Patent Description:
Sotorasib is a selective inhibitor of the KRAS G12C mutant useful in the treatment of cancers, including treatment of lung cancer, such as non-small cell lung cancer (NSCLC), pancreatic cancer and colorectal cancer. The chemical name of sotorasib is <NUM>-fluoro-<NUM>-(<NUM>-fluoro-<NUM>-hydroxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-(<NUM>-propanyl)-<NUM>-pyridinyl)-<NUM>-((<NUM>S)-<NUM>-methyl-<NUM>-(<NUM>-propenoyl)-<NUM>-piperazinyl)pyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>H)-one. Sotorasib can be represented by the following chemical structure according to Formula (A)
<CHM>.

Sotorasib and its preparation are disclosed in <CIT> e.g. in Example <NUM>. The last step includes purification by silica gel chromatography. The application is silent about the obtained solid-state form though.

<CIT> describes various crystalline forms of sotorasib including several anhydrous forms designated Form I, Form II and Form III, a hydrate form and several solvates, which were the result of an extensive polymorph screening program.

<CIT> discloses various crystalline forms of sotorasib including anhydrous forms as well as several hydrates and solvates.

Different solid-state forms of an active pharmaceutical ingredient often possess different properties. Differences in physicochemical properties of solid-state forms can play a crucial role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile and bioavailability or with improved stability or shelf-life can become accessible due to an improved solid-state form of an active pharmaceutical ingredient. Also processing or handling of the active pharmaceutical ingredient during the formulation process may be improved. New solid-state forms of an active pharmaceutical ingredient can thus have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid forms.

There is thus a need for the provision of crystalline forms of sotorasib having improved physicochemical properties.

In particular, there is a need to provide an improved crystalline form of sotorasib, which is physically stable e.g. does not undergo phase transformations during standard pharmaceutical processing and storage, which is non-hygroscopic or only slightly hygroscopic and at the same time shows high solubility and dissolution rates in physiologically relevant aqueous media.

The present invention provides a crystalline form of sotorasib, which is hereinafter also designated as "Form A".

Sotorasib Form A of the present invention posesses one or more advantageous properties selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.

For example, the crystalline Form A of the present invention is physically stable against temperature and humidity stress which is important for the reliable manufacture and stable storage of a pharmaceutical composition comprising sotorasib Form A (see Examples <NUM>, <NUM>, <NUM> and <NUM> as well as Comparative Example <NUM> hereinafter).

In addition, Form A of the present invention is more soluble in physiologically relevant aqueous media such as acetate buffer pH <NUM> and phosphate buffer pH <NUM> compared to crystalline form I of sotorasib disclosed in <CIT> (see Comparative Example <NUM> hereinafter) which is a crucial advantage for a low soluble drug substance like sotorasib in order to reach the desired in vivo blood levels.

This unique combination of advantageous properties renders the crystalline Form A of the present invention the preferred solid form of sotorasib for the preparation of a pharmaceutical composition comprising sotorasib.

In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:.

The term "sotorasib" as used herein, means <NUM>-fluoro-<NUM>-(<NUM>-fluoro-<NUM>-hydroxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-(<NUM>-propanyl)-<NUM>-pyridinyl)-<NUM>-((<NUM>S)-<NUM>-methyl-<NUM>-(<NUM>-propenoyl)-<NUM>-piperazinyl)pyrido[<NUM>,<NUM>-d]pyrimidin-<NUM>(<NUM>H)-one. Sotorasib can be represented by the chemical structure according to Formula (A).

Sotorasib may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule.

For example, sotorasib may be present as atropisomer M as represented by the chemical structure according to Formula (A1)
<CHM>.

Sotorasib may also be present as atropisomer P as represented by the chemical structure according to Formula (A2)
<CHM>.

Sotorasib as disclosed herein includes all atropisomers, both as pure individual atropisomers, enriched atropisomers or non-specific mixtures of atropisomers. Most preferably, sotorasib as disclosed herein is present as M atropisomer.

As used herein, the term "measured at a temperature in the range of from <NUM> to <NUM>" refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from <NUM> to <NUM>, i.e. at room temperature. Standard conditions can mean a temperature of about <NUM>. Typically, standard conditions can additionally mean a measurement under <NUM>-<NUM>% RH, preferably <NUM>-<NUM>% RH, more preferably <NUM>% RH.

As used herein the term "room temperature" refers to a temperature in the range of from <NUM> to <NUM>.

The term "reflection" with regard to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately <NUM> to <NUM> atoms, whereas short-range order is over a few atoms only (see "<NPL>).

The term "essentially the same" with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the <NUM>-Theta values is in the range of ± <NUM>° <NUM>-Theta, preferably in the range of ± <NUM>° <NUM>-Theta. Thus, a reflection that usually appears at <NUM>° <NUM>-Theta for example can appear between <NUM>° and <NUM>° <NUM>-Theta, preferably between <NUM>° and <NUM>° <NUM>-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.

Crystalline Form A of sotorasib of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, powder X-ray diffraction. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact reflection positions and intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for another or an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well with in the knowledge of a person skilled in the art.

The term "solid-state form" as used herein refers to any crystalline and/or amorphous phase of a compound.

As used herein, the term "amorphous" refers to a solid-state form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern with reflections.

The terms "anhydrous" or "anhydrate" as used herein refer to a crystalline solid where no water is cooperated in or accommodated by the crystal structure.

A "predetermined amount" as used herein with regard to sotorasib Form A refers to the initial amount of sotorasib Form A used for the preparation of a pharmaceutical composition having a desired dosage strength of sotorasib.

The term "effective amount" as used herein with regard to sotorasib Form A encompasses an amount of sotorasib Form A which causes the desired therapeutic and/or prophylactic effect.

As used herein, the term "about" means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within <NUM>%, more typically within <NUM>%, even more typically within <NUM>% and most typically within <NUM>% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.

The term "pharmaceutically acceptable excipient" as used herein refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, stabilizer or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrants, lubricants and glidants.

The terms "filler" or "diluent" as used herein refer to substances that are used to dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers can also serve as stabilizer or disintegrant.

The terms "disintegrant" or "disintegrating agent" as used herein refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permits the release of the active pharmaceutical ingredient as efficiently as possible to allow for its rapid dissolution.

The term "lubricant" as used herein refers to substances which are added to a powder blend to prevent the compacted powder mass from sticking to the equipment during tableting or encapsulation process.

The present invention provides a crystalline form of sotorasib, herein also designated as "Form A".

The crystalline form (Form A) of sotorasib of the present invention may be represented by the chemical structure according to Formula (A)
<CHM>.

Most preferably, the crystalline form (Form A) of sotorasib is the M atropisomer and may be represented by the chemical structure according to Formula (A1)
<CHM>.

Alternatively, the crystalline form (Form A) of sotorasib may be present as the P atropisomer and may be represented by the chemical structure according to Formula (A2)
<CHM>.

The crystalline Form A of sotorasib of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, FTIR spectroscopy, DSC, TGA and GMS. Sotorasib Form A of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, Form A of sotorasib of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

In one embodiment the invention relates to a crystalline form (Form A) of sotorasib characterized by having a PXRD comprising reflections at <NUM>-Theta angles of:.

In another embodiment, the invention relates to a crystalline form (Form A) of sotorasib characterized by having a PXRD comprising reflections at <NUM>-Theta angles of (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)° and (<NUM> ± <NUM>)°, when measured at a temperature in the range of from <NUM> to <NUM> with Cu-Kalpha<NUM>,<NUM> radiation having a wavelength of <NUM>.

In a further embodiment, the present invention relates to a crystalline form (Form A) of sotorasib characterized by having a PXRD comprising reflections at <NUM>-Theta angles of:.

In still another embodiment, the invention relates to a crystalline form (Form A) of sotorasib characterized by having a PXRD comprising reflections at <NUM>-Theta angles of (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)° and (<NUM> ± <NUM>)°, when measured at a temperature in the range of from <NUM> to <NUM> with Cu-Kalpha<NUM>,<NUM> radiation having a wavelength of <NUM>.

In another embodiment, the invention relates to a crystalline form (Form A) of sotorasib characterized by having a PXRD comprising no reflection at <NUM>-Theta angles in the range of from <NUM>° to <NUM>°, when measured at a temperature in the range of from <NUM> to <NUM> with Cu-Kalpha<NUM>,<NUM> radiation having a wavelength of <NUM>.

In yet another embodiment, the invention relates to a crystalline form (Form A) of sotorasib characterized by having a PXRD comprising no reflection at <NUM>-Theta angles in the range of from <NUM>° to <NUM>°, when measured at a temperature in the range of from <NUM> to <NUM> with Cu-Kalpha<NUM>,<NUM> radiation having a wavelength of <NUM>.

In a further embodiment, the present invention relates to a crystalline form of sotorasib (Form A) characterized by having a PXRD essentially the same as shown in <FIG> of the present invention, when measured at a temperature in the range of from <NUM> to <NUM> with Cu-Kalpha<NUM>,<NUM> radiation having a wavelength of <NUM>.

The PXRD of sotorasib Form A of the present invention can be readily distinguished from the PXRDs of the sotorasib forms disclosed in <CIT> and <CIT>. The PXRD of Form A for example shows a characteristic reflection at (<NUM> ± <NUM>)° <NUM>-Theta, whereas except for Form III which shows a reflection at <NUM>° <NUM>-Theta, none of the other forms of sotorasib disclosed in <CIT> show reflections in the same range. On the other hand the PXRD of Form A of the present invention exhibits reflections which are not present in the diffractogram of Form III of <CIT> e.g. at <NUM>-Theta angles of (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)° and (<NUM> ± <NUM>)°.

Form A of the present invention also exhibits a characteristic reflection at (<NUM> ± <NUM>)° <NUM>-Theta, which is for example not present in the diffractogram of Form <NUM> of <CIT>.

In another embodiment, the present invention relates to a crystalline form (Form A) of sotorasib, characterized by having a TGA curve showing a mass loss of not more than <NUM> w-%, preferably of not more than <NUM> w-%, such as not more than <NUM> w-%, based on the weight of the crystalline form, when heated from <NUM> to <NUM> at a rate of <NUM>/min.

In a further embodiment, the present invention relates to a crystalline form (Form A) of sotorasib characterized by showing a mass change of not more than <NUM> w-%, preferably of not more than <NUM> w-%, most preferably of not more than <NUM> w-%, such as not more than <NUM> w-% based on the weight of the crystalline form, when measured with GMS at a relative humidity in the range of from <NUM> to <NUM>% and a temperature of (<NUM> ± <NUM>)°C.

In one embodiment, the present invention relates to a crystalline form (Form A) of sotorasib characterized in being anhydrous.

In another aspect, the present invention discloses a composition comprising the crystalline form (Form A) of sotorasib of the present invention as defined in any one of the above described embodiments, said composition being essentially free of any other solid-state form of sotorasib. For example, a composition comprising the crystalline Form A of sotorasib of the present invention comprises at most <NUM> w-%, preferably at most <NUM> w-%, more preferably at most <NUM> w-%, <NUM> w-%, <NUM> w-%, <NUM> w-% or <NUM> w-% of any other solid-state form than Form A of sotorasib, based on the weight of the composition. Preferably, the any other solid-state form is selected from the group consisting of crystalline Form I, Form II and Form III of sotorasib of <CIT> or amorphous sotorasib.

In another embodiment, the invention discloses a composition comprising at least <NUM> w-%, including at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> w-%, and also including equal to about <NUM> w-% of the crystalline form (Form A) of sotorasib as defined in any one of the above described embodiments, based on the total weight of the composition. The remaining material may comprise other solid-state form(s) of sotorasib, and/or reaction impurities and/or processing impurities arising from the preparation of the composition.

In another aspect, the present invention relates to a first process for the preparation of the crystalline form (Form A) of sotorasib of the present invention or the composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments comprising:.

In still another aspect, the present invention relates to a second process for the preparation of the crystalline form (Form A) of sotorasib of the present invention or the composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments comprising:.

In a further aspect, the present invention relates to the use of the crystalline form of sotorasib (Form A) of the present invention, or the composition comprising the crystalline form of sotorasib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition comprising sotorasib.

In another aspect, the present invention relates to a pharmaceutical composition comprising the crystalline form of sotorasib (Form A) of the present invention, or the composition comprising the crystalline form of sotorasib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, preferably in a predetermined and/or effective amount, and at least one pharmaceutically acceptable excipient.

Preferably, the predetermined and/ or effective amount of the crystalline form of sotorasib (Form A) of the present invention, or the composition comprising the crystalline form of sotorasib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments is in the range of from about <NUM> to <NUM>, calculated as anhydrous sotorasib. For example, the predetermined and/ or effective amount is selected from the group consisting of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> calculated as anhydrous sotorasib. Preferably, the predetermined and/ or effective amount is selected from the group consisting of <NUM>, <NUM>, <NUM> and <NUM>, calculated as anhydrous sotorasib. Most preferably the predetermined and/ or effective amount is <NUM>, calculated as anhydrous sotorasib.

The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of fillers, disintegrants, binders, lubricants, glidants and combinations thereof. Preferably, the at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention is selected from the group consisting of fillers, disintegrants, lubricants and combinations thereof.

In a particular embodiment, the present invention relates to a pharmaceutical composition as defined in any one of the above described embodiments comprising the crystalline form of sotorasib (Form A) or the composition comprising the crystalline form of sotorasib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, a filler, a disintegrant and a lubricant.

In one embodiment, the filler is selected from the group consisting of dibasic calcium phosphate, kaolin, lactose monohydrate, dextrose, magnesium carbonate, sucrose, mannitol, glucose or other monosaccharides, dextrin or other polysaccharides, microcrystalline cellulose, powdered cellulose, cellulose derivatives, precipitated calcium carbonate, calcium sulfate, sorbitol, inositol and starch, and combinations thereof. Most preferably the filler is microcrystalline cellulose, lactose monohydrate or a combination thereof.

In one embodiment, the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, natrium stearate, glycerol monostearate, glyceryl tribehenate, sorbitan monostearate, sucrose monopalmitate, polyethylene glycol, boric acid, sodium oleate sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, stearic acid, and combinations thereof. Most preferably the lubricant is magnesium stearate.

In yet another embodiment, the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, starch (potato, corn), pregelatinized starch, microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose, sodium carboxy-methylcellulose and combinations thereof. Most preferably the disintegrant is croscarmellose sodium, microcrystalline cellulose or a combination thereof.

Preferably, the pharmaceutical composition of the present invention as defined in any one of the above described embodiments is an oral solid dosage form, more preferably a tablet or a capsule. In a particular preferred embodiment, the pharmaceutical composition of the present invention as described above is a capsule, preferably a hard gelatin capsule. Most preferably, the pharmaceutical composition of the present invention as described above is a tablet, preferably a film-coated tablet.

The pharmaceutical compositions of the present invention as defined in any one of the above described embodiments may be produced by standard manufacturing processes, which are well-known to the skilled person e.g. selected from the group consisting of micronization, blending, milling, granulation (wet or dry granulation), capsule filling, tabletting, film-coating and any combinations thereof.

In a particular aspect, the present invention relates to a process for the preparation of a pharmaceutical composition comprising the crystalline form of sotorasib (Form A) of the present invention, or the composition comprising the crystalline form of sotorasib (Form A) of the present invention as defined in any one of the above described embodiments, preferably a capsule such as a hard gelatin capsule, comprising the steps of:.

In another preferred aspect, the present invention relates to a process for the preparation of a pharmaceutical composition comprising the crystalline form of sotorasib (Form A) of the present invention, or the composition comprising the crystalline form of sotorasib (Form A) of the present invention as defined in any one of the above described embodiments, preferably a tablet such as a film-coated tablet, comprising the steps of:.

In a further aspect, the present invention relates to the crystalline form of sotorasib (Form A) or the composition comprising the crystalline form of sotorasib (Form A), or the pharmaceutical composition comprising the crystalline form of sotorasib (Form A) or the composition comprising the crystalline form of sotorasib (Form A) as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.

In a further aspect, the present invention relates to the crystalline form of sotorasib (Form A), or the composition comprising the crystalline form of sotorasib (Form A), or the pharmaceutical composition comprising the crystalline form of sotorasib (Form A) or the composition comprising the crystalline form of sotorasib (Form A) as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of a cancer with a KRAS G12C mutation.

In another aspect, the present invention relates to a method of treating a cancer with a KRAS G12C mutation, the method comprising administering an effective amount of the crystalline form of sotorasib (Form A), or the composition comprising the crystalline form of sotorasib (Form A), or the pharmaceutical composition comprising the crystalline form of sotorasib (Form A) or the composition comprising the crystalline form of sotorasib (Form A) as defined in any one of the above described aspects and their corresponding embodiments to a patient in need of such a treatment.

In one embodiment, the cancer with a KRAS G12C mutation is selected from the group consisting of lung cancer, colorectal cancer and pancreatic cancer. In a preferred embodiment, the lung cancer is non-small cell lung cancer (NSCLC).

The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention.

Amorphous sotorasib (<NUM>, e.g. prepared according to the procedure disclosed in Example <NUM> herein) was dissolved in isobutanol (<NUM>) at room temperature. The resulting clear yellow solution was magnetically stirred at RT and turned into a colorless suspension after about <NUM> hours. After a total stirring time of <NUM> hours the solid was collected by filtration, washed with n-heptane and dried for <NUM> days at <NUM> under vacuum (<NUM> mbar) to obtain sotorasib Form A. Yield: <NUM>.

Amorphous sotorasib (<NUM>, e.g. prepared according to the procedure disclosed in Example <NUM> herein) was suspended in MTBE (<NUM>) at RT and stirred for <NUM> hours. The solid was collected by filtration and dried for <NUM> hours at <NUM> under vacuum (<NUM> mbar) to obtain sotorasib Form A. Yield: <NUM>.

Amorphous sotorasib (<NUM>, e.g. prepared according to the procedure disclosed in Example <NUM> herein) was suspended in DIPE (<NUM>) at RT and stirred for <NUM> hours. The solid was collected by filtration and dried for <NUM> hours at <NUM> under vacuum (<NUM> mbar) to obtain sotorasib Form A. Yield: <NUM>.

Sotorasib (<NUM>, e.g. prepared according to the procedure disclosed in Example <NUM> of <CIT>) was dissolved in methanol (<NUM>) at room temperature. Isobutanol (<NUM>) was added and the clear yellow solution was filtered. Methanol (<NUM>) was added to the filtrate which was then transferred into a vacuum distillation equipment to remove methanol.

The distillation was performed by applying the conditions as specified in Table <NUM> below.

The distillation was stopped by reducing the jacket temperature to <NUM> when the sump temperature exceeded <NUM>. Isobutanol (<NUM>) was added to the residual sump (<NUM>) to reach the desired crystallization concentration of about <NUM> w-% sotorasib. Subsequently, the solution was annealed by applying a jacket temperature of <NUM>, seeded with sotorasib form A (<NUM>, e.g. prepared according to the process disclosed in Example <NUM> herein) and stirred for <NUM> hours at <NUM>. Then the temperature was linearly decreased to <NUM> and further slurried at <NUM> for <NUM> hours. The resulting precipitate was collected by filtration, washed twice with cold isobutanol (<NUM>) and dried under vacuum for <NUM>. Yield: <NUM>.

Sotorasib (<NUM>, e.g. prepared according to the procedure disclosed in Example <NUM> of <CIT> ) was dissolved in methanol (<NUM>). The clear solution was filtered and the solvent was removed by rotary evaporation at a bath temperature of <NUM>. The residue was further dried under vacuum (~ <NUM> mbar) at <NUM> for <NUM> hours to yield amorphous sotorasib. Yield: <NUM>.

Powder X-ray diffraction was performed with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalpha<NUM>,<NUM> radiation (wavelength <NUM>) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of <NUM> kV and a tube current of <NUM> mA, applying a stepsize of <NUM>° <NUM>-theta with <NUM> per step (<NUM> channels) in the angular range of <NUM>° to <NUM>° <NUM>-Theta at ambient conditions. A typical precision of the <NUM>-Theta values is in the range of ± <NUM>° <NUM>-Theta, preferably of ± <NUM>° <NUM>-Theta.

A representative diffractogram of sotorasib Form A of the present invention is displayed in <FIG> hereinafter. The corresponding reflection list of crystalline form A of sotorasib of the present invention is provided in Table <NUM> below.

DSC was performed on a Mettler Polymer DSC R instrument. The sample (<NUM> Form A prepared according to Example <NUM> herein) was heated in a <NUM> microliter aluminium pan with a pierced aluminium lid from <NUM> to <NUM> at a rate of <NUM>° K/min. Nitrogen (purge rate <NUM>/min) was used as purge gas.

The DSC curve of sotorasib Form A prepared according to Example <NUM> herein is displayed in <FIG> hereinafter and shows a first small endotherm with an onset temperature of about <NUM> and a peak maximum at a temperature of about <NUM> followed by a sharp endotherm with an onset temperature of about <NUM> and a peak maximum at a temperature of about <NUM>.

TGA was performed on a Mettler TGA/DSC <NUM> instrument. The sample (<NUM> Form A prepared according to Example <NUM> herein) was heated in a <NUM> microliter aluminium pan closed with an aluminium lid from <NUM> to <NUM> at a rate of <NUM>/min. The lid was automatically pierced at the beginning of the measurement. Nitrogen (purge rate <NUM>/min) was used as purge gas.

The TGA curve of sotorasib Form A prepared according to Example <NUM> herein is displayed in <FIG> hereinafter and shows a distinct step between about <NUM> and <NUM> corresponding to a mass loss of about <NUM> w-% before the sample starts to decompose at higher temperature.

Gravimetric moisture sorption was performed with an SPSx-1µ moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at ambient relative humidity (RH) of <NUM>%. RH was then decreased to <NUM>% in <NUM>% steps, followed by a further decrease to <NUM>% and to <NUM>%. Afterwards RH was increased from <NUM>% to <NUM>% in a sorption cycle and subsequently decreased to <NUM>% in a desorption cycle each in <NUM>% steps. Finally, RH was increased to ambient relative humidity of <NUM>% in <NUM>% steps. The time per step was set to a minimum of <NUM> hours and a maximum of <NUM> hours. If an equilibrium condition with a constant mass of ± <NUM>% within <NUM> hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of <NUM> hours. If no equilibrium was achieved the consecutive humidity step was applied after the maximum time of <NUM> hours. The temperature was (<NUM> ± <NUM>) °C.

The moisture sorption/desorption isotherms of sotorasib Form A of the present invention in the range from <NUM>-<NUM>% RH are displayed in <FIG>. The mass difference in the sorption cycle between <NUM> and <NUM>% RH is only about <NUM> w-% indicating the only slightly hygroscopic behaviour of this crystalline form. The lacking hysteresis between the sorption and the desorption isotherms indicates that no structural changes appear during the experiment. This assumption is strengthened by the fact that the sample still shows the same PXRD after the experiment.

Sotorasib Form A of the present invention was subjected to various temperature and humidity stress conditions for <NUM> weeks as outlined in Table <NUM> below. The samples were open stored in glass vials. The stressed samples were investigated by PXRD and as can be seen from the results summarized below no phase change occured at any stress condition.

The whole amount of microcrystalline cellulose was sieved through a <NUM> sieve. <NUM>% of the sieved microcrystalline cellulose were mixed with the whole amount of lactose monohydrate and blended in a Turbulamixer ESD-TUMI-<NUM> for <NUM> at <NUM> rpm. The obtained mixture was sieved through a <NUM> sieve. After the sieving step, the remaining microcrystalline cellulose was added and the obtained mixture was blended in the Turbulamixer ESD-TUMI-<NUM> for <NUM> at <NUM> rpm. Then complete amounts of sotorasib Form A and croscarmellose sodium were mixed with the microcrystalline cellulose/lactose monohydrate mixture in three subsequent blending and sieving steps. First, approximately <NUM>% of the microcrystalline cellulose/lactose monohydrate mixture were blended with Sotorasib Form A and crosscarmellose sodium in the Turbulamixer ESD-TUMI-<NUM> for <NUM> at <NUM> rpm. Next, the mixture was sieved through a <NUM> sieve before another <NUM>% of the microcrystalline cellulose/lactose monohydrate mixture were added through a <NUM> sieve. The obtained mixture was blended in the Turbulamixer ESD-TUMI-<NUM> for <NUM> at <NUM> rpm and thereafter sieved through a <NUM> sieve. Then, the remaining amount (approximately <NUM>%) of the microcrystalline cellulose/lactose monohydrate mixture was added to the mixture through a <NUM> sieve and the mixture was blended in Turbulamixer ESD-TUMI-<NUM> for <NUM> at <NUM> rpm.

Finally, magnesium stearate was added and the mixture was blended in the Turbulamixer ESD-TUMI-<NUM> for <NUM> at <NUM> rpm.

The thus obtained powder blend can either be pressed into tablet cores with <NUM> x <NUM> format by direct compression at <NUM> bar or filled into hard-gelain capsules of size <NUM>.

An analyses of the GMS data of sotorasib Form A of the present invention and anhydrous sotorasib Form I, Form II and Form III provided in <CIT> reveals that Form A shows almost no interaction with water vapour and can be assigned as being slightly hygroscopic. According to the disclosure of <CIT>, page <NUM>, paragraph [<NUM>] Form I shows a mass increase of <NUM>-<NUM>% in the range of <NUM>-<NUM>% RH at <NUM>, whereas Form II and Form III are hygroscopic materials both taking up well above <NUM> w-% of water, in the case of Form III even <NUM> w-% of water in the range of <NUM>-<NUM>% RH at <NUM>.

Powder dissolution experiments were carried out at a temperature of <NUM> in acetate buffer pH <NUM> and phosphate buffer pH <NUM> for the crystalline Form I of sotorasib disclosed in <CIT> and the crystalline Form A of sotorasib of the present invention. Particle sizes of both forms were kept as similar as possible to allow for proper comparison. The respective concentrations were determined at a wavelength of <NUM> in case of the acetate buffer and at <NUM> in case of the phosphate buffer.

Claim 1:
A crystalline form of sotorasib (Form A) according to the chemical structure as depicted in Formula (A)
<CHM>
characterized by having a powder X-ray diffractogram comprising reflections at <NUM>-Theta angles of (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)°, (<NUM> ± <NUM>)° and (<NUM> ± <NUM>)°, when measured at a temperature in the range of from <NUM> to <NUM> with Cu-Kalpha<NUM>,<NUM> radiation having a wavelength of <NUM>.