Patent Description:
N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide was originally described in <CIT> as the compound of Example <NUM>. It is a Raf inhibitor, particularly a CRAF- and BRAF-inhibitor, having the structure of Formula (I):
<CHM>.

The compound of Formula (I) is thus useful in the treatment of various cancers, in particular in the treatment of cancers harboring MAPK pathway alterations.

The RAS/RAF/MEK/ERK or MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of this pathway underlies many instances of tumorigenesis. Aberrant signaling or inappropriate activation of the MAPK pathway has been shown in multiple tumor types, including melanoma, lung and pancreatic cancer, and can occur through several distinct mechanisms, including activating mutations in RAS and BRAF. RAS is a superfamily of GTPases, and includes KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), which is a regulated signaling protein that can be turned on (activated) by various single-point mutations, which are known as gain of function mutations. The MAPK pathway is frequently mutated in human cancer with KRAS and BRAF mutations being among the most frequent (approximately <NUM>%).

The compound of Formula (I) may therefore be useful in the treatment of cancers such as KRAS-mutant NSCLC (non-small cell lung cancer), KRAS-mutant pancreatic cancer (e.g. KRAS-mutant pancreatic ductal adenocarcinoma (PDAC)), KRAS-mutant CRC (colorectal cancer), and NRAS-mutant melanoma.

It is not yet possible to predict whether a particular compound or salt of a compound will form polymorphs in the first place or whether any such polymorphs will be suitable for commercial use in a pharmaceutical composition which is suitable for administering to patients in need thereof, or which polymorphs will display desirable properties.

This is because different solid state forms of a particular compound often possess different properties. Solid state forms of an active pharmaceutical ingredient (API) thus play an important role in determining the ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids and in vivo bioavailability of the therapeutic drug.

Processing or handling of the active pharmaceutical ingredient during the manufacture and/or during the formulation process may also be improved when a particular solid form of the API is used. Desirable processing properties mean that certain solid forms can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid forms or mixtures of solid forms of the API provided in the prior art.

There is thus a need for solid forms of the compound of Formula (I) with properties, which will render them suitable for use in drug substance and drug product development. In accordance with the present invention, there are provided solid forms of the compound of Formula (I) that provide handling properties suitable for manufacture on industrial scale, along with methods of producing these polymorphs. Provided herein are solid forms with well-defined morphologies, and good powder properties like high bulk density, good flowability and/or good compactibility etc. In particular, it has been found that the Monohydrate Form Ha, allows improved handling and processing of the crystals during manufacturing.

<NPL> describes the "design and discovery of N-(<NUM>-(<NUM>-(<NUM>-Hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide, a selective, efficacious, and well-tolerated RAF Inhibitor targeting RAS mutant cancers: the path to the clinic".

The present invention provides crystalline forms of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in free form.

Thus, in a first aspect provided herein is a crystalline form of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in monohydrate Form HA, wherein the crystalline Monohydrate Form HA of the compound has an X-ray powder diffraction pattern with.

In a second aspect, provided herein is a process for the preparation of the polymorph form Monohydrate HA, which Formula (I) comprising the steps:.

In a fifth aspect provided herein is a pharmaceutical composition comprising a crystalline compound of Formula (I) (e.g. Monohydrate Form HA) and at least one pharmaceutically acceptable carrier or diluent.

In a sixth aspect, provided herein is the crystalline Monohydrate Form HA for use as a medicament.

In a seventh aspect, provided herein is the crystalline Monohydrate Form HA for use in the treatment of cancer.

In a eighth aspect, provided herein is a crystalline compound of Formula (I) (e.g. polymorph Form Monohydrate HA) for use in a method of treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline compound of Formula (I) (e.g. Form Monohydrate HA).

Described herein are crystalline forms of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in free form (the compound of formula I), which are described and characterised herein.

The compound N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide can be represented by the following chemical structure according to Formula (I)
<CHM>.

For manufacturing pharmaceutical compounds and their formulations, it is important that the active compound is in a form that can be conveniently handled and processed in order to obtain a commercially viable, reliable, and reproducible manufacturing process. The compound of formula (I) and can be produced in various solid forms, depending on the conditions used to produce, purify or crystallize the material.

Crystalline Forms A, B and Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide possess favorable physicochemical properties for a drug substance intended for use in an oral solid dosage form. In particular, Monohydrate HA, surprisingly provides improved handling and processing properties in comparison to Form A or Form B, which in turn enables an improved manufacturing process.

It has now been found that surprisingly the process developed enables the manufacture of solid Form Monohydrate HA in cube-like shaped crystals (sometimes aggregated crystals) with very favourable and advantageous processing properties, as described herein. In terms of improved powder handling properties, coarser and cube-like shaped crystals of Modification HA are advantageous.

Further, as described herein, fine-tuning of powder properties like bulk density, crystal size and shape of Monohydrate HA is possible by controlling key process parameters, e.g. choice of organic solvent and water, addition temperature.

Crystalline Forms A, B and Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide 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 PXRD, DSC and TGA. It may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, Forms A, B and Monohydrate HA of the compound of Formula (I) may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

The present invention provides a monohydrate of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in free form, which is described and characterised herein. Monohydrate Form HA can be defined by reference to one or more characteristic signals that result from analytical measurements including, but not necessarily limited to: the X-ray powder diffraction pattern of <FIG>, or the differential scanning calorimetry of <FIG>. Monohydrate Form HA can also be defined by reference to one or more of the following characteristic signals:
In one embodiment, the Monohydrate Form HA exhibits an X-ray powder diffraction pattern having at least one, two or three characteristic peaks expressed in degrees <NUM>-Theta (°2θ) at angles of <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>° and <NUM>° +/- <NUM>° when measured using CuKα radiation.

In another embodiment, the Monohydrate Form HA, exhibits at least one, two or three characteristic peaks at angles of <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>° and <NUM>° +/- <NUM>° when measured using CuKα radiation. In another embodiment, the Monohydrate Form HA, exhibits at least one, two, three, four or five characteristic peaks at 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 using CuKα radiation. In yet a further embodiment, the Monohydrate Form HA, exhibits an X-ray powder diffraction pattern substantially in accordance with <FIG> and Table <NUM> when measured using CuKα radiation.

In one embodiment, the Monohydrate Form HA is present in substantially pure form.

In one embodiment, the Monohydrate Form HA, exhibits a differential scanning calorimetry thermogram having a characteristic (endothermic) peak expressed in units of °C with an onset temperature of about <NUM>. In another embodiment, the Monohydrate Form HA exhibits a differential scanning calorimetry thermogram substantially in accordance with <FIG>.

In one embodiment, the Monohydrate Form HA is characterized by TGA having a curve which shows a mass loss of about <NUM> %, based on the weight of the crystalline form, when heated from about <NUM> to <NUM> at a rate of <NUM>/min, in accordance with <FIG>. In another embodiment, the Monohydrate Form HA exhibits a TGA thermogram substantially in accordance with <FIG>.

Preferably, the invention relates to a crystalline form of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in Monohydrate Form HA characterized by exhibiting cube-like shaped crystals.

In a further embodiment, the Monohydrate Form HA has a cubic crystal shape, e.g., as determined by scanning electron microscopy.

In another embodiment, described herein is a crystalline form of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in Form A. Polymorph Form A can be defined by reference to one or more characteristic signals that result from analytical measurements including, but not necessarily limited to: the X-ray powder diffraction pattern of <FIG>, or the differential scanning calorimetry of <FIG>. Polymorph form A can also be defined by reference to one or more of the following characteristic signals: In one embodiment, the polymorph Form A exhibits an X-ray powder diffraction pattern having at least one, two or three characteristic peaks expressed in degrees <NUM>-Theta (°2θ) at angles of <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>° and <NUM>° +/- <NUM>° when measured using CuKα radiation. In another embodiment, the polymorph Form A exhibits at least one, two or three characteristic peaks at angles of <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>° and <NUM>° +/- <NUM>° when measured using CuKα radiation. In another embodiment, the polymorph Form A exhibits at least one, two, three, four or five characteristic peaks at 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 using CuKα radiation. In yet a further embodiment, the polymorph Form A exhibits an X-ray powder diffraction pattern substantially in accordance with <FIG> and Table <NUM> when measured using CuKα radiation.

In one embodiment, the polymorph Form A is present in substantially pure form.

In one embodiment, the polymorph Form A exhibits a differential scanning calorimetry thermogram having a characteristic (endothermic) peak expressed in units of °C with an onset temperature of about <NUM>. In another embodiment, the polymorph Form A exhibits a differential scanning calorimetry thermogram substantially in accordance with <FIG>.

In another embodiment, described herein is a crystalline form of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in Form B. Polymorph Form B can be defined by reference to one or more characteristic signals that result from analytical measurements including, but not necessarily limited to: the X-ray powder diffraction pattern of <FIG>, or the differential scanning calorimetry of <FIG>. Polymorph form B can also be defined by reference to one or more of the following characteristic signals: In one embodiment, the polymorph Form B exhibits an X-ray powder diffraction pattern having at least one, two or three characteristic peaks expressed in degrees <NUM>-Theta (°2θ) at angles of <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>° and <NUM>° +/- <NUM>° when measured using CuKα radiation. In another embodiment, the polymorph Form B exhibits at least one, two or three characteristic peaks at angles of <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>°, <NUM>° +/- <NUM>° and <NUM>° +/- <NUM>° when measured using CuKα radiation. In another embodiment, the polymorph Form B exhibits at least one, two, three, four or five characteristic peaks at 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 using CuKα radiation. In yet a further embodiment, the polymorph Form B exhibits an X-ray powder diffraction pattern substantially in accordance with <FIG> and Table <NUM> when measured using CuKα radiation.

In one embodiment, the polymorph Form B is present in substantially pure form.

In one embodiment, the polymorph Form B exhibits a differential scanning calorimetry thermogram having a characteristic (endothermic) peak expressed in units of °C with an onset temperature of about <NUM>. In another embodiment, the polymorph Form B exhibits a differential scanning calorimetry thermogram substantially in accordance with <FIG>.

In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:
The term "free form" refers to the compound N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as the free base.

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

Measurements are taken under standard conditions common in the art, unless specified otherwise.

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>.

The term "substantially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2θ) will show some inter-apparatus variability, typically as much as <NUM>°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measures only. An expression referring to a crystalline Form A having "an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure X" may be interchanged with an expression referring to a crystalline Form A having "an X-ray powder diffraction pattern characterised by the representative X-ray powder diffraction pattern shown in Figure X".

One of ordinary skill in the art will also appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about <NUM>% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal form of Form A is not limited to the crystal form that provides an X-ray diffraction pattern completely identical to the X-ray diffraction pattern depicted in the accompanying <FIG> disclosed herein.

Any crystal forms that provide X-ray diffraction patterns substantially identical to that disclosed in the accompanying <FIG> fall within the scope of crystal Form A. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.

Crystalline Monohydrate Form HA, or Form A or Form B of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide 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, DSC and TGA analysis. 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 peak 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 within the knowledge of a person skilled in the art.

As used herein the term "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.

The terms "dehydrating" or "dehydration" as used herein, describe the at least partial removal of water from the crystal structure of the host molecule.

The terms "anhydrous form" or "anhydrate" as used herein refer to a crystalline solid were no water is cooperated in or accommodated by the crystal structure. Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal. Typically, an anhydrous form does not contain more than <NUM> w-%, preferably not more than <NUM> w-% of water, based on the weight of the crystalline form.

The term "hydrate" as used herein, refers to a crystalline solid where either water is cooperated in or accommodated by the crystal structure e.g. is part of the crystal structure or entrapped into the crystal (water inclusions). Thereby, water can be present in a stoichiometric or non-stoichiometric amount. For example, a hydrate may be referred to as a hemihydrate or as a monohydrate depending on the water/compound stoichiometry. The water content can be measured, for example, by Karl-Fischer-Coulometry.

As used herein, the term "amorphous" refers to a solid 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.

As used herein, the term "mother liquor" refers to the solution remaining after crystallization of a solid from said solution.

The term "antisolvent" as used herein refers to liquids which reduce the solubility of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide in a solvent.

As used herein, "substantially pure" or "essentially pure form" when used in reference to a form, e.g. amorphous form, Form A, Form B or Monohydrate HA, means the compound having a purity greater than <NUM> w-%, including greater than <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> w-%, and also including equal to about <NUM> w-% of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide may be deemed substantially pure in that it has a purity greater than <NUM> w-%, as measured by means that are at this time known and generally accepted in the art, where the remaining less than <NUM> w-% of material comprises other form(s) of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide and/or reaction impurities and/or processing impurities. Thus in an embodiment, provided is an amorphous form of the compound of formula (I) Form A, Form B or Monohydrate HA, having a purity greater than <NUM> w-%, including greater than <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> w-%.

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 stabilizers.

As used herein the term "binder" refers to substances, which bind the active pharmaceutical ingredient and pharmaceutically acceptable excipient together to maintain cohesive and discrete portions.

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. They aid the ejection of the tablet from the dies and can improve powder flow.

The term "glidant" as used herein refers to substances, which are used for tablet and capsule formulations in order to improve flow properties during tablet compression and to produce an anti-caking effect.

The term "effective amount" or "therapeutically effective amount" as used herein with regard to N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide encompasses an amount of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide, which causes the desired therapeutic and/or prophylactic effect.

The term "non-hygroscopic" as used herein refers to a compound showing a water uptake of at most <NUM> w-% in the sorption cycle when measured with GMS (or DVS) at a relative humidity in the range of from <NUM> to <NUM>% RH and a temperature of (<NUM> ± <NUM>) °C, based on the weight of the compound. Non-hygroscopic is preferably up to <NUM> %.

The terms "solid form" or "solid state form" as used herein interchangeably refer to any crystalline and/or amorphous phase of a compound.

In another aspect, described herein is a process for the preparation of crystalline form Monohydrate HA of the Compound of Formula (I) of the present invention as defined in any one of the aspects and their corresponding embodiments described above comprising:.

In an embodiment, the process for the preparation of crystalline form Monohydrate HA of the Compound of Formula (I) of the present invention comprises the steps:.

Preferably, the mixture of step (ii) is heated to about <NUM>-<NUM>.

The Compound of Formula (I) starting material can be prepared according to the procedure disclosed in Example <NUM> of <CIT>.

The solid starting material provided in step (i) is dissolved in a water miscible solvent:water mixture, for example, the water miscible solvent is acetone, ethanol, methanol, propanol, butanol, isopropyl alcohol, tetrahydrofuran (THF), acetonitrile and the like. Preferably, the water miscible solvent is acetonitrile, acetone, methanol, ethanol, propanol or isopropyl alcohol. Most preferably, the water miscible solvent is acetonitrile, acetone or ethanol. The ratio of solvent:water is preferably <NUM>:<NUM> based on the weight of the solvent:water.

The reaction mixture may be heated to a temperature of about <NUM> and cooled down to about -<NUM>. Preferably, the mixture of step is heated to about <NUM>-<NUM>. More preferably, the mixture is heated to <NUM>.

Optionally, to the solution or suspension, water can be added to reduce the solubility of the Compound of Formula (I) in the solvent-water mixture.

Heating the mixture in step (ii) can be conducted over a period of about <NUM> hours. Preferably, the mixture is heated for a period of <NUM> hours. Preferably, the mixture is heated to <NUM> over a period of <NUM> hours. preferably over a period of <NUM> hours.

The cooling step can be performed over a period of at least <NUM> hours, e.g. at least <NUM> hours, e.g. <NUM>-<NUM> hours. Preferably, the cooling step is performed over a period of about <NUM> hours.

Once Monohydrate Form HA is obtained in essentially pure form (e.g. in essentially pure form, this can be determined as described below, by withdrawing samples from the mixture and analyzing the sample by powder X-ray diffraction), at least a part of the crystals are separated from the mother liquor. Preferably, the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.

Optionally, in a further step the isolated crystals are washed with a suitable solvent, for example an organic solvent and/or water or a mixture thereof. Suitable organic solvents include, but are not limited to water, acetone, acetonitrile, methanol, ethanol, propanol, butanol, isopropyl alcohol, tetrahydrofuran and the like.

The obtained crystals are then dried. Drying may be performed at a temperature of about <NUM>-<NUM>, preferably, about <NUM> to <NUM>. Typically, drying can performed at about room temperature. Depending on the temperature employed, drying may be performed for a period in the range of from about <NUM> to <NUM> hours.

Preferably, drying is performed at a temperature of about <NUM> from about <NUM> to <NUM> hours, preferably about <NUM> to <NUM> hours, more preferably about <NUM> hours at <NUM>. Drying may be performed at ambient pressure and/or under reduced pressure. Preferably, drying is performed under reduced pressure, for example <NUM>-<NUM> mbar. More preferably, drying is performed under reduced pressure, at a temperature of about <NUM> for about <NUM> hours.

In another aspect, described herein is a process for the preparation of crystalline Form A of the Compound of Formula (I) as defined in any one of the aspects and their corresponding embodiments described above comprising:.

In one embodiment, the process for the preparation of crystalline Form A of the Compound of Formula (I) comprises the steps of:.

The solid starting material provided in step (i) is dissolved in an organic solvent, for example, ethyl acetate, isopropyl acetate, THF, isopropyl alcohol. However, most preferably ethyl acetate is used.

Addition of an antisolvent is preferably a hydrocarbon solvent. For example, the hydrocarbon solvent can be n-hexane, n-heptane, cycloalkane, e.g. cyclohexane. Preferably, the antisolvent is n-heptane.

Once, Form A is obtained (e.g. in essentially pure form- this can be determined as described below, e.g., by withdrawing samples from the slurry and analyzing the sample by powder X-ray diffraction), at least a part of the crystals is separated from the mother liquor. Preferably, the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.

Optionally, in a further step the isolated crystals are washed with a suitable solvent, for example an organic solvent. Suitable organic solvents comprise but are not limited to acetone, acetonitrile, methanol, ethanol, isopropyl alcohol, acetonitrile, n-heptane, ethyl acetate or mixtures thereof. Preferably, the crystals are washed with a mixture of n-heptane and ethyl acetate. The fraction of n-heptane may be from <NUM> to <NUM> percent by weight, preferably from <NUM> to <NUM> percent by weight.

Drying may be performed at a temperature of about <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably at about <NUM>. Typically, drying is performed at about room temperature. Most preferably, drying is performed at <NUM>. Depending on the temperature employed, drying may be performed for a period in the range of from about <NUM> to <NUM> hours, preferably from about <NUM> to <NUM> hours, more preferably for about <NUM> hours. Drying may be performed at ambient pressure or under reduced pressure. Preferably, drying is performed under reduced pressure, e.g. <NUM>-<NUM> mbar.

In another aspect, described herein is a process for the preparation of crystalline Form B of the Compound of Formula (I) as defined in any one of the aspects and their corresponding embodiments described above comprising:.

The solid starting material provided in step (i) is slurried in a solvent, for example, acetonitrile. Most preferably acetonitrile is the only solvent present in the slurry.

Acidification is performed at <NUM> to <NUM> using a suitable acid, such as, for example, HCl. Slurrying is conducted for at least <NUM> hours, such as <NUM> hours, <NUM> hours, <NUM> hours at a temperature of <NUM> to <NUM>. Preferably, slurrying is conducted over a period of <NUM>-<NUM> hours. Neutralisation is achieved using a suitable base, such as, for example, sodium bicarbonate. Once Form B is obtained (e.g. in essentially pure form; this can be done as described below, e.g., by withdrawing from the slurry and analyzing the sample by powder X-ray diffraction). the crystals can be recovered. Preferably, the crystals are separated from their mother liquor by any conventional method such as filtration, centrifugation, solvent evaporation or decantation, more preferably by filtration or centrifugation and most preferably by filtration.

Optionally, in a further step the isolated crystals are washed with a suitable solvent, for example an organic solvent. Suitable organic solvents comprise but are not limited to acetonitrile, n-heptane, ethyl acetate.

Slurrying encompasses any kind of movement of the solid material suspended in the solvent caused by, but not limited to e.g. agitation, stirring, mixing, shaking, vibration, sonication, wet milling and the like. Slurrying is conducted in total for about <NUM> day, or longer. The skilled person may monitor the conversion of the applied solid form of N-{<NUM>-[<NUM>-(Hydroxyethoxy)-<NUM>-(morpholin-<NUM>-yl)pyridin-<NUM>-yl]-<NUM>-methylphenyl}-<NUM>-(trifluoromethyl)pyridine-<NUM>-carboxamide to the required polymorphic form, e.g. Form B, by withdrawing samples from the slurry and analyzing the sample by powder X-ray diffraction.

Alternatively, Form A may be provided and suspended in dichloromethane for <NUM> to <NUM> days at a temperature of <NUM> to <NUM>, to produce Form B.

In a further aspect, described herein is the use of the crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as defined in any one of the aspects and their corresponding embodiments described above for the preparation of a pharmaceutical composition.

In yet another aspect, described herein is a pharmaceutical composition comprising the crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as defined in any one of the aspects and their corresponding embodiments described above, 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 A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as defined in any one of the aspects and their corresponding embodiments described above can be in unit dosage of about <NUM>-<NUM> (e.g., per day). Hence, crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as defined in any one of the aspects and their corresponding embodiments described above can be administered at a unit dosage of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM> or about <NUM>. The unit dosage may be administered once daily, or twice daily, or three times daily, or four times daily, with the actual dosage and timing of administration determined by criteria such as the patient's age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of a treating physician. Preferably, the unit dosage of crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide is administered once daily. In another preferred embodiment, the unit dosage of crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide is administered twice daily.

Crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide may in particular be administered at a dose of <NUM> once daily (QD), <NUM> once daily, <NUM> once daily, <NUM> once daily, <NUM> once daily or <NUM> once daily (QD). Crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide may also be administered at a dose of <NUM>, <NUM> twice daily, <NUM> twice daily or <NUM> twice daily (BD). The dosages quoted herein may apply to the administration of crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as monotherapy (single agent) or as part of a combination therapy.

When describing a dosage herein as 'about' a specified amount, the actual dosage can vary by up to <NUM>-<NUM>% from the stated amount: this usage of 'about' recognizes that the precise amount in a given dosage form may differ slightly from an intended amount for various reasons without materially affecting the in vivo effect of the administered compound. The unit dosage of the c-Raf inhibitor may be administered once daily, or twice daily, or three times daily, or four times daily, with the actual dosage and timing of administration determined by criteria such as the patient's age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of a treating physician.

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

In a preferred embodiment, the pharmaceutical composition comprising the crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as defined in any one of the aspects and their corresponding embodiments described above is an oral solid dosage form. Preferably, the oral solid dosage form is selected from the group consisting of tablets, capsules, etc. In a particular preferred embodiment, the oral dosage form is a tablet or a capsule, most preferably a tablet.

In a further aspect, the crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments is for use as a medicament.

In yet another aspect, crystalline Form A, or Form B or Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments is for use in the treatment of a proliferative disease, particularly a cancer.

In one embodiment, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic ductal adenocarcinoma (PDAC), cervical cancer, ovarian cancer or colorectal cancer (CRC).

In one embodiment, proliferative disease is selected from a solid tumor that harbors one or more Mitogen-activated protein kinase (MAPK) alteration(s), KRAS-mutant NSCLC (non-small cell lung cancer), NRAS-mutant melanoma, KRAS- and/or BRAF-mutant NSCLC, KRAS- and/or BRAF-mutant ovarian cancer, KRAS-mutant pancreatic cancer (e.g. KRAS-mutant pancreatic ductal adenocarcinoma (PDAC)).

In another aspect, Form A, or Form B, or the Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide is for use in a method of treating and/or preventing a proliferative disease, particularly a cancer, said method comprising administering an effective amount of the Form A, or Form B, or the Monohydrate HA of N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide as defined in the above described aspects and their corresponding embodiments to a patient in need of such a treatment.

In another preferred aspect, provided herein is a crystalline compound of Formula (I) (e.g. polymorph Form A or Form B or Monohydrate HA) for use in a method for the treatment of disorders mediated by Raf, in particular B-Raf or C-Raf, and/or MAPK pathway alterations, comprising administering to a patient in need of such treatment an effective amount of the crystalline compound of Formula (I) (e.g. polymorph Form A or Form B or Monohydrate HA).

In a further aspect, described herein is the use of a crystalline compound of formula I (e.g., polymorph Form A or Form B or Monohydrate HA) for the preparation of a medicament for the treatment of disorders mediated by Raf, in particular B-Raf or C-Raf, and/or MAPK pathway alterations.

The following Examples illustrate various aspects of the invention. Example <NUM> outlines how Compound <NUM> may be prepared. Example <NUM> shows how it may be crystallised to produce Form A. Examples <NUM> and <NUM> describe the XRPD and DSC analysis of Form A. Example <NUM> describes the process of preparation of Form B and the corresponding XRPD data are shown in Example <NUM>. Example <NUM> shows the DSC data of Form B. Examples <NUM>, <NUM>, <NUM> and <NUM> describe the process of making Monohydrate Form HA, and the XRPD, DSC and TGA analysis of Monohydrate Form HA. Examples <NUM> and <NUM> describe the stability testing of Monohydrate HA and Form B. Examples <NUM> and <NUM> show the water activity experiments of Monohydrate Form HA and Form A. Example <NUM> shows the solubility data of Monohydrate HA, Form A and Form B. The release data of Monohydrate HA and Form A are shown in Example <NUM>. Example <NUM> shows competitive slurry experiments of Form A and Form B. Example <NUM> describes the behaviour of Form A and B under compression.

X-ray powder diffraction (XRPD) analysis of all polymorph forms was performed using a Bruker D8 Discover x-ray diffractometer with XYZ stage. Measurements were taken at about <NUM> kV and <NUM> mA under the following conditions:.

The X-ray diffraction pattern was recorded at room temperature between <NUM>° and <NUM>° (<NUM>-theta) with CuKα radiation for identification of the whole pattern.

Differential scanning calorimetry (DSC) analysis of all polymorph forms was performed using a Discovery Differential Scanning Calorimeter from TA instruments under the following conditions:.

The preparation of Compound <NUM> is described in <CIT> (Example <NUM>).

To a reactor was charged crude N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide (<NUM>), ethyl acetate (<NUM>). The reaction mixture was stirred for about <NUM>. until a clear solution was obtained, then the solution was filtered and transferred to another reactor. To the mixture was charged n-heptane (<NUM>) with internal temperature maintained <NUM> ±<NUM>, over at least <NUM>. The mixture was then cooled to <NUM> ±<NUM>, over at least <NUM>. The mixture was aged for no less than <NUM> with internal temperature maintained at <NUM> ±<NUM>. The mixture was filtered and washed with n-heptane/ethyl acetate (<NUM>/<NUM>). The wet cake was dried under vacuum setting (<NUM>-<NUM> mbar) at <NUM> for <NUM> to afford crystals of Form A.

Crystalline Form A was analysed by XRPD and the ten most characteristic peaks are shown in Table <NUM> (see also <FIG>).

Crystalline Form A was found to have an onset of melting at about <NUM> (see <FIG>) according to the DSC method outlined above and Table <NUM>.

Form A is thermodynamically more stable and has a higher melting point and melting enthalpy than Form B.

To an ice cooled (<NUM> to <NUM>) solution of N-(<NUM>-methyl-<NUM>-(<NUM>-morpholino-<NUM>-(<NUM>-((tetrahydro-<NUM>H-pyran-<NUM>-yl)oxy)ethoxy)pyridin-<NUM>-yl)phenyl)-<NUM>-(trifluoromethyl)isonicotinamide (prepared according to <CIT> (Example <NUM>)) (<NUM>, <NUM> mol) in acetonitrile (<NUM>) was added <NUM> HCl (<NUM>, <NUM> vol) drop wise between <NUM> to <NUM>. After complete addition the reaction mixture was slowly allowed to warm to <NUM> to <NUM> and stirred for <NUM>. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to <NUM> to <NUM> and basified to pH = <NUM> -<NUM> using saturated sodium bicarbonate solution between <NUM> to <NUM>. The reaction mixture was stirred for <NUM> at <NUM> to <NUM>, diluted with ethyl acetate (<NUM>, <NUM> vol), stirred for about <NUM> and the layers were separated. The aqueous layer was extracted with ethyl acetate (1x <NUM> vol), the combined organic layer was washed with water (1x10 vol), brine (1x10 vol), dried over sodium sulphate, and filtered to give crystals of Form B as the residue.

Crystalline Form B was analysed by XRPD and the ten most characteristic peaks are shown in Table <NUM> (see also <FIG>).

Crystalline Form B was found to have an onset of melting at about <NUM> (see <FIG>) according to the DSC method outlined above and Table <NUM>.

To <NUM> of Form A in a <NUM> flask was added <NUM> of acetone:water (<NUM>:<NUM> (v/v) mixture). The resulting mixture was heated to <NUM>. Stirring was continued at <NUM> for <NUM> hours (clear solution was observed), and slowly cooled to RT over <NUM> hours (suspension was observed). The mixture was stirred at RT for a further <NUM>-<NUM> hours. The solid was separated via suction filtration, washed with <NUM> acetone:water (<NUM>:<NUM> (v/v) mixture), and the filter cake was dried at <NUM> under vacuum for <NUM> hours. Crystalline monohydrate form HA was obtained as an off-white solid.

Scale up: The reactor was charged with <NUM> of crude N-(<NUM>-(<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-morpholinopyridin-<NUM>-yl)-<NUM>-methylphenyl)-<NUM>-(trifluoromethyl)isonicotinamide and <NUM> of ethanol-water <NUM>:<NUM> (w/w) mixture. The content was stirred and heated to <NUM> until a clear solution was obtained. After cooling to <NUM>, <NUM> of water was added over at least <NUM> hours. After further cooling to <NUM> over at least <NUM> hours and maintaining for at least <NUM> hours the solids were filtered off, washed and dried at <NUM> under vacuum for at least <NUM> hours, to provide crystalline monohydrate form HA as a free flowing powder.

Crystalline Monohydrate Form HA was analysed by XRPD and the ten most characteristic peaks are shown in Table <NUM> (see also <FIG>).

DSC analysis of Crystalline Monohydrate Form HA shows an endothermic event from about <NUM> to <NUM> and shows an onset of dehydration at about <NUM> (see <FIG>) according to the DSC method outlined above and Table <NUM>.

Crystalline Monohydrate Form HA was analysed by thermogravimetric analysis (TGA) using a Discovery Thermogravimetric Analysis Calorimeter from TA instruments under the following conditions (see Table <NUM>).

The TGA analysis for Crystalline Monohydrate Form HA shows about <NUM> % loss of mass between about <NUM> and <NUM>, see <FIG>. Karl Fischer titration analysis shows a water content of <NUM> %, corresponding to one equivalent, thus the monohydrate.

As shown in the Table below, Monohydrate Form HA is highly stable in bulk, e.g. up to <NUM> over an extended period of time. No notable change in chemical purity, nor change in XRPD, nor change in TGA, was observed. Monohydrate Form HA is also stable upon light exposure, e.g. <NUM> kLuxh for <NUM>, and is also stable upon compression, grinding and wet granulation with water.

Monohydrate Form HA is highly stable, i.e. no significant change in degradation products and no change in physical form, even at high temperature was observed. Therefore, it can be expected to provide suitable storage properties for processing into a pharmaceutical drug product.

Degradation Products (DP) and Color (CL).

DPs are analyzed by UPLC. They are calculated as area-% products.

Form B is relatively stable, i.e. no major change in degradation products and no change in physical form, upon exposure to elevated temperature or humidity. Therefore, it can be expected to provide suitable storage properties for processing into a pharmaceutical drug product.

About <NUM> of Form A and Monohydrate HA (<NUM>:<NUM> ratio) were weighed into a vial. A saturated solution of Form A in different organic solvents is prepared. Add a different volume of the saturated solutions and water (total volume <NUM>) into the vials, respectively. The mixture was stirred at room temperature (RT) or <NUM>.

Cross-seeding compatibility experiments or single form equilibration at different water activity and different temperature to see the impact of both water activity and temperature. The water activity (aw) is the partial vapor pressure of water in a substance divided by the standard state partial vapor pressure of water.

At water activity of <NUM> and <NUM> or higher at room temperature and <NUM>, Monohydrate HA is more stable than Form A. In acetonitrile or acetone with water (<NUM>:<NUM>) the Monohydrate HA is more stable than Form A. However, in pure water or heptane, due to poor solubility, both crystal forms are still observed after <NUM> days equilibration, i.e. Form A remains unchanged and Modification HA, remains unchanged.

Thus, Modification HA shows advantages with respect to solid form stability upon contact with water over a wide range of conditions.

Form A is only obtained and stable at very low water activity, however, it can maintain its crystal form in pure water for a given period of time. This may enable Form A to be formulated as oral solid dosage form by e.g. granulation with water (see Example <NUM> below).

About <NUM> of Form A is equilibrated with <NUM> solvent by stirring at RT or <NUM>. The slurries are filtered. The wet cake is investigated by XRPD.

At water activity of <NUM> the conversion of Form A to Monohydrate HA is slow at room temperature and takes <NUM> days for complete conversion. In the solvent at water activity <NUM> and <NUM> or higher at room temperature and at <NUM> respectively, Form A converts to Monohydrate HA. In pure water, Form A remains unchanged.

Modification HA is more stable than Modification A in the aqueous-organic solvent system with water activity more than <NUM> and <NUM> at ambient temperature and <NUM>, respectively. However, due to the poor solubility in pure water, the conversion of Modification A to HA takes a longer equilibration time. Thus, as Form A stays unchanged for a sufficiently long period upon contact with water it can be considered suitable for formulation as an oral solid dosage form, e.g. by granulation with water. The amorphous form remains stable and does not convert to HA either at ambient humidity or at <NUM>% RH.

A sample was weighed in a glass vial and solvent added to make a slurry followed by stirring or shaking at <NUM> for <NUM> hours. The amount of sample and solvents depends on the target concentration, e.g. if the target concentration is <NUM>/mL, the weight of the sample should be <NUM> and the amount of solvent volume should be <NUM>. The solid and liquid are separated by centrifugation at <NUM> rpm for <NUM> minuteswith <NUM> membrane. The filtrate is then used for the solubility test after appropriate dilution. The diluent is from the UPLC method. The solids obtained after equilibration were analyzed by XRPD after being dried at <NUM> under vacuum for <NUM> hours. DSC/TGA analysis was conducted for selected samples.

The relative solubilities of the monohydrate HA and Form A and B of N-(<NUM>-methyl-<NUM>-(<NUM>-morpholino-<NUM>-(<NUM>-((tetrahydro-<NUM>H-pyran-<NUM>-yl)oxy)ethoxy)pyridin-<NUM>-yl)phenyl)-<NUM>-(trifluoromethyl)isonicotinamide were analysed and the results are shown in the tables below.

Among the compared anhydrate crystals, the physical Form B provides higher solubility in several aqueous media, particularly at low pH, e.g. pH <NUM> or <NUM>. Thus, Form B can be expected to behave advantageously in terms of better dissolution properties as oral solid dosage form, e.g. in the stomach. Both anhydrous crystal Forms A and B are more soluble in aqueous media compared to Modification HA, and may thus beadvantageous for use as oral solid dosage form medication.

Pilot manufacture batches producing Modification HA and Form A on kilogram scale were compared for their respective bulk powder properties. The particle size distribution (PSD) was determined according to the corresponding method for release. Other measurements were performed using technical methods known in the art or as described herein.

A few drops of the dispersing aid were added to an appropriate amount of test substance. The mixture was mixed intensively, e.g. on a vortex mixer, in order to wet the substance thoroughly and to form a smooth and homogeneous paste. The resultant paste was diluted with the dispersion liquid to a final volume of <NUM> - <NUM> and the dispersion mixed again. The cumulative volume distribution was determined using a laser light diffraction instrument as stated above. The parameters could be adjusted accordingly so that the test dispersion is representative, homogeneous and well dispersed.

Particle sizes were determined at the undersize values of <NUM>%, <NUM>% and <NUM>% (x10, x50, x90), and additional values in question, from the cumulative volume distribution.

Monohydrate HA crystals (prepared according to the scale up process of Example <NUM>) are significantly coarser (SEM image in <FIG>) compared to Modification A crystals (SEM image in <FIG>), which is quantitatively supported, e.g. by diameter X10: <NUM> vs. <NUM> (> factor <NUM>), obtained through particle size measurement by laser light diffraction.

This leads to significantly larger bulk density of Monohydrate HA crystals versus Modification A crystals, e.g. <NUM>/m<NUM> versus <NUM>/m<NUM> (approx. factor <NUM>).

This difference in bulk density allows easier powder handling of Monohydrate HA crystals. This also applies to improved handling of the Monohydrate HA crystals during manufacturing, i.e. better stirring of the crystal suspension, faster filtration and washing, easier sieving, as well as downstream processing of the Monohydrate HA crystal powder, i.e. preparation of blend of API with excipients.

The tailoring of powder properties like bulk density, crystal size and shape, etc. of Monohydrate HA is possible via controlling key process parameters, e.g. choice of organic solvent and water, addition temperature. It is surprising to find that, by careful monitoring of the water addition temperature as described herein, it is also possible to obtain anhydrate Form A (see Table <NUM>). In terms of improved powder handling properties, the coarser cube-like crystals of Modification HA are advantageous. Hence, Modification HA shows beneficial properties in that it is possible to tailor the shape of crystals of Modification HA obtained as described herein.

About <NUM>~<NUM> of Form A and Form B are weighed by <NUM>:<NUM> ratio into a vial, respectively. Limited solvent is added to the vial to form a suspension. Stirring is maintained at RT for <NUM> days.

In the competitive slurry experiments of Form A and B, Form A is more stable than Form B in most of the selected organic solvents, i.e. the initial mixtures convert to Form A. Only in acetonitrile a solvate is formed. However, upon equilibration in an aqueous/organic mixture of solvents, Modification HA was observed and is the most stable form, except in the ethanol/water <NUM>:<NUM> mixture.

The physical form of Form A remains unchanged upon granulation with water or compression. A slight decrease in crystallinity is observed when compressed at pressures of <NUM> to <NUM> MPa. Form B did not change XRPD pattern upon grinding, compression and granulation with water.

Modification HA exhibits compact particle morphology and high bulk density. In addition, its physical properties, e.g., in terms of shape of crystals obtained can be fine-tuned through crystallization conditions as described herein. Therefore, Modification HA crystalline form provides several advantages over other forms, such as anhydrous Forms A or B, particularly with respect to challenges encountered during industrial processing, e.g. stirring, separation, drying, powder transportation and mixing of bulk quantities.

Modification HA may also be beneficial over other solid forms such as anhydrous Form A in other manufacturing processes, e. g, hot melt extrusion conditions. Hence, Modification HA is specially advantageously suitable for development, especially for drug product manufacturing.

Claim 1:
A crystalline Monohydrate Form HA of the compound of formula I
<CHM>
wherein the crystalline Monohydrate Form HA of the compound has an X-ray powder diffraction pattern with
(i) at least one, two or three peaks having an angle of refraction <NUM> theta (θ) values selected from <NUM>, <NUM> and <NUM>; or
(ii) at least one, two or three peaks having an angle of refraction <NUM> theta (θ) values selected from <NUM>, <NUM>, <NUM>, <NUM> and <NUM> or
(iii) at least one, two, three, four or five peaks selected from <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>, wherein the <NUM> theta (θ) values are measured using CuKα radiation and are plus or minus <NUM>° 2θ.