Solid state form of adagrasib and process for preparation

Abstract

The present disclosure relates to Adagrasib solid state forms and to Adagrasib trifluoroacetic acid salt and solid state form. In embodiments crystalline polymorphs of Adagrasib and of Adagrasib trifluoroacetic acid salt, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Description

SOLID STATE FORM OF ADAGRASIB AND PROCESS FOR PREPARATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, Indian Provisional Application No. 202411049781 filed on June 28, 2024, Indian Provisional Application No. 202411053465 filed on July 12, 2024, and Indian Provisional Application No. 202411064687 filed on August 27, 2024. The entire contents of the foregoing applications are incorporated by reference herein.FIELD OF THE DISCLOSURE

[0002] The present disclosure encompasses solid state forms of Adagrasib and of Adagrasib salts, in embodiments processes for preparation thereof, and pharmaceutical compositions thereof.BACKGROUND OF THE DISCLOSURE

[0003] Adagrasib, 2-|(2.S')-4-|7-(8-chloronaphthalcn- l -yl)-2-| |(2.S')- l-mcthylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2- enoyl)piperazin-2-yl]acetonitrile, has the following chemical structure:

[0004] Adagrasib is an investigational orally available covalently-binding inhibitor of G12C, which is a mutant form of the protein KRAS. It is in clinical development for the treatment of various types of cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer, Adagrasib is also under investigation for the treatment of other KRASG12C- mutant solid tumors, Adagrasib is also under investigation for the treatment of other KRASG12C-mutant solid tumors.

[0005] WO 2017 / 201161 discloses compounds encompassing Adagrasib, and Adagrasib compound is described in International Publication No. WO 2019 / 099524. WO 2023039020 and WO 2023205074 describe process for the synthesis of Adagrasib and W02022056307describes crystalline forms of Adagrasib. The entire contents of the foregoing applications are incorporated by reference herein.

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

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

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

[0009] The present disclosure provides crystalline polymorphs of Adagrasib, processes for preparation thereof, and pharmaceutical compositions thereof. The present disclosure also provides crystalline polymorphs of Adagrasib salts, particularly trifluoro acetate salt, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs of Adagrasib and of Adagrasib salt can be used to prepare other solid state forms of Adagrasib, Adagrasib salts or co-crystals and their solid state forms.

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

[0011] The present disclosure provides crystalline forms of Adagrasib and of Adagrasib salts for use in medicine, including for the treatment of patients with non-small cell lung cancer (NSCLC) and / or colorectal cancer, or other KRASG12C-mutant solid tumors.

[0012] The present disclosure also encompasses the use of the crystalline polymorphs of Adagrasib and of Adagrasib salts of the present disclosure for the preparation of pharmaceutical compositions and / or formulations.

[0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising the crystalline polymorphs of Adagrasib or of Adagrasib salts according to the present disclosure.

[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Adagrasib or of Adagrasib salts with at least one pharmaceutically acceptable excipient.

[0015] The crystalline polymorphs of Adagrasib and of Adagrasib salts as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorphs of Adagrasib or of Adagrasib salts may be used as medicaments, such as for the treatment various types of cancers, including non-small cell lung cancer (NSCLC) and / or colorectal cancer, or other KRASG12C-mutant solid tumors.

[0016] The present disclosure also provides methods of treating various types of cancers, including non-small cell lung cancer (NSCLC) and / or colorectal cancer, or other KRASG12C- mutant solid tumors, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Adagrasib or of Adagrasib salts of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from cancer, such as non-small cell lung cancer (NSCLC) and / or colorectal cancer, or otherKRASG12C-mutant solid tumors. The present disclosure also provides uses of crystalline polymorphs of Adagrasib of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating patients with cancer, such as non-small cell lung cancer (NSCLC) and / or colorectal cancer, or other KRASG12C-mutant solid tumors.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction (XRPD) pattern of crystalline Adagrasib form Al.

[0018] Figure 2 shows a characteristic XRPD of crystalline Adagrasib Form A2.

[0019] Figure 3 shows a characteristic XRPD of crystalline Adagrasib Form A3.

[0020] Figure 4 shows a characteristic XRPD of crystalline Adagrasib Form A4.

[0021] Figure 5 shows a characteristic XRPD of crystalline Adagrasib Form A5.

[0022] Figure 6 shows a characteristic XRPD of crystalline Adagrasib Form A6.

[0023] Figure 7 shows a characteristic XRPD of crystalline Adagrasib Form A7.

[0024] Figure 8 shows a characteristic XRPD of crystalline Adagrasib trifluoro acetate Form A8.

[0025] Figure 9a shows a solid state13C NMR spectrum crystalline of Adagrasib Form A3 (full scan).

[0026] Figure 9b shows a solid state13C NMR spectrum crystalline of Adagrasib Form A3 (0-100 ppm).

[0027] Figure 9c shows a solid state13C NMR spectrum crystalline of Adagrasib Form A3 (100-200 ppm).DETAILED DESCRIPTION OF THE DISCLOSURE

[0028] The present disclosure provides crystalline polymorphs of Adagrasib, processes for preparation thereof, and pharmaceutical compositions thereof. The present disclosure also provides crystalline polymorphs of Adagrasib salts, particularly trifluoro acetate salt, processes for preparation thereof, and pharmaceutical compositions thereof.

[0029] Solid state properties of Adagrasib and Adagrasib salts, and crystalline polymorphs thereof can be influenced by controlling the conditions under which Adagrasib and crystalline polymorphs thereof are obtained in solid form.

[0030] The solid state form may be referred to herein as " Adagrasib Form name" or "Crystalline Form name of Adagrasib " or "Crystalline Adagrasib Form name" or "Crystallinepolymorph name of Adagrasib " or "Crystalline Adagrasib polymorph name" or " Adagrasib polymorph name" . For example, crystalline form Al of Adagrasib may be interchangeably referred to herein as Adagrasib Form Al or as Crystalline Adagrasib Form Al or as Crystalline polymorph Al of Adagrasib or as Crystalline Adagrasib polymorph Al or Adagrasib polymorph Al or any similar name or obvious modifications of the above described names.

[0031] A solid-state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Adagrasib or Adagrasib salt described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w / w), greater than about 90% (w / w), greater than about 95% (w / w), greater than about 98% (w / w), greater than about 99% (w / w), or about 100% of the subject crystalline polymorph of Adagrasib or Adagrasib salt. In some embodiments of the disclosure, the described crystalline polymorph of Adagrasib or Adagrasib salt may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more other crystalline polymorph of the same Adagrasib or Adagrasib salt.

[0032] In specific embodiments, the above described pure or purified Adagrasib or Adagrasib salt may relate to enantiomeric purity, i.e. pure or purified Adagrasib refers to Adagrasib that is substantially free of enantiomers of Adagrasib or Adagrasib salt. Any of the described crystalline forms of Adagrasib or Adagrasib salt of the present disclosure may be enantiomerically pure or substantially free of enantiomers of Adagrasib or Adagrasib salt (preferably containing: about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% of any other enantiomers of the Adagrasib or Adagrasib salt).

[0033] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Adagrasib or Adagrasib salt of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lowerdegree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0034] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Adagrasib referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Adagrasib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0035] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Adagrasib or Adagrasib salt, relates to a crystalline form of Adagrasib which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w / w), of either water or organic solvents as measured for example by TGA.

[0036] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0037] As used herein, the term "isolated" in reference to crystalline polymorph of Adagrasib or Adagrasib salt of the present disclosure corresponds to a crystalline polymorph of Adagrasib or Adagrasib salt that is physically separated from the reaction mixture in which it is formed.

[0038] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka 1 radiation wavelength 1.54060 A. XRPD peaks reported herein are measured using CuKal radiation, I = 1.54060 A, typically at a temperature of 25 ± 3 °C.

[0039] As will be appreciated, copper Ka radiation is composed mainly of the higher intensity CuKal radiation (wavelength of 1.54060 A) and the lower intensity CuKa2 radiation (wavelength of 1.54440 A). The wavelengths are very close and often not resolved and hence it is common to refer to the weighted averaged CuKa wavelength of 1.5418 A. As mentioned in the examples, XRPD measurements are determined using copper Ka radiation having this weighted average wavelength. Thus, XRPD measurements reported herein are measured using copper Ka radiation having wavelength 1.5418 A. Preferably the XRPD measurements are measured at a temperature of 22-25 °C.

[0040] As used herein, unless stated otherwise,13C NMR reported herein are measured at a magic angle spinning frequency cor / 27i = 20 kHz, preferably at a temperature of at 295 K ± 3 K. Preferably, the13C scale is referenced to a-glycine (176.03 ppm for13C).

[0041] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT ” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.

[0042] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mb of the solvent. In another context, the term "v / v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 mb of solvent X was added.

[0043] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, whenthat process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0044] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0045] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24 °C.

[0046] The present disclosure includes a crystalline polymorph Adagrasib designated form Al. The crystalline Form Al of Adagrasib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 8.8, 14.8, 16.7, 17.1 and 18.5 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0047] Crystalline Form A 1 of Adagrasib may be further characterized by an X-ray powder diffraction pattern having peaks at 8.8, 14.8, 16.7, 17. 1 and 18.5 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 10.8, 16.1, 19. 1 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0048] Crystalline Form Al of Adagrasib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 8.8, 10.8, 14.8, 16.1, 16.7, 17.1, 18.5, 19.1 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0049] Crystalline Form Al of Adagrasib may be alternatively characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a)-(c): (a) 3.0 to 4.8 degrees 2- theta ± 0.2 degrees 2-theta; (b) 6.2 to 8.2 degrees 2-theta ± 0.2 degrees 2-theta, and (c) 9.2 to 10.3 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form Al of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and (c) in combination.

[0050] In one embodiment of the present disclosure, crystalline Form Al of Adagrasib is isolated. Thus, crystalline Form Al of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0051] Crystalline Form Al of Adagrasib may be a hydrate or a hydrate-solvate form.

[0052] Crystalline Form Al of Adagrasib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at8.8, 14.8, 16.7, 17.1 and 18.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD patern as depicted in Figure 1, and combinations thereof.

[0053] The present disclosure includes a crystalline polymorph Adagrasib designated form A2. The crystalline Form A2 of Adagrasib may be characterized by data selected from one or more of the following: an X-ray powder diffraction patern substantially as depicted in Figure 2; an X-ray powder diffraction patern having peaks at 7.7, 9.1, 14.4, 18.8 and 22.1 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0054] Crystalline Form A2 of Adagrasib may be further characterized by an X-ray powder diffraction patern having peaks at 7.7, 9.1, 14.4, 18.8 and 22.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 13.7, 16.4, 19.4 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0055] Crystalline Form A2 of Adagrasib may be alternatively characterized by an X-ray powder diffraction patern having peaks at 7.7, 9.1, 13.7, 14.4, 16.4, 18.8, 19.4, 22.1 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0056] Crystalline Form A2 of Adagrasib may be alternatively characterized by an X-ray powder diffraction patern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a)-(c): (a) 3.6 to 4.0 degrees 2- theta ± 0.2 degrees 2-theta; (b) 5.0 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta, and (c) 10.6 to 11.0 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form A2 of Adagrasib may be characterized by an X-ray powder diffraction patern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and (c) in combination.

[0057] In one embodiment of the present disclosure, crystalline Form A2 of Adagrasib is isolated. Thus, crystalline Form A2 of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0058] Crystalline Form A2 of Adagrasib may be a hydrate-solvate form.

[0059] Crystalline Form A2 of Adagrasib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD patern having peaks at 7.7, 9.1, 14.4, 18.8 and 22.1 degrees 2-theta± 0.2 degrees 2-theta; an XRPD patern as depicted in Figure 2, and combinations thereof.

[0060] The present disclosure further includes a process for preparing Crystalline Form A2 of Adagrasib. The process comprises crystallizing Adagrasib from a mixture of solvent and an antisolvent in the presence of formic acid. Particularly, the solvent and antisolvent mixturecomprises from about 0.5% (v / v) to about 15% (v / v) of formic acid, or from about 1% (v / v) to about 15% (v / v), or from about 0.5% (v / v) to about 10% (v / v). Preferably the amount of formic acid in the solvent mixture is from about 1% (v / v) to about 10% (v / v).

[0061] Typically, the solvent is alcohol solvent and the antisolvent is ether solvent. For example, alcohol solvents are C1-C4 alcohol, preferably ethanol and ether antisolvent are C2- Cs ether, preferably dibutyl ether. Thus, the mixture of solvent and antisolvent is preferably a mixture of ethanol and dibutyl ether.

[0062] Particularly, the ratio (v / v) of solvent to antisolvent according to any aspect or embodiment of the process is: about 1:2 to about 1:8, about 1:2 to about 1:6, about 1:3 to about 1:5, or about 1:4.

[0063] According to any aspect or embodiment of the process, the mixture of solvent and antisolvent is used in an amount of: about 5 to about 80 ml per gram of Adagrasib, about 8 to about 70 ml per gram of Adagrasib, or about 9 to about 64 ml per gram of Adagrasib.

[0064] According to any aspect or embodiment of the process, the crystallization may be carried at a temperature of about 20 °C to about 80 °C, about 20 °C to about 70 °C, or about 23 °C to about 62 °C. The crystallization may comprise cooling. Optionally the process may comprise maintaining the mixture for a suitable period of time, preferably a period of: about 1 to about 8 hours, about 2 to about 6 hours, about 3 to about 5 hours, or about 4 hours, preferably at a temperature of about 18 °C to about 30 °C, about 22 °C to about 28 °C, about 22 °C to about 26 °C, or about 25 °C.

[0065] The formic acid can be present in the solvent or anti-solvent prior to the addition of Adagrasib, or alternatively, formic acid can be added to a solution comprising Adagrasib and the solvent mixture. Particularly, formic acid can be first present in the solvent. In specific embodiment, the process comprises dissolving Adagrasib in a solvent comprising formic acid, preferably at the above specified amounts, and adding antisolvent. In other embodiments, the process comprises dissolving Adagrasib in a solvent mixture, for example ethanol and dibutyl ether, and adding formic acid, preferably at the above specified amounts.

[0066] The above described process can further include isolating the obtained crystalline form, and drying. Drying can be done for example under vacuum, for sufficient amount of time. Optionally, the drying can be carried out at a temperature of: about 20 °C to about 30 °C, about 22 °C to about 28 °C, or about 25 °C, preferably for a period of time of: about 5 minutes to about 2 hours, about 5 minutes to about 1 hour, about 5 minutes to about 30 minutes, or about 10 minutes to about 15 minutes. The process can also include converting the obtained form A2 of Adagrasib to form A3 of Adagrasib. The conversion may be achieved by drying form A2 ofAdagrasib. In specific embodiment, the present disclosure includes form A2 of Adagrasib for use in preparation of form A3 of Adagrasib.

[0067] The present disclosure includes a crystalline polymorph Adagrasib designated form A3. The crystalline Form A3 of Adagrasib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 10.7, 12.7, 15.0, 22.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta; or by a solid state13C NMR spectrum having peaks at: 166.9,105.9, 103.5, 66.9, 62.9 and 56.8 ppm ± 0.2 ppm; or by a solid state13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 137.0 ppm ± 2 ppm:29.9, 31.1, 33.5, 70.1, 74.1 and 80.2 ppm ± 0.1 ppm; or by a solid state13C NMR spectrum having chemical shift difference from a peak at 166.9 ppm ± 1 ppm of 29.9 ppm ± 0.1 ppm; or by a solid state13C NMR spectrum as depicted in any one of Figures 9a, 9b or 9c; and / or combinations of these data.

[0068] Crystalline Form A3 of Adagrasib may be further characterized by an X-ray powder diffraction pattern having peaks at 10.7, 12.7, 15.0, 22.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 8.5, 13.6, 21.5 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0069] Crystalline Form A3 of Adagrasib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 8.5, 10.7, 12.7, 13.6, 15.0, 21.5, 22.3, 23.3 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0070] In particular, crystalline Form A3 may be described by an XRPD pattern having characteristic peaks at 8.5, 9.0, 9.4, 10.7, 12.1, 12.7, 13.6, 14.4, 15.0, 16.0, 16.4, 17.0, 18.1, 18.4, 18.8, 19.5, 19.9, 20.3, 20.8, 21.5, 22.3, 22.8, 23.3, 23.9, 24.6, 25.2, 25.8, 26.5, 27.3, 27.5, 29.1, 29.9, 30.9, 32.3, 33.3, 33.9, 34.7, 35.5, 36.4, 36.7 and 37.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0071] Crystalline Form A3 may be described by an XRPD pattern as described in any of the above aspects or embodiments, and also having an absence of peaks at any one, two or three of (a), (b) or (c): (a) from 3.5 to 4.0 degrees 2-theta ± 0.2 degrees 2-theta; (b) 5.0 to 6.6 degrees 2-theta ± 0.2 degrees 2-theta; and (c) from 11.2 to 11.8 degrees 2-theta ± 0.2 degrees 2-theta. In particular, crystalline Form A3 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and (c) in combination.

[0072] In one embodiment of the present disclosure, crystalline Form A3 of Adagrasib is isolated. Thus, crystalline Form A3 of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0073] Crystalline Form A3 of Adagrasib may be an anhydrous form. Thus, Form A3 of Adagrasib according to any aspect or embodiment of the disclosure may be an anhydrous form.

[0074] Crystalline Form A3 of Adagrasib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 10.7, 12.7, 15.0, 22.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0075] Crystalline Form A3 of Adagrasib described above may have advantageous properties as described above. In particular, crystalline Form A3 of Adagrasib has high Bulk Density (BD) and Tapped Density (TD), indicating better packing and good flow properties. Also, Form A3 has low Hausner Ratio (HR) which is indicative of a material having good flow.

[0076] In addition, Crystalline Form A3 of Adagrasib is stable under conditions of extreme (high and low) relative humidity conditions, and to other conditions, such as heating and grinding (either neat or in the presence of typical pharmaceutical processing solvents).

[0077] The present disclosure further includes a process for preparing Crystalline Form A3 of Adagrasib. The process comprises drying Crystalline Form A2 of Adagrasib. Preferably, the drying is carried out at a temperature of about from about 40 °C to about 80 °C, or from 55 °C to about 65 °C preferably about 60 °C, preferably wherein the drying is under a vacuum, such as in a vacuum tray dryer, for a period of at least 10 hours, for example from 10 hours to 20 hours, or from 12 hours to 20 hours, or from 14 hours to 20 hours, or about 16 hours.

[0078] The present disclosure includes a crystalline polymorph Adagrasib designated form A4. The crystalline Form A4 of Adagrasib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 9.2, 9.6, 17.1, 20.7 and 22.9 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0079] Crystalline Form A4 of Adagrasib may be further characterized by an X-ray powder diffraction pattern having peaks at 9.2, 9.6, 17.1, 20.7 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 14.4, 18.3, and 26.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0080] Crystalline Form A4 of Adagrasib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 9.2, 9.6, 14.4, 17.1, 18.3, 20.7, 22.9 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0081] Crystalline Form A4 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a)-(c): (a) 3.6 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta; (b) 5.2 to 6.6 degrees 2-theta ± 0.2 degrees 2-theta, and (c) 12.8 to 13.6 degrees 2-theta ± 0.2 degrees 2-theta. In particular, Form A4 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and(b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and(c) in combination.

[0082] In one embodiment of the present disclosure, crystalline Form A4 of Adagrasib is isolated. Thus, crystalline Form A4 of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0083] Crystalline Form A4 of Adagrasib may be a hydrate-solvate form.

[0084] Crystalline Form A4 of Adagrasib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 9.2, 9.6, 17.1, 20.7 and 22.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0085] The present disclosure includes a crystalline polymorph Adagrasib designated form A5. The crystalline Form A5 of Adagrasib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 4.6, 9.2, 21.0, 24.4 and 26.9 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0086] Crystalline Form A5 of Adagrasib may be further characterized by an X-ray powder diffraction pattern having peaks at 4.6, 9.2, 21.0, 24.4 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 14.0, 19.9 and 23.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0087] Crystalline Form A5 of Adagrasib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 4.6, 9.2, 14.0, 19.9, 21.0, 23. 1, 24.4 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0088] Crystalline Form A5 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a)-(c): (a) 3.8 to 4. 1 degrees 2-theta ± 0.2 degrees 2-theta; (b) 5.2 to 7.3 degrees 2-theta ± 0.2 degrees 2-theta, and (c) 9.8 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta. In particular, Form A5 of Adagrasib may be characterizedby an X-ray powder diffraction patern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and(b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and(c) in combination.

[0089] In one embodiment of the present disclosure, crystalline Form A5 of Adagrasib is isolated. Thus, crystalline Form A5 of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0090] Crystalline Form A5 of Adagrasib may be an anhydrous form.

[0091] Crystalline Form A5 of Adagrasib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD patern having peaks at 4.6, 9.2, 21.0, 24.4 and 26.9 degrees 2 -theta ± 0.2 degrees 2-theta; an XRPD patern as depicted in Figure 5, and combinations thereof.

[0092] The present disclosure includes a crystalline polymorph Adagrasib designated form A6. The crystalline Form A6 of Adagrasib may be characterized by data selected from one or more of the following: an X-ray powder diffraction patern substantially as depicted in Figure 6; an X-ray powder diffraction patern having peaks at 4.7, 15.9, 18.3, 19.1 and 20.1 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0093] Crystalline Form A6 of Adagrasib may be further characterized by an X-ray powder diffraction patern having peaks at 4.7, 15.9, 18.3, 19.1 and 20.1 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 8.4, 14.2, 21.4 and 27.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0094] Crystalline Form A6 of Adagrasib may be alternatively characterized by an X-ray powder diffraction patern having peaks at 4.7, 8.4, 14.2, 15.9, 18.3, 19.1, 20.1, 21.4 and 27.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0095] Crystalline Form A6 of Adagrasib may be characterized by an X-ray powder diffraction patern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two or three of (a)-(c): (a) 3.5 to 4. 1 degrees 2-theta ± 0.2 degrees 2-theta; (b) 6.0 to 7.8 degrees 2-theta ± 0.2 degrees 2-theta, and (c) 9.0 to 11.0 degrees 2-theta ± 0.2 degrees 2-theta. In particular, Form A6 of Adagrasib may be characterized by an X-ray powder diffraction patern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone; or (a) and(b) in combination; or (a) and (c) in combination; or (b) and (c) in combination; or (a), (b) and(c) in combination.

[0096] In one embodiment of the present disclosure, crystalline Form A6 of Adagrasib is isolated. Thus, crystalline Form A6 of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0097] Crystalline Form A6 of Adagrasib may be a hydrate form. In specific embodiments, crystalline Form A6 of Adagrasib may be a trihydrate form. Thus, crystalline Form A6 of Adagrasib as described in any aspect or embodiment herein, may be a trihydrate.

[0098] Crystalline Form A6 of Adagrasib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 4.7, 15.9, 18.3, 19.1 and 20.1 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.

[0099] The present disclosure includes a crystalline polymorph Adagrasib designated form A7. The crystalline Form A7 of Adagrasib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 7; an X-ray powder diffraction pattern having peaks at 14.3, 18.4, 20.6, 22.8 and 24.2 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0100] Crystalline Form A7 of Adagrasib may be further characterized by an X-ray powder diffraction pattern having peaks at 14.3, 18.4, 20.6, 22.8 and 24.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 9.1, 13.9, 19.4, and 26.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0101] Crystalline Form A7 of Adagrasib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 9.1, 13.9, 14.3, 18.4, 19.4, 20.6, 22.8, 24.2 and 26.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0102] Crystalline Form A7 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two, three, or four of (a)-(d): (a) 3.5 to 5.2 degrees 2- theta ± 0.2 degrees 2-theta; (b) 6.5 to 7.5 degrees 2-theta ± 0.2 degrees 2-theta, (c) 8.0 to 8.5 degrees 2-theta ± 0.2 degrees 2-theta, and (d) 9.8 to 10.2 degrees 2-theta ± 0.2 degrees 2-theta. In particular, Form A7 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone, or (d) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (a) and (d) in combination; or (b) and (c) in combination, or (b) and (d) in combination; or (a), (b) and (c) in combination , or (a), (b) and (d) in combination, or (a), (b), (c) and (d) in combination.

[0103] In one embodiment of the present disclosure, crystalline Form A7 of Adagrasib is isolated. Thus, crystalline Form A7 of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0104] Crystalline Form A7 of Adagrasib may be a hydrate or a hydrate-solvate form. In specific embodiments, crystalline Form A7 of Adagrasib may be a formic acid solvate-hydrate form. Thus, crystalline Form A7 of Adagrasib as described in any aspect or embodiment herein, may be a formic acid solvate-hydrate form.

[0105] Crystalline Form A7 of Adagrasib may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 14.3, 18.4, 20.6, 22.8 and 24.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7, and combinations thereof.

[0106] The present disclosure includes Adagrasib trifluoro acetate salt. Specifically, it includes crystalline trifluoro acetate salt if Adagrasib.

[0107] The present disclosure includes crystalline polymorph of Adagrasib trifluoro acetate salt designated form A8. The crystalline Form A8 of Adagrasib trifluoro acetate salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at 14.1, 17.1, 18.3, 19.5 and 21.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0108] Crystalline Form A8 of Adagrasib trifluoro acetate salt may be further characterized by an X-ray powder diffraction pattern having peaks at 14.1, 17.1, 18.3, 19.5 and 21.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 10.0, 13.5, 16.3 and 20.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0109] Crystalline Form A8 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at any one, two, three, or four of (a)-(d): (a) 3.6 to 4.2 degrees 2- theta ± 0.2 degrees 2-theta; (b) 4.8 to 5.2 degrees 2-theta ± 0.2 degrees 2-theta, (c) 7.8 to 8.2 degrees 2-theta ± 0.2 degrees 2-theta, and (d) 8.8 to 9.1 degrees 2-theta ± 0.2 degrees 2-theta. In particular, Form A8 of Adagrasib may be characterized by an X-ray powder diffraction pattern having peaks as described in any aspect or embodiment herein, and also having an absence of peaks at: (a) alone; or (b) alone; or (c) alone, or (d) alone; or (a) and (b) in combination; or (a) and (c) in combination; or (a) and (d) in combination; or (b) and (c) in combination, or (b) and (d) in combination; or (a), (b) and (c) in combination , or (a), (b) and (d) in combination, or (a), (b), (c) and (d) in combination.

[0110] Crystalline Form A8 of Adagrasib trifluoro acetate salt may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.0, 13.5, 14.1, 16.3 17.1, 18.3, 19.5, 20.5 and 21.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0111] In one embodiment of the present disclosure, crystalline Form A8 of Adagrasib trifluoro acetate salt is isolated. Thus, crystalline Form A8 of Adagrasib according to any aspect or embodiment of the present disclosure may be isolated.

[0112] Crystalline Form A8 of Adagrasib trifluoro acetate salt may be characterized by each of the above characteristics alone / or by all possible combinations, e.g., an XRPD pattern having peaks at 14.1, 17.1, 18.3, 19.5 and 21.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 8, and combinations thereof.

[0113] In specific embodiment, the present disclosure includes Crystalline Forms Al, A2, A3, A4, A5 A6 and A7 of Adagrasib and crystalline form A8 of Adagrasib trifluoro acetate salt which are polymorphically pure; i.e., it is substantially free of any other forms, as described herein above. Thus, crystalline Forms Al, A2, A3, A4, A5, A6, and A7 of Adagrasib according to any aspect or embodiment of the present disclosure, may be polymorphically pure, i.e. may be substantially free of any other crystalline and / or amorphous forms of Adagrasib. Crystalline Form A8 of Adagrasib trifluoro acetate salt according to any aspect or embodiment of the present disclosure, may be polymorphically pure, i.e. may be substantially free of any other crystalline and / or amorphous forms of Adagrasib trifluoro acetate salt.

[0114] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Adagrasib, Adagrasib salts or co-crystals and their solid state forms.

[0115] The present disclosure encompasses a process for preparing other solid state forms of Adagrasib, Adagrasib salts or co-crystals and their solid state forms thereof. The process includes preparing any one of the solid state forms of Adagrasib or of Adagrasib salts by the processes of the present disclosure, and converting that form to a different form of Adagrasib, Adagrasib salt or co-crystal and solid state forms thereof. In particular embodiment, the solid- state forms of Adagrasib of the present disclosure, particularly Adagrasib form A3, may be used to prepare amorphous Adagrasib.

[0116] The present disclosure provides the above-described crystalline polymorphs of Adagrasib or of Adagrasib salts for use in the preparation of pharmaceutical compositions comprising Adagrasib and / or crystalline polymorphs thereof.

[0117] The present disclosure also encompasses the use of crystalline polymorphs of Adagrasib or Adagrasib salts of the present disclosure for the preparation of pharmaceuticalcompositions of crystalline polymorph Adagrasib or of Adagrasib salt and / or crystalline polymorphs thereof.

[0118] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Adagrasib or of Adagrasib salt of the present disclosure with at least one pharmaceutically acceptable excipient.

[0119] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Adagrasib or Adagrasib salts of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0120] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0121] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0122] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate,methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0123] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0124] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0125] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0126] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

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

[0128] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0129] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and / or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose,ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

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

[0131] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0132] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0133] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

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

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

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

[0137] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and / or milled, dried, and thenscreened and / or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and / or a lubricant.

[0138] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[0139] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

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

[0141] A pharmaceutical formulation of Adagrasib or of Adagrasib salt can be administered. Adagrasib may be formulated for administration to a mammal, in embodiments to a human, by injection. Adagrasib can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[0142] The crystalline polymorphs of Adagrasib or Adagrasib salts and the pharmaceutical compositions and / or formulations of Adagrasib or of Adagrasib salts of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with cancer, such as non-small cell lung cancer (NSCEC) and / or colorectal cancer, or other KRASG12C-mutant solid tumors.

[0143] The present disclosure also provides methods of treating of patients with cancer, such as non-small cell lung cancer (NSCEC) and / or colorectal cancer, or other KRASG12C- mutant solid tumors, by administering a therapeutically effective amount of any one or acombination of the crystalline polymorphs of Adagrasib or of Adagrasib salts of the present disclosure, or at least one of the above pharmaceutical compositions and / or formulations, to a subject in need of the treatment.

[0144] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.Powder X-ray Diffraction ("XRPD") method

[0145] X-ray diffraction was performed on X-Ray powder diffractometer:

[0146] Bruker D8 Advance; Copper Ka radiation (X = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.Measurement parameters:Scan range: 2 - 40 degrees 2-theta;Scan mode: continuous;Step size: 0.05 degrees;Time per step: 0.5 s;Sample spin: 30 rpm;Sample holder: PMMA specimen holder ring.

[0147] All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sampleSolid-state13C-NMR method

[0148] The solid-state NMR spectra are measured at 11.7 T using a Bruker Avance III HD 500 US / WB NMR spectrometer (Karlsruhe, Germany, 2013) with a 3.2-mm probehead.The13C CP / MAS NMR spectra were recorded using a standard cross-polarization pulse sequence at a spinning frequency of 20 kHz. The cross-polarization contact time was set to 2 ms, and SPINAL64 dipolar decoupling was applied during signal acquisition. The spectral width was 300 ppm with a resonance offset of 100 ppm. The number of scans was adjusted to achieve a signal-to-noise ratio (S / N) at least 50. The13C chemical shifts were referenced to a-glycine (176.03 ppm for carbonyl carbon. All experiments were conducted under active cooling to maintain the sample temperature at a constant 295 K (room temperature).EXAMPLESPreparation of starting materials

[0149] Starting material Adagrasib can be prepared according to methods known from the literature, for example according to the disclosure in International Publication No. WO 2019 / 099524, for example according to the procedure described in Example 478, or by any other process described in the literature.Example 1: Preparation of Adagrasib crystal form Al

[0150] Adagrasib (1.0 g,) was dissolved in ethyl formate (5 ml) at a temperature of about 25 °C. The obtained solution was filtered through a 0.45 micron filter and the obtained clear solution was added into diisopropylether (50 ml). The obtained reaction mixture was maintained under stirring at a temperature of about 45-50 °C for about 18 hours and a solid was formed. The obtained solid was filtered and dried under vacuum for a period of about 10- 15 minutes. The obtained solid was analyzed by XRPD and the obtained crystalline form was designated as Form Al of Adagrasib. The XRPD pattern is presented in Figure 1.

[0151] Form Al prepared according to this example is a hydrate or solvate -hydrate of Adagrasib.Example 2: Preparation of Adagrasib crystal form Al

[0152] Adagrasib (0.03 g) was dissolved in ethanol (0.72 ml) at a temperature of about 25 °C. Then, dibutyl ether (2 ml) was added to the clear solution at a temperature of about 25 °C, and a mixture was formed. After 24 hours, the obtained solid was filtered and dried under vacuum for about a period of about 10-15 minutes. The obtained solid was analyzed by XRPD, Form Al was obtained.Example 3: Preparation of Adagrasib crystal form A2

[0153] Adagrasib (0.05 g) was suspended in dibutyl ether (3 ml) at a temperature of about 40 °C. Then, ethanol (0.7 ml) was added slowly to the suspension to obtain a clear solution. The clear solution was cooled down to a temperature of about 10 °C over a period of about 40 minutes (cooling rate 1 °C per minute). A solid obtained at a temperature of about 10 °C and the solid was filtered and dried under vacuum at about 25 °C for about 10-15 minutes. Theobtained solid was analyzed by XRD and the obtained crystalline form was designated as Form A2 of Adagrasib. The XRPD pattern is presented in Figure 2.

[0154] Form A2 prepared according to this example is a hydrate or solvate -hydrate of Adagrasib.Example 4: Preparation of Adagrasib crystal form A2

[0155] Adagrasib (1.0 g) was suspended in dibutyl ether (60 ml) at a temperature of about 40 °C. Then, ethanol (20 ml) was added slowly to the suspension to obtain a clear solution. The clear solution was cooled down to a temperature of about 0 °C over a period of about 40 minutes (cooling rate 1 °C per minute). When temperature reached about 0 °C a seed of Form A2 (0.02g) was added and the mixture maintained at a temperature of about 0 °C for about 4 hours. A solid obtained at a temperature of about 0 °C and the solid was fdtered and dried under vacuum at a temperature of about 25 °C for about 10-15 minutes. The obtained solid was analyzed by XRPD, crystalline form A2 of Adagrasib obtained.

[0156] Form A2 prepared according to this example is a hydrate or solvate -hydrate of Adagrasib.Example 5: Preparation of Adagrasib crystal form A3

[0157] Adagrasib (0.05 g,) was suspended in dibutyl ether (3 ml) at a temperature or about 40 °C. Then, ethanol (0.7 ml) was added slowly to the suspension to obtain a clear solution. The clear solution was cooled down to a temperature of about 10 °C over a period of about 40 minutes (cooling rate 1 °C per minute). A solid obtained at a temperature of about 10 °C and the solid was filtered and dried under vacuum at about 25 °C for about 10-15 minutes. Then, the solid was further dried in a vacuum tray drier for about 16 hours at a temperature of about 60 °C. The obtained solid was analyzed by XRD and the obtained crystalline form was designated as Form A3 of Adagrasib. The XRPD pattern is presented in Figure 3.

[0158] Form A3 prepared according to this example is an anhydrous form.Example 6: Preparation of Adagrasib crystal form A4

[0159] Adagrasib (0.05 g, Form A2) was suspended in heptane (3 ml) at 60 °C. The obtained slurry was maintained for four hour at a temperature of about 60 °C. The obtained solid was filtered and dried under vacuum at a temperature of about 25 °C for about 10-15 minutes. The obtained solid was analyzed by XRPD and the obtained crystalline form was designated as Form A4 of Adagrasib. The XRPD pattern is presented in Figure 4

[0160] Form A4 prepared according to this example is a hydrate or solvate -hydrate of Adagrasib.Example 7: Preparation of Adagrasib crystal form A5

[0161] Adagrasib (0.05 g, Form A2) was suspended in heptane (3 ml) at a temperature of about 60 °C. The obtained slurry was maintained for about two hour at a temperature of about 60 °C. The obtained solid was filtered and dried under vacuum at a temperature of about 25 °C for about 10-15 minutes. Then, the solid was further dried in a vacuum tray drier for about 16 hours at a temperature of about 60 °C. The obtained solid was analyzed by XRPD and the obtained crystalline form was designated as Form A5 of Adagrasib. The XRPD pattern is presented in Figure 5.

[0162] Form A5 prepared according to this example is an anhydrous form.Example 8: Preparation of Adagrasib crystal form A2

[0163] Adagrasib (1.0 g) was dissolved in a solution of ethanol and 1% (v / v) of formic acid (total volume 2 ml) at a temperature of about 40 °C and a clear solution formed. Dibutyl ether (8 ml) was added to the clear solution at a temperature of about 40 °C. Then, the clear solution was cooled down to a temperature of about 25 °C over a period of about 20 minutes at a cooling rate of about 1 °C per minute, and then it was maintained at a temperature of about 25 °C for about 4 hours. The obtained solid fdtered and dried under vacuum at about 25 °C for about 10- 15 minutes. The obtained solid was analyzed by XRD, crystalline Form A2 of Adagrasib obtained.

[0164] Form A2 is hydrate or solvate-hydrate form of Adagrasib.Example 9: Preparation of Adagrasib crystal form A2Adagrasib (0.05 g) was dissolved in a solution of ethanol and 10% (v / v) of formic acid (total volume 0.2 ml) at a temperature of about 25 °C and a clear solution formed. Dibutyl ether (3 ml) was added to the solution at about 25 °C. A solid obtained immediately and maintained at about 25 °C for 4 hours. The obtained solid was fdtered and dried under vacuum at about 25 °C for about 10-15 minutes. The obtained solid was analyzed by XRD, crystalline Form A2 of Adagrasib obtained.

[0165] Form A2 may be a hydrate or solvate-hydrate of Adagrasib.Example 10: Preparation of Adagrasib crystal form A2

[0166] Adagrasib (0.075 g) was dissolved in a mixture of ethanol (0.7 ml) and dibutyl ether (3 ml) at a temperature of about 40 °C, and a clear solution was formed. Formic acid (20pL) was added to the solution at a temperature of about 25 °C. A solid obtained immediately and maintained at about 25 °C for about 4 hours. The obtained solid was filtered and dried under vacuum at about 25 °C for about 10-15 minutes. The obtained solid was analyzed by XRD, crystalline Form A2 of Adagrasib obtained.

[0167] Form A2 may be a hydrate or solvate-hydrate of Adagrasib.Example 11: Preparation of Adagrasib crystal form A6

[0168] Adagrasib (0.05 g, Form B) was suspended in diisopropylether (3 ml) at a temperature of about 40 °C. Then, a premix solution of ethanol (0.6 ml) and of acetic acid (0.02 ml) was added slowly to the suspension and a clear solution was formed. The clear solution was cooled down to a temperature of about 0 °C over a period of 40 minutes, and then it was further maintained under stirring for 18 hours. After 18 hours a solid obtained at a temperature of about 0 °C and the solid was filtered and dried under vacuum at about 25 °C for a period of about 10-15 minutes. The obtained solid was analyzed by XRD and the obtained crystalline form was designated as Form A6 of Adagrasib. The XRPD pattern is presented in Figure 6.

[0169] Form A6 obtained according to this example may be a Trihydrate of Adagrasib.Example 12: Preparation of Adagrasib crystal form A7

[0170] Adagrasib (0.1 g) was suspended in n-Heptane (6 ml) at a temperature of about 40 °C. A premix solution of Acetone (1.4 ml) and Formic acid (0.07 ml) added slowly to the suspension to obtain clear solution. The clear solution was cooled down to a temperature of about 0 °C over a period of about 40 minutes, and then it was further maintained under stirring for 18 hours. After 18 hours, a solid obtained at a temperature of about 0 °C and the solid was filtered and dried under vacuum at about 25 °C for about 10-15 minutes. The obtained solid was analyzed by XRD and the obtained crystalline form was designated as Form A7 of Adagrasib. The XRPD pattern is presented in Figure 7.

[0171] Form A7 obtained according to this example may be a formic acid solvate-hydrate of Adagrasib.Example 13: Preparation of Adagrasib crystal form A8

[0172] Adagrasib (0.03 g) was dissolved in a premix of ethanol (0.14 ml) and Trifluoro acetic acid (0.07 ml) at a temperature of about 25 °C. Then, dibutyl ether (1 ml) was added to the clear solution at about 25 °C, and the obtained clear solution was maintained under stirring for 24 hours. After 24 hour a solid obtained and was filtered and dried under vacuum for about 10-15 minutes. The obtained solid was analyzed by XRD and the obtained crystalline form was designated as Form A8 of Adagrasib. The XRPD pattern is presented in Figure 8.

[0173] Form A8 may be a Trifluoro acetate salt of Adagrasib.Example 14: Preparation of Adagrasib crystal form A3

[0174] Adagrasib form A2 (1.0 g) was dried under vacuum tray drier at 60 °C for 16 hours. The obtained solid was analyzed by XRD, crystalline Form A3 of Adagrasib obtained.Example 15: Flowability Study

[0175] According to bulk density / tapped density and Hausner ratio calculations, Form A3 is characterized by having a good flow. By comparison, Forms A and B were found to have only a passable or poor flow.Example 16 - Stability StudiesStorage stability at different relative humidities

[0176] Samples of Form A3 of Adagrasib were subjected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below:Table ]

[0177] These results demonstrate that Form A3 of Adagrasib is stable after exposure to extremes of high and low relative humidities for at least 7 days. Moreover, as evidence by the preparation of Form A3 by exposure to elevated temperature (60 °C) under high vacuum, this form is highly stable under both low humidity / high temperature conditions. By way of contrast,according to the disclosure of WO 2022 / 056307, Forms C, D, and E are prone to water loss, in some cases with hysteresis, under DSC conditions.Grinding experiments

[0178] Samples of Form A3 of Adagrasib were subjected to strong grinding, and to solvent drop grinding in water. Grinding was carried out on the samples alone, or in the presence of water. In these experiments, about 20 mg of the sample is placed in a mortar and ground with a pestle for 2 minutes. The solvent, when used, as added to the crystalline material before grinding, in a volume of 10 microlitres. XRPD analysis performed on each of the samples after the grinding experiment, confirmed no change in the starting material (Table 2):Table 2

[0179] The results demonstrate that Form A3 of Adagrasib is resistant to polymorphic changes even when exposed to grinding with water, and is highly suitable for preparing pharmaceutical formulations.Thermal stability

[0180] A sample of Form A3 of Adagrasib was subjected to heating up to 100 °C for 30 minutes. XRPD analysis of the sample confirmed no change in the starting material (Table 3):Table 3

Claims

Claims:

1. A crystalline Adagrasib Form A3 characterized by data selected from one or more of the following: i) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.7, 12.7, 15.0, 22.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta, ii) an XRPD pattern as depicted in Figure 3; iii) a solid state 13C NMR spectrum having peaks at about: 166.9, 105.9, 103.5, 66.9, 62.9 and 56.8 ppm ± 0.2 ppm; iv) a solid state 13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 137.0 ppm ± 2 ppm: 29.9, 31.1, 33.5, 70.1, 74.1 and 80.2 ppm ± 0.1 ppm; v) a solid state 13C NMR spectrum having chemical shift difference from a peak at 166.9 ppm ± 1 ppm of 29.9 ppm ± 0.1 ppm; vi) a solid state 13C NMR spectrum as depicted in any one of Figures 9a, 9b, or 9c; and vii) any combination thereof.

2. The crystalline Adagrasib Form A3 according to Claim 1, further characterized by an XRPD pattern having characteristic peaks at: 10.7, 12.7, 15.0, 22.3 and 23.3degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two three, or four, additional peaks at 8.5, 13.6, 21.5 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

3. The crystalline Adagrasib Form A3 according to any one of Claim 1 or Claim 2, further characterized by an XRPD pattern having characteristic peaks at: 8.5, 10.7, 12.7, 13.6, 15.0,21.5, 22.3, 23.3 and 24.6 degrees 2-theta ± 0.2 degrees 2-theta.

4. The crystalline Adagrasib Form A3 according to any one of Claims 1, 2, or 3, further characterized by an XRPD pattern having characteristic peaks at: 8.5, 9.0, 9.4, 10.7, 12.1, 12.7,13.6, 14.4, 15.0, 16.0, 16.4, 17.0, 18.1, 18.4, 18.8, 19.5, 19.9, 20.3, 20.8, 21.5, 22.3, 22.8, 23.3, 23.9, 24.6, 25.2, 25.8, 26.5, 27.3, 27.5, 29.1, 29.9, 30.9, 32.3, 33.3, 33.9, 34.7, 35.5, 36.4, 36.7 and 37.8 degrees 2-theta ± 0.2 degrees 2-theta.

5. The crystalline Adagrasib Form A3 according to any one of Claims 1, 2, 3, or 4, further characterized by an XRPD pattern having an absence of peaks in either one, two or three of the following areas: (i) from 3.5 to 4.0 degrees 2-theta ± 0.2 degrees 2-theta; (ii) from 5.0 to 6.6 degrees 2-theta ± 0.2 degrees 2-theta and (iii) from 11.2 to 11.8 degrees 2-theta ± 0.2 degrees 2-theta6. The crystalline Adagrasib Form A3 according to any one of Claims 1, 2, 3, 4, or 5, which is isolated.

7. The crystalline Adagrasib Form A3 according to any one of Claims 1, 2, 3, 4, 5, or 6, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Adagrasib.

8. The crystalline Adagrasib Form A3 according to any one of Claims 1, 2, 3, 4, 5, 6, or 7, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Adagrasib.

9. Use of the crystalline Adagrasib Form A3 according to any one of Claims 1 to 8, for the preparation of a pharmaceutical composition and / or formulation, preferably wherein the pharmaceutical formulation is a tablet or a capsule.

10. A pharmaceutical composition comprising the crystalline Adagrasib Form A3 according to any one of Claims 1 to 8.

11. A process for preparing the pharmaceutical composition according to Claim 10, comprising combining the crystalline Adagrasib Form A3 according to any one of Claims 1 to 8 with at least one pharmaceutically acceptable excipient.

12. The crystalline Adagrasib Form A3 according to any one of Claims 1 to 8, or the pharmaceutical composition according to Claim 10, for use as a medicament.

13. The crystalline Adagrasib Form A3 according to any one of Claims 1 to 8, or a pharmaceutical composition according to Claim 10, for use in treating cancer, particularlysmall cell lung cancer (NSCLC) and / or colorectal cancer, or other KRASG12C-mutant solid tumors.

14. A method for treating cancer, particularly small cell lung cancer (NSCLC) and / or colorectal cancer, or other KRASG12C-mutant solid tumors, comprising administering a therapeutically effective amount of the crystalline Adagrasib Form A3 according to any one of Claims 1 to 8, or the pharmaceutical composition according to Claim 10, to a subject in need of the treatment.

15. Use of the crystalline Adagrasib Form A3 according to any one of Claims 1 to 8 in the preparation of another solid state form of Adagrasib, or Adagrasib salts and co-crystals and their crystalline forms.

16. A process for preparing a solid state form of Adagrasib, or Adagrasib salts and cocrystals and their crystalline forms comprising preparing the crystalline Adagrasib Form A3 according to any one of Claims 1 to 8, and converting it to another a solid state form thereof.

17. A process for preparing the crystalline Adagrasib Form A3 according to any one of Claims 1 to 8, comprising drying a crystalline Adagrasib Form A2.

18. The process according to Claim 17, wherein the drying is carried out at a temperature of from about 40 °C to about 80 °C, preferably from 55 °C to about 65 °C preferably about 60 °C.

19. The process according to any one of Claims 17 or 18, wherein the drying is carried out under reduced pressure, or under vacuum, preferably in a vacuum tray dryer.

20. The process according to any one of Claims 17, 18, or 19, wherein drying is carried out for a period of at least 10 hours, for example from 10 hours to 20 hours, or from 12 hours to 20 hours, or from 14 hours to 20 hours, or about 16 hours.

21. A process for preparing a crystalline Adagrasib Form A2, comprising crystallizing the crystalline Adagrasib Form A2 from a mixture of solvent and an antisolvent in the presence of formic acid.

22. The process according to Claim 21, wherein the amount of formic acid in the solvent and an antisolvent mixture is from about 0.5% (v / v) to about 15% (v / v) of formic acid, or from about 1% (v / v) to about 15% (v / v), or from about 0.5% (v / v) to about 10% (v / v), preferably from about 1% (v / v) to about 10% (v / v).

23. The process according to any one of Claims 21 or 22, wherein the solvent is alcohol solvent, preferably C1-C4 alcohol, preferably ethanol; and the antisolvent is ether solvent, preferably C2-C8 ether, preferably dibutyl ether; and preferably wherein the solvent and antisolvent mixture is ethanol and dibutyl ether.

24. The process according to any one of Claims 21, 22, or 23, wherein the ratio (v / v) of solvent to antisolvent is: about 1:2 to about 1:8, about 1:2 to about 1:6, about 1:3 to about 1:5, or about 1:4.

25. The process according to any one of Claims 21, 22, 23, or 24, wherein the mixture of solvent and antisolvent is in an amount of: about 5 to about 80 ml per gram of Adagrasib, about 8 to about 70 ml per gram of Adagrasib, or about 9 to about 64 ml per gram of Adagrasib26. The process according to any one of Claims 21, 22, 23, 24, or 25, wherein formic acid is present in the solvent before addition of Adagrasib.

27. A process according any one of Claims 21, 22, 23, 24, 25, or 26, wherein the crystallization is carried at a temperature of about 20 °C to about 80 °C, about 20 °C to about 70 °C, or about 23 °C to about 62 °C.

28. The process according to any one of Claims 21, 22, 23, 24, 25, 26, or 27, wherein the crystallization comprises cooling.

29. The process according to any one of Claims 21, 22, 23, 24, 25, 26, 27, or 28, wherein the process comprise maintaining the mixture for a period of: about 1 to about 8 hours, about 2 to about 6 hours, about 3 to about 5 hours, or about 4 hours, preferably at a temperature of about 18 °C to about 30 °C, about 22 °C to about 28 °C, about 22 °C to about 26 °C, or about 25 °C.

30. The process according to any one of Claims 21, 22, 23, 24, 25, 26, 27, 28, or 29, further including isolating the crystalline Adagrasib Form A2, preferably by fdtration, and drying.

31. The process according to any one of Claims 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, wherein the drying is carried out at a temperature of: about 20 °C to about 30 °C, about 22 °C to about 28 °C, or about 25 °C, preferably for a period of time of: about 5 minutes to about 2 hours, about 5 minutes to about 1 hour, about 5 minutes to about 30 minutes, or about 10 minutes to about 15 minutes to prepare the crystalline Adagrasib Form A2.

32. The process according to any one of Claims 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or31, further comprising drying the crystalline Adagrasib Form A2 to obtain Crystalline Adagrasib Form A3.

33. The process according to any one of Claims 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32, wherein the drying is carried out under reduced pressure, or under vacuum, preferably in a vacuum tray dryer.

34. The process according to any one of Claims 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, and 33, wherein drying is done at a temperature of about from 40 °C to about 80 °C, or from 55 °C to about 65 °C preferably about 60 °C.

35. The process according to any one of Claims 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein drying is carried out for a period of at least 10 hours, preferably from 10 hours to 20 hours, more preferably about 16 hours.

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