of the polymorph.

The term “pharmaceutical composition” is intended to encompass a pharmaceutically effective amount of ivosidenib 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.

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 patient, most 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 term “solvate” refers to a combination or aggregate formed by one or more molecules of a solute e.g. ivosidenib, and one or more molecules of a solvent. The one or more molecules of the solvent may be present in stoichiometric or non-stoichiometric amounts to the one or more molecules of the solute.

The terms “treat”, “treating” and “treatment” refer to the 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 a molecular complex provided herein, with or without other additional active agents, after the onset of symptoms of a disease.

The term “overnight” refers to the period of time between the end of one working day to the subsequent working day in which a time frame of about 12 to about 18 hours has elapsed between the end of one procedural step and the instigation of the following step in a procedure.

Percentage weight (% w/w) is calculated as the mass of one component divided by the total mass of the mixture, multiplied by 100%.

Description of the Figures

Figure 1 is a representative XRPD pattern of ivosidenib anhydrate.

Figure 2 is representative XRPD overlay of ivosidenib anhydrate before storage (bottom), ivosidenib anhydrate after storage at 25 °C/97% RH (relative humidity) for 7 days, ivosidenib anhydrate after storage at 40 °C/75% RH for 7 days, ivosidenib anhydrate after storage at 25 °C/97% RH for 28 days, and ivosidenib anhydrate after storage at 40 °C/75% RH for 28 days (top).

Figure 3 is a representative TGA thermogram and a DSC thermogram of ivosidenib anhydrate.

Figure 4 is a representative X-ray powder diffraction (XRPD) pattern of ivosidenib PEG-400 molecular complex. Figure 5 is a representative TGA thermogram and a DSC thermogram of ivosidenib PEG-400 molecular complex.

Figure 6 is a representative GVS isotherm plot of ivosidenib PEG-400 molecular complex.

Figure 7 is a representative XRPD pattern overlay of ivosidenib PEG-400 molecular complex before and after the GVS experiment.

Figure 8 is a representative ¹H-NMR spectrum of ivosidenib PEG-400 molecular complex.

Figure 9 is a representative XRPD pattern of ivosidenib PEG-4000 molecular complex.

Figure 10 is a representative TGA thermogram and a DSC thermogram of ivosidenib PEG-4000 molecular complex.

Figure 11 is a representative GVS isotherm plot of ivosidenib PEG-4000 molecular complex.

Figure 12 is a representative XRPD pattern overlay of ivosidenib PEG-4000 molecular complex before and after the GVS experiment.

Figure 13 is a representative ¹H-NMR spectrum of ivosidenib PEG-4000 molecular complex.

Figure 14 is a representative XRPD pattern of ivosidenib PEG-6000 molecular complex.

Figure 15 is a representative TGA thermogram and a DSC thermogram of ivosidenib PEG-6000 molecular complex.

Figure 16 is a representative GVS isotherm plot of ivosidenib PEG-6000 molecular complex.

Figure 17 is a representative XRPD pattern overlay of ivosidenib PEG-6000 molecular complex before and after the GVS experiment.

Figure 18 is a representative ¹H-NMR spectrum of ivosidenib PEG-6000 molecular complex.

Figure 19 is a representative XRPD pattern of ivosidenib PEG-8000 molecular complex.

Figure 20 is a representative TGA thermogram and a DSC thermogram of ivosidenib PEG-8000 molecular complex.

Figure 21 is a representative GVS isotherm plot of ivosidenib PEG-8000 molecular complex. Figure 22 is a representative XRPD pattern overlay of ivosidenib PEG-8000 molecular complex before and after the GVS experiment.

Figure 23 is a representative ¹H-NMR spectrum of ivosidenib PEG-8000 molecular complex.

Figure 24 illustrate how centrifugal forces are applied to particles in the Speedmixer™. Figure 24A is a view from above showing the base plate and basket. The base plate rotates in a clockwise direction.

Figure 24B is a side view of the base plate and basket.

Figure 24C is a view from above along line A in Figure 24B. The basket rotates in an anti-clockwise direction.

Description of the Invention

The present invention seeks to overcome the disadvantages associated with the prior art. The invention provides a crystalline form of ivosidenib, which is ivosidenib anhydrate. In certain embodiments, the anhydrate is purifiable. In certain embodiments, the anhydrate is stable. In certain embodiments, the anhydrate is easy to isolate and handle. In certain embodiments, the process for preparing the anhydrate is scalable.

It is also an object of the present invention to provide a molecular complex of ivosidenib which is a crystalline molecular complex of ivosidenib and a polyethyleneglycol (PEG). In certain embodiments, the crystalline molecular complex is purifiable. In certain embodiments, the crystalline molecular complex facilitates obtaining ivosidenib in an improved purity. In certain embodiments, the crystalline molecular complex is stable. In certain embodiments, the crystalline molecular complex is easy to isolate and handle. In certain embodiments, the process for preparing the crystalline molecular complex is scalable.

The crystalline forms described herein may be characterised using a number of methods known to the skilled person in the art, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance (NMR) spectroscopy (including solution and solid-state NMR). The purity of the crystalline forms provided herein may be determined by standard analytical methods, such as thin layer chromatography (TLC), gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS).

Ivosidenib anhvdate

In one aspect, the present invention provides a crystalline form of ivosidenib, which is ivosidenib anhydrate. The anhydrate may have an X-ray powder diffraction pattern comprising one or more peaks (for example 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks) selected from the group consisting of about 6.2, 8.6, 10.2, 10.7, 11.9, 12.4, 13.0, 13.8, 14.4, 14.8, 16.0, 16.1 , 16.4, 17.4, 17.9, 18.5, 19.4, 20.2, 20.4, 20.7, 21.3, 22.0, 22.2, 22.5, 22.8, 23.1 , 23.9, 24.7, 25.3, 25.7, 26.3, 26.9, 27.3, 27.7, 28.1 , 29.1 , 29.7, and 30.7 degrees two-theta ± 0.2 degrees two-theta. In one embodiment, the anhydrate may have the X-ray powder diffraction pattern substantially as shown in Figure 1.

The anhydrate may have a DSC thermogram comprising an endothermic event with an onset temperature at about 212.6 °C. In one embodiment, the anhydrate may have a DSC thermogram substantially as shown in Figure 3.

US9968595 describes two ivosidenib crystalline polymorphs - designated Form 1 and Form 2. The DSC thermogram for Form 1 has an endothermic event with an onset at about 140.1 °C. The DSC thermogram for Form 2 has an endothermic event with an onset at about 145.62 °C. The anhydrate of the invention has a significantly higher melting point than either Forms 1 and 2 i.e. 212.6 °C vs 140.1 °C or 145.62 °C. Without wishing to be bound by theory, the inventors believe a higher melting point is advantageous because the anhydrate of the invention is more thermodynamically stable than previously reported polymorphs, and the density of the crystalline anhydrate is higher.

The anhydrate may have a TGA thermogram comprising no substantial mass loss when heated from about ambient temperature to about 250 °C. In one embodiment, the anhydrate may have a TGA plot substantially as shown in Figure 3.

Crystalline ivosidenib anhydrate may be prepared by a process comprising the steps of:

(a) contacting ivosidenib with a solvent selected from the group consisting of water, 1- pentanol, dibutyl ether, and a combination thereof;

(b) forming a solution or suspension of ivosidenib in the solvent;

(c) cooling the solution or suspension obtained in step (b); and

(d) recovering the ivosidenib anhydrate as a crystalline solid.

In one embodiment, the solvent is water. In another embodiment, the solvent is 1-pentanol. In another embodiment, the solvent is dibutyl ether.

The quantity of solvent is not particularly limiting provided there is enough solvent to dissolve the ivosidenib and form a solution, or suspend the ivosidenib. The w/v ratio of ivosidenib to solvent may be in the range of about 1 g of ivosidenib : about 0.5 to about 100 ml solvent, such as about 1 g of ivosidenib : about 1 to about 75 ml solvent, for example, about 1 g of ivosidenib : about 2 to about 50 ml solvent. The ivosidenib may be contacted with the solvent at ambient temperature or less. Alternatively, the ivosidenib may be contacted with the solvent at a temperature greater than ambient i.e. greater than 30 °C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure underwhich the contacting step is conducted. In one embodiment, the contacting step is carried out at atmospheric pressure (i.e. 1.0135 x 10⁵ Pa). In one embodiment, the contacting step may be carried out at one or more temperatures in the range of > about 35 °C to about < 70 °C. In some embodiments, the contacting step is carried out at one or more temperatures > about

36 °C. In some embodiments, the contacting step is carried out at one or more temperatures > about

37 °C. In some embodiments, the contacting step is carried out at one or more temperatures > about

38 °C. In some embodiments, the contacting step is carried out at one or more temperatures > about

39 °C. In some embodiments, the contacting step is carried out at one or more temperatures > about

40 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

69 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

68 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

67 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

66 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

65 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

64 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

63 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

62 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

61 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

60 °C. In one embodiment, the contacting step is carried out at one or more temperatures in the range of > about 40 °C to < about 60 °C.

In one embodiment, the contacting step is carried out at a temperature of about 50 °C when the solvent is 1-pentanol. In another embodiment, the contacting step is carried out at a temperature of about 60 °C when the solvent is water. In another embodiment, the contacting step is carried out at a temperature of about 50 °C when the solvent is dibutyl ether.

The dissolution or suspension of ivosidenib may be encouraged through the use of an aid such as stirring, shaking and/or sonication.

In step (c), the solution or suspension is cooled such that the resulting solution or suspension has a temperature below that of the solution or suspension step (b). The rate of cooling may be from about 0.05 °C/minute to about 1 °C/minute, such as about 0.1 °C/minute to about 0.5 °C/minute, for example about 0.1 °C/minute. When a solution of ivosidenib is cooled, a suspension may eventually be observed. When a suspension of ivosidenib is cooled, no perceptible change in the appearance of the suspension may occur. The solution or suspension may be cooled to a temperature of less than ambient temperature. In one embodiment, the solution or suspension may be cooled to one or more temperatures in the range of > about 0 °C to about < 20 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 1 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 2 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 3 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 4 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 5 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 15 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 14 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 13 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 12 °C. In some embodiments, the solution or suspension may be cooled to one or more temperatures < about 11 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 10 °C. In one embodiment, the solution or suspension is cooled to one or more temperatures in the range of about 5°C to about 10 °C.

In an alternative embodiment, the solution or suspension formed in step (b) may be cooled in step (c) to about ambient temperature, optionally seeded with crystalline ivosidenib anhydrate (which was previously prepared and isolated by the method described herein) before cooling is continued to a temperature of less than ambient temperature as described above.

In step (d), the ivosidenib anhydrate is recovered as a crystalline solid. The crystalline anhydrate may be recovered by directly by filtering, decanting or centrifuging. If desired, the suspension may be mobilised with additional portions of the solvent prior to recovery of the crystalline solid. Alternatively, a proportion of the solvent may be evaporated prior to recovery of the crystalline solid.

Howsoeverthe crystalline anhydrate is recovered, the separated anhydrate may be washed with solvent (e.g. 1-pentanol, dibutyl ether and/or water) and dried. Drying may be performed using known methods, for example, at temperatures in the range of about 10 °C to about 60 °C, such as about 20 °C to about 40 °C, for example, ambient temperature under vacuum (for example about 1 mbarto about 30 mbar) for about 1 hour to about 24 hours. It is preferred that the drying conditions are maintained below the point at which the anhydrate degrades and so when the anhydrate is known to degrade within the temperature or pressure ranges given above, the drying conditions should be maintained below the degradation temperature or vacuum.

In another aspect, the present invention relates to a pharmaceutical composition comprising crystalline ivosidenib anhydrate as described herein and a pharmaceutically acceptable excipient.

In another aspect, the present invention relates to a method for treating cancer in a patient comprising administering a therapeutically effective amount of crystalline ivosidenib anhydrate as described herein to the patient. The method of treatment includes the treatment of acute myeloid leukaemia and biliary tract cancer.

In another aspect, the present invention relates to crystalline ivosidenib anhydrate as described herein for use in treating cancer, such as the treatment of acute myeloid leukaemia or biliary tract cancer.

Ivosidenib PEG molecular complexes

In another aspect, the present invention provides a crystalline molecular complex of ivosidenib and a polyethylene glycol (PEG). The crystalline molecular complex finds utility as an API (Active Pharmaceutical Ingredient) suitable for formulation or as an intermediate in processes for the preparation of ivosidenib API. The crystalline molecular complex may also facilitate obtaining ivosidenib in an improved purity.

PEGs are polyethers, which are typically soluble in aqueous solutions and organic solvents. PEGs are commercially available as substantially linear PEGs, branched PEGs, multi-arm PEGs and Y-shaped PEGs. Most PEGs comprise a distribution of molecular weights (i.e. they are polydisperse) and are not of a single molecular weight. In one embodiment of the present invention, the PEG is a substantially linear PEG having an average molecular weight s about 20,000 daltons (g/mol). The average molecular weight of PEGs may be determined using the method specified in the US National Formulary 30 (NF 30) Monograph for Polyethylene Glycol.

The PEG utilised to form the ivosidenib PEG molecular complex is not particularly limiting providing the PEG is capable of forming the molecular complex. Examples of suitable PEGs include but are not limited to PEG-400 (having a molecular weight M_w of about 380 to about 420 daltons), PEG-4000 (having a molecular weight M_w of about 3600 to about 4400 daltons), PEG-6000 (having a molecular weight M_w of about 5400 to about 6600 daltons) or PEG-8000 (having a molecular weight M_w of about 7000 to about 9000 daltons).

In one embodiment, the molecular complex is a crystalline ivosidenib PEG-400 molecular complex. The PEG-400 molecular complex may have an X-ray powder diffraction pattern comprising one or more peaks (for example 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks) selected from the group consisting of about 6.2, 7.7, 8.7, 10.0, 10.4, 11.1 , 11.7, 12.0, 12.5, 14.1 , 14.9, 15.9, 16.9, 17.3, 18.0, 18.3, 18.7, 19.3, 19.7, 20.1 , 21 .0, 21 .7, 22.1 , 22.8, 23.5, 24.4, 24.6, 25.2, 26.7, 27.3, 28.1 , and 30.9 degrees two-theta ± 0.2 degrees two-theta. In one embodiment, the molecular complex may have the X-ray powder diffraction pattern substantially as shown in Figure 4. The molecular complex may have a DSC thermogram comprising an endothermic event with an onset temperature at about 68.6 °C; and another endothermic event with an onset temperature at about 186.4 °C. The DSC thermogram of the molecular complex may also comprise an exothermic event with an onset at about 124.2 °C. As the exothermic event is a kinetic event, the skilled person would understand that the onset is variable and may occur at different temperatures depending on the conditions under which the sample is analysed, for example, the DSC instrument used to analyse the sample. In one embodiment, the molecular complex may have a DSC thermogram substantially as shown in Figure 5.

The molecular complex may have a TGA thermogram comprising no substantial mass loss when heated from about ambient temperature to about 150 °C. In one embodiment, the molecular complex may have a TGA plot substantially as shown in Figure 5.

The GVS isotherm plot shows that the molecular complex was characterised by a water uptake of about 4% w/w uptake at 25 °C/90% RH (see Figure 6). The XRPD after analysis showed that the crystalline form was substantially unchanged for the ivosidenib PEG-400 molecular complex (see Figure 7).

The ¹H-NMR spectrum of the molecular complex indicates that the molecular complex comprises about 19% w/w of PEG-400 (see Figure 8).

In one embodiment, the molecular complex is a crystalline ivosidenib PEG-4000 molecular complex. The PEG-4000 molecular complex may have an X-ray powder diffraction pattern comprising one or more peaks (for example 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks) selected from the group consisting of about 3.5, 7.0, 9.1 , 10.4, 11.5, 11.8, 12.0, 12.3, 13.4,14.5, 15.2, 15.5, 15.8, 17.0, 17.4, 18.0, 18.5, 18.7, 19.1 , 19.8, 20.2, 20.6, 20.9, 21.5, 21.7, 22.5, 22.9, 23.3, 23.7, 24.0, 24.5, 24.8, 25.2, 25.5, 26.0, 26.7, 27.3, and 29.3 degrees two-theta ± 0.2 degrees two-theta. In one embodiment, the molecular complex may have the X-ray powder diffraction pattern substantially as shown in Figure 9.

The molecular complex may have a DSC thermogram comprising an endothermic event with an onset temperature at about 116.8 °C. Without wishing to be bound by theory, it is believed that this event is due to the dissociation of the molecular complex.

In certain embodiments, the molecular complex may also comprise an endothermic event with an onset temperature at about 51 .9 °C. Without wishing to be bound by theory, it is believed that this event may occur when excess PEG-4000 from the preparation of the molecular complex is present.

In certain embodiments, the molecular complex may also comprise an exothermic event with an onset temperature at about 154.6 °C. Without wishing to be bound by theory, it is believed that this event appears to be due to the recrystallisation of the dissociated ivosidenib to the anhydrate. In certain embodiments, the molecular complex may also comprise an endothermic event with an onset temperature at about 202.5 °C. Without wishing to be bound by theory, it is believed that this event can be attributed to ivosidenib anhydrate.

In one embodiment, the molecular complex may have a DSC thermogram substantially as shown in Figure 10.

The molecular complex may have a TGA thermogram comprising a mass loss of about 1.3% when heated from about ambient temperature to about 250 °C. In one embodiment, the molecular complex may have a TGA plot substantially as shown in Figure 10.

The GVS isotherm plot shows that the molecular complex was characterised by a water uptake of about 2.6% w/w uptake at 25 °C/90% RH (see Figure 11). TheXRPD after analysis showed that the crystalline form was substantially unchanged for the ivosidenib PEG-4000 molecular complex (see Figure 12).

The ¹H-NMR spectrum of the molecular complex indicates that the molecular complex comprises about 13% w/w of PEG-4000 (see Figure 13).

In one embodiment, the molecular complex is a crystalline ivosidenib PEG-6000 molecular complex. The PEG-6000 molecular complex may have an X-ray powder diffraction pattern comprising one or more peaks (for example 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks) selected from the group consisting of about 7.1 , 8.6, 9.2, 10.5, 11.5, 11.7, 12.0, 12.3, 12.8, 13.5, 14.5, 15.6, 17.3, 18.0, 18.7, 19.2, 19.8, 20.6, 21.0, 21.6, 22.6, 22.9, 23.3, 25.5, 26.5, and 27.3 degrees two-theta ± 0.2 degrees two-theta. In one embodiment, the molecular complex may have the X-ray powder diffraction pattern substantially as shown in Figure 14.

The molecular complex may have a DSC thermogram comprising two endothermic events with onset temperatures at about 110.0 °C, and about 207.0 °C. Wthout wishing to be bound by theory, it is believed that the event with an onset temperature of about 110.0 °C is due to the dissociation of the molecular complex and the event with an onset temperature of about 207.0 °C can be attributed to ivosidenib anhydrate.

In certain embodiments, the molecular complex may also comprise an endothermic event with an onset temperature at about 50.2 °C. Without wishing to be bound by theory, it is believed that this event may occur when excess PEG-6000 from the preparation of the molecular complex is present.

The DSC thermogram of the molecular complex may also comprise an exothermic event with an onset temperature at about 165.3 °C. Without wishing to be bound by theory, the skilled person would understand that the onset is variable and may occur at different temperatures depending on the conditions under which the sample is analysed, for example, the DSC instrument used to analyse the sample, as the exothermic event is a kinetic event.

In one embodiment, the molecular complex may have a DSC thermogram substantially as shown in Figure 15.

The molecular complex may have a TGA thermogram comprising a mass loss of about 0.3% when heated from about ambient temperature to about 200 °C. In one embodiment, the molecular complex may have a TGA plot substantially as shown in Figure 15.

The GVS isotherm plot shows that the molecular complex was characterised by a water uptake of about 8% w/w uptake at 25 °C/90% RH (see Figure 16). The XRPD after analysis showed that the crystalline form was substantially unchanged for the ivosidenib PEG-6000 molecular complex (see Figure 17).

The ¹H-NMR spectrum of the molecular complex indicates that the molecular complex comprises about 14% w/w of PEG-6000 (see Figure 18).

In one embodiment, the molecular complex is a crystalline ivosidenib PEG-8000 molecular complex. The PEG-8000 molecular complex may have an X-ray powder diffraction pattern comprising one or more peaks (for example 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks) selected from the group consisting of about 7.0, 8.6, 9.2, 10.4, 10.8, 11.5, 11.8, 12.0, 12.3, 12.8, 13.2, 14.4, 14.7, 15.6, 18.0, 18.5, 19.1 , 19.6, 20.6, 20.9, 21 .1 , 21 .6, 22.5, 22.9, 23.4, 25.4, 26.5, and 27.3 degrees two-theta ± 0.2 degrees two-theta. In one embodiment, the molecular complex may have the X-ray powder diffraction pattern substantially as shown in Figure 19.

The molecular complex may have a DSC thermogram comprising two endothermic events with onset temperatures at about 112.7 °C, and about 210.1 °C.

Without wishing to be bound by theory, it is believed that the event with an onset temperature of about 112.7 °C is due to the dissociation of the molecular complex and the event with an onset temperature of about 210.1 °C can be attributed to ivosidenib anhydrate.

In certain embodiments, the molecular complex may also comprise an endothermic event with an onset temperature at about 49.6 °C. Without wishing to be bound by theory, it is believed that this event may occur when excess PEG-8000 from the preparation of the molecular complex is present.

In one embodiment, the molecular complex may have a DSC thermogram substantially as shown in Figure 20. The molecular complex may have a TGA thermogram comprising no substantial mass loss when heated from about ambient temperature to about 200 °C. In one embodiment, the molecular complex may have a TGA plot substantially as shown in Figure 20.

The GVS isotherm plot shows that the molecular complex was characterised by a water uptake of about 4% w/w uptake at 25 °C/90% RH (see Figure 21). The XRPD after analysis showed that the crystalline form was substantially unchanged for the ivosidenib PEG-8000 molecular complex (see Figure 22).

The ¹H-NMR spectrum of the molecular complex indicates that the molecular complex contains about 10% w/w of PEG-8000 (see Figure 23).

The molecular complex of ivosidenib and a PEG may be prepared by a process comprising reacting ivosidenib and a PEG using low energy ball milling or low energy grinding.

The ivosidenib may be present as the free base, or anhydrate.

The PEG may be selected from the PEGs described above. The PEG may be present in sufficient quantities to form the desired molecular complex. In one embodiment, the % w/w quantity of PEG is from about 5 to about 25% w/w of PEG to ivosidenib, such as about 7 to about 20% w/w of PEG to ivosidenib. In one embodiment, the % w/w quantity of PEG is > about 10% w/w, for example, when the PEG is PEG-8000. In another embodiment, the % w/w quantity of PEG is > about 13% w/w, for example, when the PEG is PEG-4000. In another embodiment, the % w/w quantity of PEG is > about 14% w/w, for example, when the PEG is PEG-6000. In another embodiment, the % w/w quantity of PEG is > about 19% w/w, for example, when the PEG is PEG-400.

When low energy ball milling is utilised, the milling process may be controlled by various parameters including the speed at which the milling takes place, the length of milling time and/or the level to which the milling container is filled.

The speed at which the milling takes place may be from about 50 rpm to about 1000 rpm. In one embodiment, the speed may be from about 75 rpm to about 750 rpm. In another embodiment, the speed may be from about 80 rpm to about 650 rpm. In one embodiment, the speed may be about 500 rpm.

Low energy grinding involves shaking the materials within a grinding container. The grinding occurs via the impact and friction of the materials within the container. The process may be controlled by various parameters including the frequency at which the grinding takes place, the length of grinding time and/or the level to which the container is filled. The frequency at which the grinding takes place may be from about 1 Hz to about 100 Hz. In one embodiment, the frequency may be from about 10 Hz to about 70 Hz. In another embodiment, the frequency may be from about 20 Hz to about 50 Hz. In one embodiment, the frequency may be about 30 Hz.

Regardless of whether milling or grinding is used, milling or grinding media may be used to assist the reaction. In this instance, the incorporation of hard, non-contaminating media can additionally assist in the breakdown of particles where agglomeration has occurred, for example, as a result of the manufacturing process or during transit. Such breakdown of the agglomerates further enhances the reaction of ivosidenib with the PEG. The use of milling/grinding media is well-known within the field of powder processing and materials such as stabilised zirconia and other ceramics are suitable provided they are sufficiently hard or ball bearings e.g. stainless steel ball bearings.

Regardless of whether milling or grinding is used, an improvement in the process can be made by controlling the particle ratio, the size of the milling/grinding media and other parameters as are familiar to the skilled person.

The length of milling or grinding time may be from about 1 minute to about 2 days, for example, about 10 minutes to about 5 hours, such as about 20 minutes to 3 hours.

The process may be carried out in the presence of a solvent such as water. The solvent may act to minimise particle welding. The addition of the solvent may be particularly helpful if the ivosidenib and/or PEG being reacted has agglomerated prior to use, in which case the solvent can assist with breaking down the agglomerates.

The quantity of solvent is not particularly limiting provided there is enough solvent to dissolve the ivosidenib and/or PEG and form a solution, or suspend the ivosidenib and/or PEG. The w/v ratio of ivosidenib to solvent may be in the range of about 1 g ivosidenib : about 0.25 ml to about 10 ml of solvent, for example, about 1 g ivosidenib : about 0.3 ml to about 5 ml of solvent, such as about 1 g ivosidenib : about 0.5 ml to about 1.2 ml of solvent.

The ivosidenib and PEG may be contacted with the solvent at ambient temperature or less. Alternatively, the ivosidenib may be contacted with the solvent at a temperature greater than ambient i.e. greater than 30 °C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure under which the contacting step is conducted. In one embodiment, the contacting step is carried out at atmospheric pressure (i.e. 1.0135 x 10⁵ Pa).

The ivosidenib PEG molecular complex is recovered as a crystalline solid. The crystalline molecular complex may be recovered by directly by filtering, decanting or centrifuging. If desired, the suspension may be triturated and/or mobilised with additional portions of the solvent prior to recovery of the crystalline solid. Alternatively, a proportion of the solvent may be evaporated prior to recovery of the crystalline solid.

Howsoever the crystalline molecular complex is recovered, the separated molecular complex may be washed with solvent and dried. Drying may be performed using known methods, for example, at temperatures in the range of about 10 °C to about 60 °C, such as about 20 °C to about 40 °C, for example, ambient temperature under vacuum (for example about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. It is preferred that the drying conditions are maintained below the point at which the molecular complex degrades and so when the molecular complex is known to degrade within the temperature or pressure ranges given above, the drying conditions should be maintained below the degradation temperature or vacuum.

Alternatively, the ivosidenib PEG molecular complex may be prepared by a process comprising the step of applying dual asymmetric centrifugal forces to a mixture of ivosidenib and PEG to form the molecular complex.

The ivosidenib may be present as the free base, or anhydrate.

The PEG may be selected from the PEGs described above. The PEG may be present in sufficient quantities to form the desired molecular complex. In one embodiment, the % w/w quantity of PEG is from about 5 to about 25% w/w of PEG to ivosidenib, such as about 7 to about 20% w/w of PEG to ivosidenib. In one embodiment, the % w/w quantity of PEG is about 10% w/w, for example, when the PEG is PEG-8000. In another embodiment, the % w/w quantity of PEG is about 13% w/w, for example, when the PEG is PEG-4000. In another embodiment, the % w/w quantity of PEG is about 14% w/w, for example, when the PEG is PEG-6000. In another embodiment, the % w/w quantity of PEG is about 19% w/w, for example, when the PEG is PEG-400.

The molecular complex of ivosidenib PEG is formed using dual asymmetric centrifugal forces. By “dual asymmetric centrifugal forces” we mean that two centrifugal forces, at an angle to each other, are simultaneously applied to the particles. In order to create an efficient mixing environment, the centrifugal forces preferably rotate in opposite directions. The Speedmixer™ by Hauschild (http://www.speedmixer.co.uk/index.php) utilises this dual rotation method whereby the motor of the Speedmixer™ rotates the base plate of the mixing unit in a clockwise direction (see Figure 24A) and the basket is spun in an anti-clockwise direction (see Figures 24B and 24C).

The process may be controlled by various parameters including the rotation speed at which the process takes place, the length of processing time, the level to which the mixing container is filled, the use of milling media and/or the control of the temperature of the components within the milling pot. The dual asymmetric centrifugal forces may be applied for a continuous period of time. By “continuous” we mean a period of time without interruption. The period of time may be from about 1 second to about 10 minutes, such as about 5 seconds to about 5 minutes, for example, about 10 seconds to about 200 seconds e.g. 2 minutes.

Alternatively, the dual asymmetric centrifugal forces may be applied for an aggregate period of time. By “aggregate” we mean the sum or total of more than one periods of time (e.g. 2, 3, 4, 5 or more times). The advantage of applying the centrifugal forces in a stepwise manner is that excessive heating of the particles can be avoided. The dual asymmetric centrifugal forces may be applied for an aggregate period of about 1 second to about 20 minutes, for example about 30 seconds to about 15 minutes and such as about 10 seconds to about 10 minutes e.g. 6 minutes. In one embodiment, the dual asymmetric centrifugal forces are applied in a stepwise manner with periods of cooling therebetween. In another embodiment, the dual asymmetric centrifugal forces may be applied in a stepwise manner at one or more different speeds.

The speed of the dual asymmetric centrifugal forces may be from about 200 rpm to about 4000 rpm. In one embodiment, the speed may be from about 300 rpm to about 3750 rpm, for example about 500 rpm to about 3500 rpm. In one embodiment, the speed may be about 3500 rpm. In another embodiment, the speed may be about 2300 rpm.

The level to which the mixing container is filled is determined by various factors which will be apparent to the skilled person. These factors include the apparent density of the ivosidenib and PEG, the volume of the mixing container and the weight restrictions imposed on the mixer itself.

Milling media as described above may be used to assist the reaction. In certain embodiments, the dual asymmetric centrifugal forces may be applied in a stepwise manner in which milling media may be used for some, but not all, periods of time.

The process may be carried out in the presence of a solvent selected from the group consisting of water, methanol, and a mixture thereof. The solvent or solvent mixture may act to minimise particle welding. The addition of the solvent or solvent mixture may be particularly helpful if the ivosidenib and/or PEG being reacted has agglomerated prior to use, in which case the solvent or solvent mixture can assist with breaking down the agglomerates.

When the dual asymmetric centrifugal forces are applied for an aggregate period of time, the presence or absence of solvent may be changed for each period of time. For example, the process may comprise a first period of time in which the environment is dry (i.e. ivosidenib and PEG are reacted together optionally with milling media in the absence of solvent), and a second period of time in which the environment is wet after the addition of solvent. The ivosidenib PEG molecular complex is recovered as a crystalline solid. The crystalline molecular complex may be recovered by directly by filtering, decanting or centrifuging. If desired, the suspension may be mobilised with additional portions of the solvent prior to recovery of the crystalline solid. Alternatively, a proportion of the solvent may be evaporated prior to recovery of the crystalline solid.

Alternatively, the crystalline ivosidenib PEG molecular complex may be prepared by a process comprising the steps of:

(a) contacting ivosidenib with a solvent selected from the group consisting of methanol, water, and a combination thereof;

(b) forming a solution or suspension of ivosidenib in the solvent;

(c) cooling the solution or suspension obtained in step (b); and

(d) recovering the ivosidenib PEG molecular complex as a crystalline solid.

In one embodiment, the solvent is methanol. In another embodiment, the solvent is water. In another embodiment, the solvent is a mixture of methanol and water.

When the solvent is a mixture of methanol and water, the v/v ratio of methanol : water may be any suitable ratio, such as about 1 ml : 10 ml to about 10 ml :1 ml, for example about 9 ml : 1 ml.

The quantity of solvent is not particularly limiting provided there is enough solvent to dissolve the ivosidenib and form a solution, or suspend the ivosidenib. The w/v ratio of ivosidenib to solvent may be in the range of about 1 g of ivosidenib : about 0.5 to about 25 ml solvent, such as about 1 g of ivosidenib : about 1 to about 20 ml solvent, for example, about 1 g of ivosidenib : about 5 to about 15 ml solvent. In one embodiment, the w/v ratio of ivosidenib to solvent may be in the range of about 1 g of ivosidenib : about 5 ml of solvent. In another embodiment, the w/v ratio of ivosidenib to solvent may be in the range of about 1 g of ivosidenib : about 15 ml of solvent.

The ivosidenib may be contacted with the solvent at ambient temperature or less. Alternatively, the ivosidenib may be contacted with the solvent at a temperature greater than ambient i.e. greater than 30 °C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure under which the contacting step is conducted. In one embodiment, the contacting step is carried out at atmospheric pressure (i.e. 1 .0135 x 10⁵ Pa). In one embodiment, the contacting step may be carried out at one or more temperatures in the range of > about 35 °C to about < 80 °C. In some embodiments, the contacting step is carried out at one or more temperatures > about

79 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

78 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

77 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

76 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

75 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

74 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

73 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

72 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

71 °C. In some embodiments, the contacting step is carried out at one or more temperatures < about

70 °C. In one embodiment, the contacting step is carried out at one or more temperatures in the range of > about 40 °C to < about 70 °C, for example, about 60 °C.

The solution or suspension may be held at the desired temperature (optionally with stirring) for a period of time, for example, from about 1 minute to about 24 hours, such as about 10 minutes to about 1 hour. In one embodiment, the period of time may be about 30 minutes.

The solution or suspension may be cooled such that the resulting solution or suspension has a temperature below that of the solution or suspension in the contacting step. The rate of cooling may be from about 0.05 °C/minute to about 1 .5 °C/minute, such as about 0.1 °C/minute to about 1 °C/minute. When a solution of ivosidenib PEG molecular complex is cooled, a suspension may eventually be observed. When a suspension of ivosidenib PEG molecular complex is cooled, no perceptible change in the appearance of the suspension may occur. The solution or suspension may be cooled to a temperature of less than ambient temperature. In one embodiment, the solution or suspension may be cooled to one or more temperatures in the range of > about 0 °C to about < 20 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 1 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 2 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 3 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 4 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures > about 5 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 15 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 14 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 13 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 12 °C. In some embodiments, the solution or suspension may be cooled to one or more temperatures < about 11 °C. In some embodiments, the solution or suspension is cooled to one or more temperatures < about 10 °C. In one embodiment, the solution or suspension is cooled to one or more temperatures in the range of about 5°C to about 10 °C.

In an alternative embodiment, the solution or suspension formed after the contacting step may be cooled to a temperature between about 40 °C and ambient temperature, optionally seeded one or more times (e.g. 1 , 2, 3 ,4 or 5 times) with crystalline ivosidenib PEG molecular complex (which has been previously prepared and isolated by a method described herein) before cooling is continued to a temperature of less than ambient temperature as described above.

The ivosidenib PEG molecular complex is recovered as a crystalline solid. The crystalline molecular complex may be recovered by directly by filtering, decanting or centrifuging. If desired, the suspension may be mobilised with additional portions of the solvent prior to recovery of the crystalline solid. Alternatively, a proportion of the solvent may be evaporated prior to recovery of the crystalline solid.

Howsoever the crystalline molecular complex is recovered, the separated molecular complex may be washed with solvent (e.g. methanol, water, or mixtures thereof as described above) and dried. Drying may be performed using known methods, for example, at temperatures in the range of about 10 °C to about 60 °C, such as about 20 °C to about 40 °C, for example, ambient temperature under vacuum (for example about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. It is preferred that the drying conditions are maintained below the point at which the molecular complex degrades and so when the molecular complex is known to degrade within the temperature or pressure ranges given above, the drying conditions should be maintained below the degradation temperature or vacuum.

In another aspect, the present invention relates to a pharmaceutical composition comprising crystalline ivosidenib PEG molecular complex as described herein and a pharmaceutically acceptable excipient. In another aspect, the present invention relates to a method for treating cancer in a patient comprising administering a therapeutically effective amount of crystalline ivosidenib PEG molecular complex as described herein to the patient. The method of treatment includes the treatment of acute myeloid leukaemia and biliary tract cancer.

In another aspect, the present invention relates to crystalline ivosidenib PEG molecular complex as described herein for use in treating cancer, such as the treatment of acute myeloid leukaemia or biliary tract cancer.

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.

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

1 Instrument and Methodology Details

1.1 X-ray Powder Diffraction (XRPD)

1.1.1 Bruker AXS D8 Advance

XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a Q-2Q 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° 20

• Step size: 0.05° 20

• Collection time: 0.5 s/step (total collection time: 6.40 min)

1.1.2 PANalytical Empyrean

XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry. A 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam. A PIXcel³⁰ detector, placed on the diffracted beam, was fitted with a receiving slit and 0.04 rad Soller slits. The software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analysed and presented using Diffrac Plus EVA or HighScore Plus.

Samples were prepared and analysed in a metal 96 well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1 - 2 mg) were used as received.

The scan mode for the metal plate used the gonio scan axis.

The details of the standard screening data collection method are:

• Angular range: 2.5 to 32.0° 2Q

• Step size: 0.0130° 2Q

• Collection time: 12.75 s/step (total collection time of 2.07 min)

The instrument is performance checked weekly using a silicon powder reference to the peak position of 28.441 ± 0.200° 2Q.

1.2 Nuclear Magnetic Resonance (NMR)

1.2.1 Solution State NMR

¹H NMR spectra were collected on a Bruker 400 MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Samples were prepared in MeOD-cf₆ solvent, unless otherwise stated. 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.

1.3 Differential Scanning Calorimetry (DSC)

1.3.1 TA Instruments Q2000

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, was heated at 10 °C/min from 25 °C to 325 °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.

1.3.2 TA Instruments Discovery DSC

DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position autosampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 325 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample. The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.

1.4 Thermo-Gravimetric Analysis (TGA)

1.4.1 TA Instruments Q500

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 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 from ambient temperature to 350 °C. A nitrogen purge at 60 ml/minwas maintained over the sample.

1.4.2 TA Instruments Discovery TGA

TGA data were collected on a TA Instruments Discovery TGA, equipped with a 25 position autosampler. Typically, 5 - 10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 25 ml/min was maintained over the sample.

The instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.

1.5 Gravimetric Vapour Sorption (GVS)

Hygroscopicity of a solid material may be determined by means of gravimetric vapour sorption (GVS) analysis, sometimes known by dynamic vapour sorption (DVS) analysis. The experiment subjects a sample material which is held in a fine wire basket on a microbalance within a temperature and humidity controlled environment (chamber). Using the software, the collected data can then be processed to determine the isotherm points at the increment ranges specified during the experiment and show the overall water uptake of the material.

Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software. The sample temperature was maintained at 25 °C by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min. The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 - 100 %RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by a microbalance (accuracy ±0.005 mg).

Typically, 5 - 30 mg of sample was placed in a fared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40 %RH and 25 °C (typical room conditions). A moisture sorption isotherm was performed as outlined below (2 scans per complete cycle). The standard isotherm was performed at 25 °C at 10 %RH intervals over a 0 - 90 %RH range. Typically, a double cycle (4 scans) was carried out. Data analysis was carried out within Microsoft Excel using the DVS Analysis Suite.

Table 1 Method for SMS DVS Intrinsic experiments

The sample was recovered after completion of the isotherm and re-analysed by XRPD (Section 1.1). Example 1 - PEG-400 Molecular Complex

Ivosidenib (50 mg) and PEG-400 (30 pi) were dispensed to a HPLC vial with two stainless steel grinding balls (3 mm diameter) ground on a Fritsch planetary mill (500 rpm) for 2 hours. The material was triturated in water (50 pi) to yield a wet powder which was slurried in water (500 pi) for approximately 5 minutes. The material was filtered under positive pressure and dried for 2 days.

The following table provides an XRPD peak listing for the ivosidenib PEG-400 molecular complex:

The ivosidenib PEG-400 molecular complex was also characterised as follows:

• TGA and DSC analysis (see Figure 5);

• GVS isotherm analysis (see Figure 6); · XRPD analysis before and after the GVS experiment (see Figure 7); and

• ¹H-NMR analysis of ivosidenib PEG-400 molecular complex (see Figure 8).

Example 2 - PEG-4000 Molecular Complex

Ivosidenib (30 mg) and PEG-4000 (20 mg) was dispensed to HPLC vial with two stainless steel grinding balls (3 mm diameter) and water (15 pi) and ground on a Fritsch planetary mill (500 rpm) for 2 hours. The sample was then triturated with water (500 pi) for 2 minutes, filtered and dried under vacuum for 30 minutes.

Example 3 - PEG-4000 Molecular Complex Ivosidenib (150 mg) and PEG-4000 (15 mg, 10 wt%) were dissolved in methanol/water (9:1 v/v) (2.25 ml, 15 volumes) at 60 °C with stirring and held for 1 hour. The solution was cooled from 60 °C to 40 °C at 0.5 °C/minute and seeded with solids from Example 2 at 40 °C. The solution was further cooled from 40 °C to 20 °C at 0.5 °C/minute and re-seeded at 20 °C. The seeds persisted and the mixture was cooled from 20 °C to 5 °C at 0.1 ⁰C/minute. The white suspension was filtered under positive pressure. Yield 35 mg

Example 4 - PEG-4000 Molecular Complex Ivosidenib (1 .5 g) and PEG-4000 (225 mg, 15 wt%) were suspended in MeOH:water (9:1 vlv) (7.5 ml,

5 volumes) with a magnetic stirrer bar. The material was heated to 60 °C at 500 rpm and a solution was obtained and held at 60 °C with stirring for 30 minutes.

The solution was cooled from 60 °C to 20 °C at 1 °C/minute. At 20 °C, after signs of initial precipitation, the solution was seeded with solids prepared in Example 3 (3 - 5 mg). The seeds persisted and a white suspension observed after ca. 2 minutes. The slurry was cooled form 20 °C to 5 °C at 0.1 °C/minute.

A thick white suspension was obtained at 5 °C. A pre-cooled Buchner flask, funnel and 0.45 pm nylon membrane was used to filter the suspension under suction. 2 aliquots of 1 ml of MeOH:water (9:1 vlv) were used to recover residues from the vessel and to wash the cake. The solid was dried under vacuum and ambient temperature for 20 minutes then dried in a vacuum oven at ambient temperature (~ 5 mbar) for approximately 21 hours. Dry yield = 1 .38 g

Example 5 - characterisation of the ivosidenib PEG-4000 molecular complex The following table provides an XRPD peak listing for the ivosidenib PEG-4000 molecular complex:

The ivosidenib PEG-4000 molecular complex was also characterised as follows:

• TGA and DSC analysis (see Figure 10);

• GVS isotherm analysis (see Figure 11); · XRPD analysis before and after the GVS experiment (see Figure 12); and

• ¹H-NMR analysis of ivosidenib PEG-4000 molecular complex (see Figure 13).

Example 6 - PEG-6000 Molecular Complex

Ivosidenib (60 mg) and PEG-6000 (40 mg) were dispensed to HPLC vial with two stainless steel grinding balls (3 mm diameter) and water (30 pi) and ground on a Fritsch planetary mill (500 rpm) for 2 hours. The material was triturated in water (500 pi) and filtered under positive pressure, washed with water (500 pi) and dried in a vacuum oven at 30 °C (~5 mbar) for 2 days.

The following table provides an XRPD peak listing for the ivosidenib PEG-6000 molecular complex:

The ivosidenib PEG-6000 molecular complex was also characterised as follows:

• TGA and DSC analysis (see Figure 15);

• GVS isotherm analysis (see Figure 16); · XRPD analysis before and after the GVS experiment (see Figure 17); and

• ¹H-NMR analysis of ivosidenib PEG-6000 molecular complex (see Figure 18).

Example 7 - PEG-8000 Molecular Complex

Ivosidenib (30 mg) and PEG-8000 (40 mg) were dispensed to HPLC vial with two stainless steel grinding balls (3 mm diameter) and water (35 pi) and ground on a Fritsch planetary mill (500 rpm) for 2 hours. The material was triturated in water (500 pi) and filtered under positive pressure, washed with water (500 pi) and dried in a vacuum oven at 40 °C (~5 mbar) for 90 minutes.

The following table provides an XRPD peak listing for the ivosidenib PEG-8000 molecular complex:

The ivosidenib PEG-8000 molecular complex was also characterised as follows:

• TGA and DSC analysis (see Figure 20);

• GVS isotherm analysis (see Figure 21);

• XRPD analysis before and after the GVS experiment (see Figure 22); and

• ¹H-NMR analysis of ivosidenib PEG-8000 molecular complex (see Figure 23).

Example 8 - Ivosidenib Anhydrate Ivosidenib (30 mg) was dissolved in 1-pentanol (60 mI, 2 volumes) with stirring (400 rpm) at 50 °C. The solution was cooled to 5 °C at 0.1 °C/minute A white slurry was observed at 5 °C and an aliquot removed for analysis by XRPD. Example 9 - Ivosidenib Anhydrate

Ivosidenib (30 mg) was suspended in dibutyl ether (1 .5 ml, 50 volumes) with stirring (400 rpm) at 50 °C. The suspension was cooled to 5 °C at 0.1 °C/minute. The suspension at 5 °C was filtered under positive pressure. Example 10 - Ivosidenib Anhydrate

Ivosidenib (200 mg) was suspended in dibutyl ether (2 ml, 10 volumes) with stirring (400 rpm) at 50 °C for 30 minutes. The suspension was cooled to 5 °C at 0.1 °C/minute. The suspension at 5 °C was filtered under positive pressure. Example 11 - Ivosidenib Anhydrate

Ivosidenib (520 mg) was suspended in water (8.0 ml) was slurried at 60 °C for 3 days. The suspension was filtered and dried at ambient.

Example 12 - Characterisation of Ivosidenib Anhydrate The following table provides an XRPD peak listing for ivosidenib anhydrate:

Stability studies of ivosidenib anhydrate under four storage conditions were also carried out. Figure 2 is representative XRPD overlay of ivosidenib anhydrate before storage (bottom), ivosidenib anhydrate after storage at 25 °C/97% RH (relative humidity) for 7 days, ivosidenib anhydrate after storage at 40 °C/75% RH for 7 days, ivosidenib anhydrate after storage at 25 °C/97% RH for 28 days, and ivosidenib anhydrate after storage at 40 °C/75% RH for 28 days (top). The anhydrate remains stable under two different temperature and humidity conditions for at least 28 days.

Ivosidenib anhydrate was also characterised by TGA and DSC analysis (see Figure 3).

Claims

1 . A crystalline form of ivosidenib, which is crystalline ivosidenib anhydrate.

2. A crystalline form of ivosidenib according to claim 1 having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of about 6.2, 8.6, 10.2, 10.7, 11.9, 12.4, 13.0, 13.8, 14.4, 14.8, 16.0, 16.1 , 16.4, 17.4, 17.9, 18.5, 19.4, 20.2, 20.4, 20.7, 21.3, 22.0, 22.2, 22.5, 22.8, 23.1 , 23.9, 24.7, 25.3, 25.7, 26.3, 26.9, 27.3, 27.7, 28.1 , 29.1 , 29.7, and 30.7 degrees two-theta ± 0.2 degrees two-theta.

3. A crystalline form of ivosidenib according to claim 2, which has an X-ray powder diffraction pattern substantially as shown in Figure 1 .

4. A crystalline form of ivosidenib according to any one of claims 1 to 3, which has a DSC thermogram comprising an endothermic event with an onset temperature at about 212.6 °C, preferably, the DSC thermogram substantially as shown in Figure 3.

5. A process for preparing crystalline ivosidenib anhydrate, the process comprising the steps of:

(b) forming a solution or suspension of ivosidenib in the solvent;

(c) cooling the solution or suspension obtained in step (b); and

(d) recovering the ivosidenib anhydrate as a crystalline solid.

6. A molecular complex which is a crystalline molecular complex of ivosidenib and a polyethylene glycol.

7. A molecular complex according to claim 6, wherein the polyethylene glycol is selected from the group consisting of PEG-400, PEG-4000, PEG-6000 and PEG-8000.

8. A molecular complex according to claim 7, wherein the crystalline molecular complex is a crystalline molecular complex of ivosidenib and PEG-400, and the crystalline molecular complex comprises about 19% w/w PEG-400.

9. A molecular complex according to claim 8, wherein the molecular complex is a crystalline ivosidenib PEG-400 molecular complex having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of about 6.2, 7.7, 8.7, 10.0, 10.4, 11.1 ,

11.7, 12.0, 12.5, 14.1 , 14.9, 15.9, 16.9, 17.3, 18.0, 18.3, 18.7, 19.3, 19.7, 20.1 , 21.0, 21.7, 22.1 ,

22.8, 23.5, 24.4, 24.6, 25.2, 26.7, 27.3, 28.1 , and 30.9 degrees two-theta ± 0.2 degrees two- theta.

10. A molecular complex according to claim 9, which has the X-ray powder diffraction pattern substantially as shown in Figure 4.

11. A molecular complex according to any one of claims 8 to 10, which has a DSC thermogram comprising an endothermic event with an onset temperature at about 68.6 °C; and another endothermic event with an onset temperature at about 186.4 °C.

12. A molecular complex according to claim 11 , which has a DSC thermogram substantially as shown in Figure 5.

13. A molecular complex according to any one of claims 8 to 12, which has a TGA thermogram comprising no substantial mass loss when heated from about ambient temperature to about 150 °C.

14. A molecular complex according to claim 13, which has a TGA plot substantially as shown in Figure 5.

15. A molecular complex according to claim 7, wherein the crystalline molecular complex is a crystalline molecular complex of ivosidenib and PEG-4000, and the crystalline molecular complex comprises about 13% w/w PEG-4000.

16. A molecular complex according to claim 15, wherein the molecular complex is a crystalline ivosidenib PEG-4000 molecular complex having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of about 3.5, 7.0, 9.1 , 10.4, 11 .5, 11 .8, 12.0, 12.3, 13.4,14.5, 15.2, 15.5, 15.8, 17.0, 17.4, 18.0, 18.5, 18.7, 19.1 , 19.8, 20.2, 20.6, 20.9, 21.5, 21.7, 22.5, 22.9, 23.3, 23.7, 24.0, 24.5, 24.8, 25.2, 25.5, 26.0, 26.7, 27.3, and 29.3 degrees two-theta ± 0.2 degrees two-theta.

17. A molecular complex according to claim 16, which has the X-ray powder diffraction pattern substantially as shown in Figure 9.

18. A molecular complex according to any one of claims 15 to 17, which has a DSC thermogram comprising an endothermic event with an onset temperature at about 116.8 °C.

19. A molecular complex according to claim 18, which has a DSC thermogram substantially as shown in Figure 10.

20. A molecular complex according to any one of claims 15 to 19, which has a TGA thermogram comprising a mass loss of about 1.3% when heated from about ambient temperature to about 250 °C.

21. A molecular complex according to claim 20, which has a TGA plot substantially as shown in Figure 10.

22. A molecular complex according to claim 7, wherein the crystalline molecular complex is a crystalline molecular complex of ivosidenib and PEG-6000, and the crystalline molecular complex comprises about 14% w/w PEG-6000.

23. A molecular complex according to claim 22, wherein the molecular complex is a crystalline ivosidenib PEG-6000 molecular complex having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of about 7.1 , 8.6, 9.2, 10.5, 11 .5, 11 .7, 12.0, 12.3, 12.8, 13.5, 14.5, 15.6, 17.3, 18.0, 18.7, 19.2, 19.8, 20.6, 21.0, 21.6, 22.6, 22.9, 23.3, 25.5, 26.5, and 27.3 degrees two-theta ± 0.2 degrees two-theta.

24. A molecular complex according to claim 23, which has the X-ray powder diffraction pattern substantially as shown in Figure 14.

25. A molecular complex according to any one of claims 22 to 24, which has a DSC thermogram comprising two endothermic events with onset temperatures at about 110.0 °C, and about 207.0 °C.

26. A molecular complex according to claim 25, which has a DSC thermogram substantially as shown in Figure 15.

27. A molecular complex according to any one of claims 22 to 26, which has a TGA thermogram comprising a mass loss of about 0.3% when heated from about ambient temperature to about 200 °C.

28. A molecular complex according to claim 27, which has a TGA plot substantially as shown in Figure 15.

29. A molecular complex according to claim 7, wherein the crystalline molecular complex is a crystalline molecular complex of ivosidenib and PEG-8000, and the crystalline molecular complex comprises about 10% w/w PEG-8000.

30. A molecular complex according to claim 29, wherein the molecular complex is a crystalline ivosidenib PEG-8000 molecular complex having an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of about 7.0, 8.6, 9.2, 10.4, 10.8, 11 .5,

11.8, 12.0, 12.3, 12.8, 13.2, 14.4, 14.7, 15.6, 18.0, 18.5, 19.1 , 19.6, 20.6, 20.9, 21.1 , 21.6, 22.5,

22.9, 23.4, 25.4, 26.5, and 27.3 degrees two-theta ± 0.2 degrees two-theta.

31 . A molecular complex according to claim 30, which has the X-ray powder diffraction pattern substantially as shown in Figure 19.

32. A molecular complex according to any one of claims 29 to 31 , which has a DSC thermogram comprising two endothermal events with onset temperatures at about 112.7 °C, and about 210.1 °C.

33. A molecular complex according to claim 32, which has a DSC thermogram substantially as shown in Figure 20.

34. A molecular complex according to any one of claims 29 to 33, which has a TGA thermogram comprising no substantial mass loss when heated from about ambient temperature to about 200 °C.

35. A molecular complex according to claim 34, which has a TGA plot substantially as shown in Figure 20.

36. A process for preparing a crystalline molecular complex of ivosidenib and a polyethylene glycol, which process comprises using low energy ball milling or low energy grinding to form the crystalline molecular complex.

37. A process for preparing a crystalline molecular complex of ivosidenib and a polyethylene glycol, which process comprises the step of applying dual asymmetric centrifugal forces to a mixture of ivosidenib and the polyethylene glycol to form the crystalline molecular complex.

38. A process for preparing a crystalline molecular complex of ivosidenib and a polyethylene glycol, which process comprises the steps of:

(b) forming a solution or suspension of ivosidenib in the solvent;

(c) cooling the solution or suspension obtained in step (b); and

(d) recovering the ivosidenib PEG molecular complex as a crystalline solid.

39. A pharmaceutical composition comprising crystalline ivosidenib anhydrate according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

40. A method for treating cancer in a patient comprising administering a therapeutically effective amount of crystalline ivosidenib anhydrate according to any one of claims 1 to 4 to the patient.

41 . A method according to claim 40, wherein the method of treatment is the treatment of acute myeloid leukaemia or biliary tract cancer.

42. Crystalline ivosidenib anhydrate according to any one of claims 1 to 4 for use in treating cancer.

43. Crystalline ivosidenib anhydrate according to claim 42 for use in the treatment of acute myeloid leukaemia or biliary tract cancer.

44. A pharmaceutical composition comprising a crystalline molecular complex of ivosidenib and a polyethylene glycol according to any one of claims 6 to 35 and a pharmaceutically acceptable excipient.

45. A method for treating cancer in a patient comprising administering a therapeutically effective amount of a crystalline molecular complex of ivosidenib and a polyethylene glycol according to any one of claims 6 to 35.

46. A method according to claim 45, wherein the method of treatment is the treatment of acute myeloid leukaemia or biliary tract cancer.

47. A crystalline molecular complex of ivosidenib and a polyethylene glycol according to any one of claims 6 to 35 for use in treating cancer.

48. A crystalline molecular complex of ivosidenib and a polyethylene glycol according to any one of claims 6 to 35 for use in the treatment of acute myeloid leukaemia or biliary tract cancer.