Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to crystalline forms of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide.
• present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising the
• crystalline forms as well of methods of making and methods of using the crystalline forms in the treatment of a proliferative disease, particularly a cancer.
• A/-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide was originally described in WO 2014/151616 as the compound of Example 1 156. It is a Raf inhibitor, particularly a CRAF- and BRAF-inhibitor, having the structure of Formula (I):
• 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
• 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 colonal cancer
• NRAS-mutant melanoma KRAS-mutant pancreatic ductal adenocarcinoma
• Solid state forms of an active pharmaceutical ingredient 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.
• solid forms of the compound of Formula (I) with properties, which will render them suitable for use in drug substance and drug product development.
• 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.
• the Monohydrate Form H A allows improved handling and processing of the crystals during manufacturing.
• the present invention provides crystalline forms of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in free form.
• a third aspect provided herein is a crystalline form of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in Form A.
• a fourth aspect provided herein is a crystalline form of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in Form B.
• a pharmaceutical composition comprising a crystalline compound of Formula (I) (e.g. Monohydrate Form H A , or the crystalline Form A, or the crystalline Form B) and at least one pharmaceutically acceptable carrier or diluent.
• a crystalline compound of Formula (I) e.g. Monohydrate Form H A , or the crystalline Form A, or the crystalline Form B
• at least one pharmaceutically acceptable carrier or diluent e.g. Monohydrate Form H A , or the crystalline Form A, or the crystalline Form B
• crystalline Monohydrate Form H A or the crystalline Form A, or the crystalline Form B, for use as a medicament.
• crystalline Monohydrate Form H A or the crystalline Form A, or the crystalline Form B, for use in the treatment of cancer.
• a crystalline compound of formula I ⁇ e.g., polymorph Form A or Form B or Monohydrate H A ) in the manufacture of a medicament for the treatment of cancer.
• a method of treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline compound of Formula (I) (e.g. polymorph Form A or Form B or Monohydrate H A ).
• a crystalline compound of Formula (I) e.g. polymorph Form A or Form B or Monohydrate H A .
• Figure 1 shows the X-ray powder diffraction spectrum of crystalline Form A.
• Figure 2 shows the DSC thermogram of crystalline Form A.
• Figure 3 shows the X-ray powder diffraction spectrum of crystalline Form B.
• Figure 4 shows the DSC thermogram of crystalline Form B.
• Figure 5 shows X-ray powder diffraction spectrum of crystalline Monohydrate Form PI A .
• Figure 6 shows the DSC thermogram of crystalline Monohydrate Form PIA.
• Figure 7 shows the TGA thermogram of crystalline Monohydrate Form PI A .
• Figure 8 shows the SEM image of crystalline Monohydrate Form PI A .
• Figure 9 shows the SEM image of crystalline Form A.
• the present invention provides crystalline forms of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in free form (the compound of formula I), which are described and characterised herein.
• 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 PI A of A/-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin- 4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide of the present invention possess favorable physicochemical properties for a drug substance intended for use in an oral solid dosage form.
• Monohydrate H A surprisingly provides improved handling and PAT058446-WO-PCT02
• Crystalline Forms A, B and Monohydrate FI A of A/-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin- 4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide 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 PXRD, DSC and TGA. It may be characterized by one of the aforementioned analytical methods or by combining two or more of them.
• Forms A, B and Monohydrate H A of the compound of Formula (I) of the present invention 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 A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in free form, which is described and characterised herein.
• Monohydrate Form H 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 Figure 5, or the differential scanning calorimetry of Figure 6.
• Monohydrate Form H A can also be defined by reference to one or more of the following characteristic signals:
• the Monohydrate Form H A exhibits an X-ray powder diffraction pattern having at least one, two or three characteristic peaks expressed in degrees 2-Theta (°2Q) at angles of 7.3° +/- 0.2°, 10.7° +/- 0.2° and 23.0° +/- 0.2° when measured using CuKa radiation.
• the Monohydrate Form H A exhibits at least one, two or three
• the Monohydrate Form H A exhibits at least one, two, three, four or five characteristic peaks at angles of 7.3° +/- 0.2°, 10.7° +/- 0.2°, 16.3° +/- 0.2°, 16.7° +/- 0.2°, 17.4° +/- 0.2°, 23.0° +/- 0.2°, 24.3° +/- 0.2°, 25.3° +/- 0.2°, 28.3° +/- 0.2° and 32.0° +/- 0.2° when measured using CuKa radiation.
• the Monohydrate Form H A exhibits an X-ray powder diffraction pattern substantially in accordance with Figure 5 and Table 5 when measured using CuKa radiation.
• the Monohydrate Form H A is present in substantially pure form.
• the Monohydrate Form H A exhibits a differential scanning calorimetry thermogram having a characteristic (endothermic) peak expressed in units of °C with an onset temperature of about 94 e C. In another embodiment, the Monohydrate Form H A exhibits a differential scanning calorimetry thermogram substantially in accordance with Figure 6.
• the Monohydrate Form H A is characterized by TGA having a curve which shows a mass loss of about 3.7 %, based on the weight of the crystalline form, when heated from about 43 to 135 °C at a rate of 10 K/min, in accordance with Figure 7.
• the Monohydrate Form H A exhibits a TGA thermogram substantially in accordance with Figure 7.
• the invention relates to a crystalline form of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in Monohydrate Form H A characterized by exhibiting cube-like shaped crystals.
• the Monohydrate Form H A has a cubic crystal shape, e.g., as determined by scanning electron microscopy.
• the present invention provides a crystalline form of A/-(3-(2-(2- hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(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 Figure 1 , or the differential scanning calorimetry of Figure 2.
• Polymorph form A can also be defined by reference to one or more of the following
• the polymorph Form A exhibits an X-ray powder diffraction pattern having at least one, two or three characteristic peaks expressed in degrees 2-Theta (°2Q) at angles of 5.8° +/- 0.2°, 1 1.7° +/- 0.2° and 14.8° +/- 0.2° when measured using CuKa radiation.
• the polymorph Form A exhibits at least one, two or three characteristic peaks at angles of 5.8° +/- 0.2°, 1 1 .7° +/- 0.2°, 14.8° +/- 0.2°, 15.2° +/- 0.2° and 18.7° +/- 0.2° when measured using CuKa radiation.
• the polymorph Form A exhibits at least one, two, three, four or five characteristic peaks at angles of 5.8° +/- 0.2°, 10.0° +/- 0.2°, 1 1.7° +/- 0.2°, 12.6° +/- 0.2°, 13.1 ° +/- 0.2°, 14.8° +/- 0.2°, 15.2° +/- 0.2°, 18.7° +/- 0.2°, 20.2° +/- 0.2° PAT058446-WO-PCT02
• the polymorph Form A exhibits an X-ray powder diffraction pattern substantially in accordance with Figure 1 and Table 3 when measured using CuKa radiation.
• the polymorph Form A is present in substantially pure form.
• 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 142 °C. In another embodiment, the polymorph Form A exhibits a differential scanning calorimetry thermogram substantially in accordance with Figure 2.
• the present invention provides a crystalline form of A/-(3-(2-(2- hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(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 Figure 3, or the differential scanning calorimetry of Figure 4.
• Polymorph form B can also be defined by reference to one or more of the following
• the polymorph Form B exhibits an X-ray powder diffraction pattern having at least one, two or three characteristic peaks expressed in degrees 2-Theta (°2Q) at angles of 5.8° +/- 0.2°, 1 1.7° +/- 0.2° and 14.8° +/- 0.2° when measured using CuKa radiation.
• the polymorph Form B exhibits at least one, two or three characteristic peaks at angles of 5.8° +/- 0.2°, 1 1 .7° +/- 0.2°, 14.8° +/- 0.2°, 15.2° +/- 0.2° and 18.7° +/- 0.2° when measured using CuKa radiation.
• the polymorph Form B exhibits at least one, two, three, four or five characteristic peaks at angles of 5.8° +/- 0.2°, 10.0° +/- 0.2°, 1 1.7° +/- 0.2°, 12.6° +/- 0.2°, 13.1 ° +/- 0.2°, 14.8° +/- 0.2°, 15.2° +/- 0.2°, 18.7° +/- 0.2°, 20.2° +/- 0.2° and 25.1 ° +/- 0.2° when measured using CuKa radiation.
• the polymorph Form B exhibits an X-ray powder diffraction pattern substantially in accordance with Figure 3 and Table 4 when measured using CuKa radiation.
• the polymorph Form B is present in substantially pure form.
• 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 1 16 °C. In another embodiment, the polymorph Form B exhibits a differential scanning calorimetry thermogram substantially in accordance with Figure 4. PAT058446-WO-PCT02
• free form refers to the compound A/-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4- yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide as the free base.
• room temperature refers to a temperature in the range of from 20 to 30 °C.
• the term“measured at a temperature in the range of from 20 to 30 °C” refers to a measurement under standard conditions.
• standard conditions mean a temperature in the range of from 20 to 30 °C, i.e. at room temperature.
• Standard conditions can mean a temperature of about 22 °C.
• peak positions 2Q
• peak positions 2Q
• 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”.
• an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
• intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed.
• relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account.
• a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% 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 the instant invention is not limited to the crystal form that provides an X-ray diffraction pattern completely identical to the X- PAT058446-WO-PCT02
• Crystalline Monohydrate Form PIA or Form A or Form B of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide 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, DSC and TGA analysis.
• 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.
• 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.
• polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
• dehydrating or“dehydration” as used herein, describe the at least partial removal of water from the crystal structure of the host molecule.
• 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.
• an anhydrous form does not contain more than 2.0 w-%, preferably not more than 1 .0 w-% of water, based on the weight of the crystalline form.
• hydrate 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.
• 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. PAT058446-WO-PCT02
• 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.
• mother liquor refers to the solution remaining after crystallization of a solid from said solution.
• antisolvent refers to liquids which reduce the solubility of A/-(3-(2-(2- hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide in a solvent.
• substantially pure or“essentially pure form” when used in reference to a form means the compound having a purity greater than 90 w-%, including greater than 90, 91 , 92, 93, 94, 95, 96, 97, 98, and 99 w- %, and also including equal to about 100 w-% of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(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.
• a crystalline form of /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide may be deemed substantially pure in that it has a purity greater than 90 w-%, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 w-% of material comprises other form(s) of A/-(3-(2-(2- hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide and/or reaction impurities and/or processing impurities.
• an amorphous form of the compound of formula (I) Form A, Form B or Monohydrate FI A having a purity greater than 90 w-%, including greater than 90, 91 , 92, 93, 94, 95, 96, 97, 98, and 99 w- %.
• pharmaceutically acceptable excipient 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.
• 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. PAT058446-WO-PCT02
• binding refers to substances, which bind the active pharmaceutical ingredient and pharmaceutically acceptable excipient together to maintain cohesive and discrete portions.
• 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.
• lubricant 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.
• glidant 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.
• /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide encompasses an amount of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, which causes the desired therapeutic and/or prophylactic effect.
• non-hygroscopic refers to a compound showing a water uptake of at most 2 w-% in the sorption cycle when measured with GMS (or DVS) at a relative humidity in the range of from 0 to 95% RH and a temperature of (25.0 ⁇ 0.1 ) °C, based on the weight of the compound.
• Non-hygroscopic is preferably up to 0.2 %.
• solid form or“solid state form” as used herein interchangeably refer to any crystalline and/or amorphous phase of a compound.
• the present invention relates to a process for the preparation of crystalline form Monohydrate H A 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:
• the process for the preparation of crystalline form Monohydrate H A of the Compound of Formula (I) of the present invention comprises the steps:
• the mixture of step (ii) is heated to about 40-70 °C.
• the Compound of Formula (I) starting material can be prepared according to the procedure disclosed in Example 1 156 of WO 2014/151616 A1 .
• the solid starting material provided in step (i) is dissolved in a water miscible solvent:water mixture
• the water miscible solvent is acetone, ethanol, methanol, propanol, butanol, isopropyl alcohol, tetrahydrofuran (THF), acetonitrile and the like.
• the water miscible solvent is acetonitrile, acetone, methanol, ethanol, propanol or isopropyl alcohol.
• the water miscible solvent is acetonitrile, acetone or ethanol.
• the ratio of solvent:water is preferably 1 :2 based on the weight of the solvent:water.
• the reaction mixture may be heated to a temperature of about 100 °C and cooled down to about -20 °C.
• the mixture of step is heated to about 40-70 °C. More preferably, the mixture is heated to 50 °C.
• 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 4 hours.
• the mixture is heated for a period of 2 hours.
• the mixture is heated to 50 °C over a period of 4 hours preferably over a period of 2 hours.
• the cooling step can be performed over a period of at least 4 hours, e.g. at least 6 hours, e.g. 4- 24 hours. Preferably, the cooling step is performed over a period of about 4 hours.
• 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.
• 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.
• the isolated crystals are washed with a suitable solvent, for example an organic solvent and/or water or a mixture thereof.
• 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 20-80 °C, preferably, about 30 to 70 °C. 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 2 to 72 hours.
• drying is performed at a temperature of about 40 °C from about 4 to 24 hours, preferably about 7 to 15 hours, more preferably about 8 hours at 40 °C. Drying may be performed at ambient pressure and/or under reduced pressure. Preferably, drying is performed under reduced pressure, for example 0-100 mbar. More preferably, drying is performed under reduced pressure, at a temperature of about 40 °C for about 8 hours.
• the present invention relates to a process for the preparation of crystalline Form A 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:
• the process for the preparation of crystalline Form A of the Compound of Formula (I) of the present invention 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. Plowever, most preferably ethyl acetate is used.
• organic solvent for example, ethyl acetate, isopropyl acetate, THF, isopropyl alcohol. Plowever, most preferably ethyl acetate is used.
• an antisolvent is preferably a hydrocarbon solvent.
• the hydrocarbon solvent can be n-hexane, n-heptane, cycloalkane, e.g. cyclohexane.
• the antisolvent is n-heptane.
• 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.
• 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.
• the isolated crystals are washed with a suitable solvent, for example an organic solvent.
• 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.
• the crystals are washed with a mixture of n-heptane and ethyl acetate.
• the fraction of n-heptane may be from 90 to 50 percent by weight, preferably from 80 to 60 percent by weight.
• Drying may be performed at a temperature of about 20 to 100 °C, preferably 40 to 80 °C, more preferably at about 60 °C. Typically, drying is performed at about room temperature. Most preferably, drying is performed at 60 °C. Depending on the temperature employed, drying may be performed for a period in the range of from about 6 to 72 hours, preferably from about 12 to 20 hours, more preferably for about 15 hours. Drying may be performed at ambient pressure or under reduced pressure. Preferably, drying is performed under reduced pressure, e.g. 0-100 mbar.
• the present invention relates to a process for the preparation of crystalline Form B 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:
• 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.
• a solvent for example, acetonitrile. Most preferably acetonitrile is the only solvent present in the slurry.
• Acidification is performed at 5 to 10 °C using a suitable acid, such as, for example, HCI.
• Slurrying is conducted for at least 5 hours, such as 5 hours, 7 hours, 10 hours at a temperature of 30 to 15 °C.
• slurrying is conducted over a period of 5-10 hours.
• Neutralisation is achieved using a suitable base, such as, for example, sodium bicarbonate.
• 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.
• 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.
• the isolated crystals are washed with a suitable solvent, for example an organic solvent.
• 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 1 day, or longer.
• the skilled person may monitor the conversion of the applied solid form of A/- ⁇ 3-[2-(Hydroxyethoxy)-6-(morpholin-4- yl)pyridin-4-yl]-4-methylphenyl ⁇ -2-(trifluoromethyl)pyridine-4-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.
• Drying may be performed at a temperature of about 20 to 100 °C, preferably 40 to 80 °C, more preferably at about 60 °C. Typically, drying is performed at about room temperature. Most preferably, drying is performed at 60 °C. Depending on the temperature employed, drying may be performed for a period in the range of from about 6 to 72 hours, preferably from about 12 to 20 hours, more preferably for about 15 hours. Drying may be performed at ambient pressure or under reduced pressure. Preferably, drying is performed under reduced pressure, e.g. 0-100 mbar.
• Form A may be provided and suspended in dichloromethane for 1 to 5 days at a temperature of 40 to 60 °C, to produce Form B.
• the present invention relates to the use of the crystalline Form A, or Form B or Monohydrate PI A of /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide of the present invention as defined in any one of the aspects and their corresponding embodiments described above for the preparation of a pharmaceutical composition.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising the crystalline Form A, or Form B or Monohydrate PI A of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(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.
• the predetermined and/or effective amount of the crystalline Form A, or Form B or Monohydrate PI A of /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide as defined in any one of the aspects and their corresponding embodiments described above can be in unit dosage of about 50-1200 mg ( e.g per day).
• Plence, crystalline Form A, or Form B or Monohydrate PI A of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(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 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1 100 mg, about 1 150 mg or about 1200 mg.
• 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.
• the unit dosage of crystalline Form A, or Form B or Monohydrate PI A of /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide is administered once daily.
• the unit dosage of crystalline Form A, or Form B or Monohydrate PI A of A/-(3-(2-(2- hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide is administered twice daily.
• Crystalline Form A, or Form B or Monohydrate PI A of A/-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide may in particular be administered at a dose of 100 mg once daily (QD), 200 mg once daily, 300 mg once daily, 400 mg once daily, 800 mg once daily or 1200 mg once daily (QD).
• (trifluoromethyl)isonicotinamide may also be administered at a dose of 100 mg, 200 mg twice daily, 400 mg twice daily or 600 mg twice daily (BD).
• the dosages quoted herein may apply to the administration of crystalline Form A, or Form B or Monohydrate H A of A/-(3-(2-(2- hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide as monotherapy (single agent) or as part of a combination therapy.
• the actual dosage can vary by up to 5-7% 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
• composition of the present invention is preferably selected from the group consisting of fillers, diluents, binders, disintegrants, lubricants, glidants and combinations thereof.
• the pharmaceutical composition comprising the crystalline Form A, or Form B or Monohydrate H A of A/-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide as defined in any one of the aspects and their corresponding embodiments described above is an oral solid dosage form.
• the oral solid dosage form is selected from the group consisting of tablets, capsules, etc.
• the oral dosage form is a tablet or a capsule, most preferably a tablet.
• the present invention relates to the crystalline Form A, or Form B or Monohydrate H A of /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.
• the present invention relates to the crystalline Form A, or Form B or Monohydrate H A of /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide or the pharmaceutical composition comprising the same as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of a proliferative disease, particularly a cancer.
• the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic ductal adenocarcinoma (PDAC), cervical cancer, ovarian cancer or colorectal cancer (CRC).
• NSCLC non-small cell lung cancer
• PDAC pancreatic ductal adenocarcinoma
• CRC colorectal cancer
• 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)).
• MAPK Mitogen-activated protein kinase
• the invention concerns 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 PIA of /V-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4- yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide as defined in the above described aspects and their corresponding embodiments to a patient in need of such a treatment.
• the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic ductal adenocarcinoma (PDAC), cervical cancer, ovarian cancer or colorectal cancer (CRC).
• NSCLC non-small cell lung cancer
• PDAC pancreatic ductal adenocarcinoma
• CRC colorectal cancer
• 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)).
• MAPK Mitogen-activated protein kinase
• a method for the treatment of disorders mediated by Raf comprising administering to a patient in need of such treatment an effective amount of a crystalline compound of Formula (I) (e.g. polymorph Form A or Form B or Monohydrate H A ).
• a crystalline compound of Formula (I) e.g. polymorph Form A or Form B or Monohydrate H A .
• the invention relates to the use of a crystalline compound of formula I ⁇ e.g., polymorph Form A or Form B or Monohydrate H A ) 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.
• Example 1 outlines how Compound 1 may be prepared.
• Example 2 shows how it may be crystallised to produce Form A.
• Examples 3 and 4 describe the XRPD and DSC analysis of Form A.
• Example 5 describes the process of preparation of Form B and the corresponding XRPD data are shown in Example 6.
• Example 7 shows the DSC data of Form B.
• Examples 8, 9, 10 and 11 describe the process of making Monohydrate Form H A , and the XRPD, DSC and TGA analysis of Monohydrate Form H A .
• Examples 12 and 13 describe the stability testing of Monohydrate H A and Form B.
• Examples 14 PAT058446-WO-PCT02
• WO 2020/230028 PCT/IB2020/054491 and 15 show the water activity experiments of Monohydrate Form PI A and Form A.
• Example 16 shows the solubility data of Monohydrate RI A , Form A and Form B. The release data of Monohydrate PIA and Form A are shown in Example 17.
• Example 18 shows competitive slurry experiments of Form A and Form B.
• Example 19 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 40 kV and 1 mA under the following conditions:
• the X-ray diffraction pattern was recorded at room temperature between 2° and 45° (2-theta) with CuK c radiation for identification of the whole pattern.
• DSC Differential scanning calorimetry
• Crystalline Form A was analysed by XRPD and the ten most characteristic peaks are shown in T able 3 (see also Figure 1 ).
• Crystalline Form A was found to have an onset of melting at about 142 e C (see Figure 2) according to the DSC method outlined above and Table 2.
• Form A is thermodynamically more stable and has a higher melting point and melting enthalpy than Form B.
• the reaction mixture was stirred for 30 min at 15 to 20 °C, diluted with ethyl acetate (36.5 L, 10 vol), stirred for about 5 min and the layers were separated.
• the aqueous layer was extracted with ethyl acetate (1 x 5 vol), the combined organic layer was washed with water (1 x10 vol), brine (1 x10 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 4 (see also Figure 3).
• Crystalline Form B was found to have an onset of melting at about 1 16 e C (see Figure 4) according to the DSC method outlined above and Table 2.
• Crystalline Monohydrate Form H A was analysed by thermogravimetric analysis (TGA) using a Discovery Thermogravimetric Analysis Calorimeter from TA instruments under the following conditions (see Table 6).
• Example 12 Stability Testing of Monovdrate HA
• Monohydrate Form H A is highly stable in bulk, e.g. up to 80 °C over an extended period of time. No notable change in chemical purity, nor change in XRPD, nor change in TGA, was observed. Monohydrate Form H A is also stable upon light exposure, e.g. 1200 kLuxh for 12 h, and is also stable upon compression, grinding and wet granulation with water.
• DPs are analyzed by UPLC. They are calculated as area-% products.
• Monohydrate Form PI A 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.
• 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.
• the water activity (a w ) is the partial vapor pressure of water in a substance divided by the standard state partial vapor pressure of water.
• Acetonitrile:water 1 :1 10 10 HA HA
• Acetone : water 1 :1 10 10 HA HA
• Acetonitrile:water 1 :1 10 10 HA HA
• Acetone : water 1 :1 10 10 HA HA
• Heptane 10 10 Form A + H A Form A + H A PAT058446-WO-PCT02
• Monohydrate H A is more stable than Form A.
• acetonitrile or acetone with water (1 :1 ) the Monohydrate H A is more stable than Form A.
• both crystal forms are still observed after 5 days equilibration, i.e. Form A remains unchanged and
• Modification H A 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 15 below).
• Form A is equilibrated with 0.5 ml. solvent by stirring at RT or 50 °C. The slurries are filtered. The wet cake is investigated by XRPD.
• Form A converts to Monohydrate H A . In pure water, Form A remains unchanged.
• Modification H A is more stable than Modification A in the aqueous-organic solvent system with water activity more than 0.3 and 0.5 at ambient temperature and 50 °C, respectively.
• the conversion of Modification A to H A takes a longer equilibration time.
• 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 H A either at ambient humidity or at 92% RH.
• Example 16 Solubility of Form A, B, Monohydrate HA
• a sample was weighed in a glass vial and solvent added to make a slurry followed by stirring or shaking at 25 °C for 24 hours.
• the amount of sample and solvents depends on the target concentration, e.g. if the target concentration is 10mg/mL, the weight of the sample should be 10mg and the amount of solvent volume should be 1 mL.
• the solid and liquid are separated by centrifugation at 13000 rpm for 2 minuteswith 0.2 pm 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 40 °C under vacuum for 2 hours. DSC/TGA analysis was conducted for selected samples.
• Table 12 Solubility of Form A and Form B in aqueous and organic solvent media at 25 e C.
• Form B provides higher solubility in several aqueous media, particularly at low pH, e.g. pH 1 or 2.
• Form B can be expected to behave advantageously in terms of better dissolution properties as oral solid dosage form, e.g. in the PAT058446-WO-PCT02
• Example 17 Powder properties of Modification H A and Form A
• Dispersing aid Tween 20 Fluka No. 93773, approx. 10% in dispersion liquid Dispersion liquid Deionized water
• Dispersion device Suspension cell e.g. SUCELL, Sympatec GmbPI, Germany
• Particle sizes were determined at the undersize values of 10%, 50% and 90% (x10, x50, x90), and additional values in question, from the cumulative volume distribution.
• Monohydrate H A crystals (prepared according to the scale up process of Example 8) are significantly coarser (SEM image in Figure 8) compared to Modification A crystals (SEM image in Figure 9), which is quantitatively supported, e.g. by diameter X10: 131 pm vs. 2 pm (> factor 10), obtained through particle size measurement by laser light diffraction.
• This difference in bulk density allows easier powder handling of Monohydrate H A crystals. This also applies to improved handling of the Monohydrate H A 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 H A crystal powder, i.e. preparation of blend of API with excipients.
• Form A and Form B are weighed by 1 :1 ratio into a vial, respectively.
• Heptane 50 50 Form A + Form B Isopropanol 50 50 Form A PAT058446-WO-PCT02
• 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. Plowever, upon equilibration in an aqueous/organic mixture of solvents, Modification Fi A was observed and is the most stable form, except in the ethanol/water 90:10 mixture.
• Form A remains unchanged upon granulation with water or compression. A slight decrease in crystallinity is observed when compressed at pressures of 3 to 6 MPa. Form B did not change XRPD pattern upon grinding, compression and granulation with water.
• Modification H A exhibits compact particle morphology and high bulk density.
• its physical properties, e.g., in terms of shape of crystals obtained can be fine-tuned through crystallization conditions as described herein. Therefore, Modification PI A 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 H A 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 H A is specially advantageously suitable for development, especially for drug product manufacturing.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyridine Compounds (AREA)

Priority Applications (13)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (1)

Family

ID=70740724

Family Applications (1)

Country Status (13)

Cited By (20)

Citations (1)

Family Cites Families (136)

• 2020
  • 2020-05-12 EP EP20726561.2A patent/EP3969449B1/en active Active
  • 2020-05-12 ES ES20726561T patent/ES3025633T3/es active Active
  • 2020-05-12 JP JP2021567779A patent/JP2022531969A/ja active Pending
  • 2020-05-12 US US17/610,321 patent/US12187703B2/en active Active
  • 2020-05-12 MX MX2021013817A patent/MX2021013817A/es unknown
  • 2020-05-12 EP EP25156963.8A patent/EP4563150A3/en active Pending
  • 2020-05-12 AU AU2020276695A patent/AU2020276695B2/en active Active
  • 2020-05-12 WO PCT/IB2020/054491 patent/WO2020230028A1/en not_active Ceased
  • 2020-05-12 CA CA3138123A patent/CA3138123A1/en active Pending
  • 2020-05-12 KR KR1020217037040A patent/KR102881316B1/ko active Active
  • 2020-05-12 CN CN202080033836.5A patent/CN113795490A/zh active Pending
  • 2020-05-13 TW TW109115917A patent/TWI849124B/zh active
• 2021
  • 2021-10-06 IL IL287030A patent/IL287030A/en unknown
  • 2021-11-09 CL CL2021002963A patent/CL2021002963A1/es unknown
• 2024
  • 2024-11-25 US US18/958,311 patent/US20250188054A1/en active Pending

Patent Citations (1)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events