Solid forms of 5-[3-[[(3R)-1-ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-YL]-2,3- dihydrobenzofuran-4-ol

Abstract

The present invention provides solid forms of 5-[3-[[(3R)-1-Ethyl-3-piperidyl]amino]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol, as well as therapeutic uses thereof and pharmaceutical composition comprising them.

Description

P39563NEW SOLID FORMS OF 5-[3-[[(3R)-l-ETHYL-3-PIPERIDYL]AMINO]-5-METHYL-l,2,4- TRIAZIN-6-YL]-2,3- DIHYDR0BENZ0FURAN-4-0LFIELD OF INVENTION

[0001] The present invention provides new solid forms of 5-[3-[[(3R)- 1 -Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, as well as therapeutic uses thereof and pharmaceutical compositions comprising said forms.BACKGROUND OF THE INVENTION

[0002] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide inhibits IL-ip production at micromolar concentrations in response to the activation of NLRP3 but not NLRC4 or NLRP1. Other previously characterised weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-P-nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are nonspecific.

[0003] WO2022253936 discloses the compound of formula (I), also referred to as 5-[3-[[(3R)- l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, a triazine-containing compound disclosed as an inhibitor of NLRP3.

[0004] There is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties and / or those that provide a useful alternative to known compounds.

[0005] Polymorphs are different crystalline forms of the same compound. Polymorphs typically have a different crystal structure due to a different packing of the molecules in the lattice. Polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical studies, the exact dosage form used may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selectedP39563 polymorphic form in high purity when the compound is used in clinical studies or commercial products since any impurities may produce undesired effects (e.g. toxicity). Certain polymorphs may also exhibit enhanced stability or may be more readily manufactured in high purity in large quantities, and are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.

[0006] Accordingly, for pharmaceutical development and commercialization, there is a need to identify solid forms of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]- 2,3- dihydrobenzofuran -4-ol having desirable properties such as high crystallinity, high purity, and favourable physical stability, chemical stability, dissolution and mechanical properties. The present invention provides 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6- yl]-2,3 - dihydrobenzofuran-4-ol in novel solid forms, namely crystalline polymorphic Form E.DEFINITIONS

[0007] “Crystallization” and “recrystallization” may be used interchangeably; referring to a process that leads to a stable polymorph or crystalline form of a particular chemical compound wherein the chemical compound prior to the process can be in amorphous form, or dissolved or suspended in a solvent system. For example, the crystallization steps can be done by forming a crystal with a solvent and an anti -solvent.

[0008] ” XRPD” refers the analytical method of X-Ray Powder Diffraction. The repeatability of the angular values is in the range of °29 ±0.2°. The term “approximately” given in combination with an angular value denotes the repeatability which is in the range of 2 -theta. The relative XRPD peak intensity is dependent upon many factors such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. Relative intensities may vary considerably from one measurement to another due to preferred orientation effects. According to USP 941 (US Pharmacopoeia, 37th Edition, General Chapter 941), relative intensities between two samples of the same material may vary considerably due to “preferred orientation” effects. Anisotropic materials adopting preferred orientation will lead to anisotropic distribution of properties such as modulus, strength, ductility, toughness, electrical conductivity, thermal expansion, etc., as described e.g. in Kocks U.F. et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000). In XRPD but also Raman spectroscopy, preferredorientations cause a change in the intensity distribution. Preferred orientation effects are particularly pronounced with crystalline APIs of relatively large particle size.

[0009] "Polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions forming the crystal. In general, reference throughout this specification will be to a polymorphic form of 5 -[3-[[(3R)-l- Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol. The term “polymorphic form” as used herein may or may not include other crystalline solid state molecular forms including hydrates (e.g. bound water present in the crystalline structure) of the same compound. Polymorphs typically have a different crystal structure due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and / or unit cell parameters which directly influences its physical properties such as the X-ray diffraction characteristics of crystals or powder.

[0010] “Amorphous” refers to solid materials that lack the long-range order that is characteristic of a crystalline solid.

[0011] The term “solvate” refers herein to a molecular complex comprising a compound of formula (I) and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., ethanol). “Hydrate” refers herein to a solvate comprising a compound of formula (I) and a stoichiometric or non-stoichiometric amount of water.

[0012] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier”, and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.

[0013] The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.P39563

[0014] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes can be made and equivalents can be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. All separate embodiments can be combined.SUMMARY OF THE INVENTION

[0015] A first aspect of the present invention provides a crystalline form of 5-[3-[[(3R)-l- Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, or a hydrate or solvate thereof.

[0016] A second aspect of the present invention provides a crystalline polymorphic form of 5 - [3 -[[(3 R)- l-Ethyl-3 -piperidyl] amino] -5 -methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran -4-ol, or a hydrate or solvate thereof. Preferred examples of such polymorphs include the polymorphs referred to herein as Form E, Form C and Form A. Other examples of such polymorphs include the polymorphs referred to herein as Form D and Pattern 11.

[0017] A third aspect of the present invention provides a pharmaceutical composition comprising a crystalline form of the first aspect of the invention or a polymorphic form of the second aspect of the invention, and a pharmaceutically acceptable excipient.

[0018] Further aspects of the present invention provide medical uses and methods of treatment of a disease, disorder or condition, most especially by NLRP3 inhibition.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 illustrates a X-ray powder diffraction pattern of the polymorphic Form E of 5- [3 -[[(3 R)- l-Ethyl-3 -piperidyl] amino] -5 -methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol.

[0020] Figure 2 illustrates a thermogram of the polymorphic Form E of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by differential scanning calorimetry (DSC). A sharp melting signal was observed (onset 120 °C).

[0021] Figure 3 illustrates a thermogram of the polymorphic Form E of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by thermogravimetric analysis (TGA).P39563

[0022] Figure 4 illustrates a Raman spectrum of the polymorphic Form E of 5-[3-[[(3R)-l- Ethyl-3 -piperidyl] amino] -5-methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol.

[0023] Figure 5 illustrates a IR spectrum of the polymorphic Form E of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0024] Figure 6 illustrates a water vapour sorption / desorption curve of the polymorphic Form E of 5 -[3 -[[(3 R)-l-Ethyl-3 -piperidyl] amino] -5-methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol obtained by dynamic vapour sorption (DVS). Form E exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %- RH with about 0.1 %-w / w of water sorption. This can be assessed as non-hygroscopic.

[0025] Figure 7 illustrates a X-ray powder diffraction pattern of Form C of 5-[3-[[(3R)-l- Ethyl-3 -piperidyl] amino] -5-methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol.

[0026] Figure 8 illustrates a thermogram of Form C of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by differential scanning calorimetry (DSC). A sharp melting signal was observed (onset 125 °C).

[0027] Figure 9 illustrates a thermogram of Form C of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by thermogravimetric analysis (TGA).

[0028] Figure 10 illustrates a water vapour sorption / desorption curve of Form C of 5-[3- [[(3R)- l-Ethyl-3-piperidyl]amino] -5-methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol obtained by dynamic vapour sorption (DVS). Form C exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 0.3 %-w / w of water sorption. This can be assessed as slightly hygroscopic.

[0029] Figure 11 illustrates a Raman spectrum of Form C of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0030] Figure 12 illustrates an IR spectrum of Form C of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0031] Figure 13 illustrates the result of a simulated X-ray powder diffraction pattern of Form A based on the X-ray single crystal diffraction measurement of the polymorphic Form A of 5 - [3 -[[(3 R)- l-Ethyl-3 -piperidyl] amino] -5 -methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol.P39563

[0032] Figure 14 illustrates a thermogram of Form A of 5-[3-[[(3R)-l -Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by differential scanning calorimetry (DSC). A sharp melting signal was observed (onset 116 °C).

[0033] Figure 15 illustrates a thermogram of Form A of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by thermogravimetric analysis (TGA).

[0034] Figure 16 illustrates a water vapour sorption / desorption curve of Form A of 5-[3- [[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by dynamic vapour sorption (DVS). Form A exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 0.2 %-w / w of water sorption. This can be assessed as slightly hygroscopic.

[0035] Figure 17 illustrates a Raman spectrum of Form A of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0036] Figure 18 illustrates an IR spectrum of Form A of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0037] Figure 19 illustrates a X-ray powder diffraction pattern of the Form B of 5-[3-[[(3R)-l- Ethyl-3 -piperidyl] amino] -5-methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol.

[0038] Figure 20 illustrates a thermogram of the Form B of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by differential scanning calorimetry (DSC). A non-baseline separated double peak is observed at 82 °C (peak temperature) and 100 °C (peak temperature).

[0039] Figure 21 illustrates a thermogram of the Form B of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by thermogravimetric analysis (TGA). Three weight losses can be observed. The first weight loss between 25 and 60 °C represents 0.5 %-w / w. The second weight loss of 2.5 %-w / w between 60 and 90 °C and the third weight loss of 1.9 %-w / w between 90 and 150 °C.

[0040] Figure 22 illustrates a Raman spectrum of the Form B of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0041] Figure 23 illustrates a IR spectrum of the Form B of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.P39563

[0042] Figure 24 illustrates a water vapour sorption / desorption curve of the Form B of 5-[3- [[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by dynamic vapour sorption (DVS). During the drying step Form B dries and converts mostly into Form A. This is confirmed by an XRPD measurement from the material after the DVS measurement. Form B exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: the reversible water uptake until 90 %-RH with about 0.8 %-w / w represents the conversion of originated Form A (during drying step) into Form B. The conversion of Form A into Form B and back, can be observed during both phases of the sorption. Due to the conversion, no meaningful hygroscopicity can be assessed.

[0043] Figure 25 illustrates a X-ray powder diffraction pattern of the polymorphic Form D of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrob enzofuran-4- ol.

[0044] Figure 26 illustrates a thermogram of the polymorphic Form D of 5-[3-[[(3R)-l-Ethyl- 3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by differential scanning calorimetry (DSC). A sharp melting signal was observed (onset 136 °C).

[0045] Figure 27 illustrates a thermogram of the polymorphic Form D of 5-[3-[[(3R)-l-Ethyl- 3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by thermogravimetric analysis (TGA).

[0046] Figure 28 illustrates a Raman spectrum of the polymorphic Form D of 5-[3-[[(3R)-l- Ethyl-3 -piperidyl] amino] -5-methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol.

[0047] Figure 29 illustrates a IR spectrum of the polymorphic Form D of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0048] Figure 30 illustrates a water vapour sorption / desorption curve of the polymorphic Form D of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by dynamic vapour sorption (DVS). Form D exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %- RH with about 0.2 %-w / w of water sorption. This can be assessed as slightly hygroscopic.

[0049] Figure 31 illustrates a X-ray powder diffraction pattern of the polymorphic Pattern 11 of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.P39563

[0050] Figure 32 illustrates a thermogram of the polymorphic Pattern 11 of 5-[3-[[(3R)-l- Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by differential scanning calorimetry (DSC). A sharp melting signal was observed (onset 112 °C).

[0051] Figure 33 illustrates a thermogram of the polymorphic Pattern 11 of 5-[3-[[(3R)-l- Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by thermogravimetric analysis (TGA).

[0052] Figure 34 illustrates a Raman spectrum of the polymorphic Pattern 11 of 5-[3-[[(3R)-l- Ethyl-3 -piperidyl] amino] -5-methyl- 1, 2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol.

[0053] Figure 35 is a IR spectrum of the polymorphic Pattern 11 of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol.

[0054] Figure 36 illustrates a water vapour sorption / desorption curve of the polymorphic Pattern 11 of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol obtained by dynamic vapour sorption (DVS). Pattern 11 exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: during the first cycle the remaining water / solvent is released with no significant change to Pattern 11. After drying no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 1.4 %-w / w of water sorption. This can be assessed as slightly hygroscopic.DETAILED DESCRIPTION OF THE INVENTION

[0055] Differences between solid forms of an active pharmaceutical compound can have profound effects on the properties of the compound. For example, differences can arise in the crystallinity, solubility, intrinsic dissolution rate, bioavailability, stability to mechanical stress, storage stability, and stability in aqueous and other media of a polymorphic form of a compound as compared to the amorphous and other polymorphic forms of the same compound.

[0056] The present invention provides a crystalline form of 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, or a hydrate or solvate thereof, which has certain advantages over the amorphous form. The present invention also provides polymorphs of the crystalline form of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5- methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, or a hydrate or solvate thereof, which have certain advantages over other polymorphs and over the amorphous form.P39563

[0057] A first aspect of the present invention provides a crystalline form of 5-[3-[[(3R)-l- Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, or a hydrate or solvate thereof. 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]- 2,3- dihydrobenzofuran -4-ol (also referred to as the free acid) has the formula:

[0058] The crystalline form of the first aspect of the present invention may also encompass salts and co-crystals. A salt may have any ratio of the conjugate base to the salt ion.

[0059] The crystalline form of the first aspect of the present invention may be anhydrous or in the form of a hydrate or other solvate. Such solvates may be formed with common organic solvents, including but not limited to alcoholic solvents e.g. methanol, ethanol or isopropanol. Mixed solvates and hydrates are also possible. In one embodiment, the crystalline form of 5-[3- [[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol is an anhydrate. In another embodiment, the crystalline formof 5-[3-[[(3R)-l-Ethyl-3- piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol is a hydrate.

[0060] The crystalline form of the first aspect of the invention preferably has a degree of crystallinity of 50% or more (e.g. 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99% or more). As used herein a crystalline form of the first aspect of the invention is typically referred to as crystalline, if it has a degree of crystallinity of 90% or more (e.g. 95% or more, or 99% or more). As used herein the degree of crystallinity is the weight percentage of the crystalline form of the first aspect of the invention which is in one or more polymorphic forms, expressed as a percentage of the total weight of the salt. Typically the degree of crystallinity is determined by XRPD or DSC.

[0061] A crystalline form of the first aspect of the invention may exist in one or more polymorphic forms. Polymorphism refers to the ability of a solid substance to exist in one or more distinct crystal structures (i.e. with one or more distinct arrangements of molecules relative to each other in the crystal lattice). Different polymorphs of a substance may haveP39563 different physical properties such as bioavailability, solubility, intrinsic dissolution rate and calorimetric behaviour (e.g. melting point). Different polymorphs may also exhibit differences in stability (e.g. differences in stability with respect to conversion to other crystalline or amorphous forms or differences in stability to grinding). The physical properties of an active pharmaceutical ingredient may affect the drug product safety, performance, and efficacy. It is therefore advantageous to identify polymorphic forms of a drug substance which have pharmaceutically acceptable properties.

[0062] Accordingly, a second aspect of the present invention provides a crystalline polymorphic form of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, or a hydrate or solvate thereof.

[0063] A polymorphic form of the second aspect of the invention preferably comprises more than 80% of a single crystalline polymorph of the compound, preferably more than 90%, more preferably more than 95%, even more preferably more than 98%, and most preferably more than 99% as measured by XRPD or DSC, preferably as measured by XRPD.

[0064] Preferred examples of polymorphic forms of the second aspect include the polymorphs referred to herein as Form E, Form C and Form A. Other examples of such polymorphs include the polymorphs referred to herein as Form D and Pattern 11.

[0065] The Form A, Form C, Form D, Form E and Pattern 11 polymorphs can be characterised by techniques including X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA) and / or Thermogravimetric Analysis coupled to Fourier-Transform Infrared Spectroscopy (TGA-FTIR). Other means of characterization include IR and Raman Spectroscopies.

[0066] As used herein, XRPD data are typically those which can be obtained using CuKal radiation at 20 °C. As used herein, the term “approximate” or “approximately” when used in connection with the position of an XRPD peak typically refers to the stated position ±0.2 °29. As used herein, DSC, TGA and TGA-FTIR data are typically those which can be obtained using a heating rate of 10 K / min, 5 K / min and 10 K / min respectively.

[0067] Form E polymorph

[0068] The Form E polymorph is a first particular preferred polymorphic form. It was found to have good solubility and be thermodynamically stable at ambient conditions. The Form E polymorph is therefore suitable for development as a drug product and maintain shelf-life.P39563

[0069] The Form E polymorph typically has an XRPD diffractogram comprising peaks at approximately: 11.5 (±0.2) °29, 21.4 (±0.2) °29, and 17.8 (±0.2) °29. More typically, the Form E polymorph has an XRPD diffractogram comprising peaks at approximately: 11.5 (±0.2) °29, 21.4 (±0.2) °29, 17.8 (±0.2) °29, 12.2 (±0.2) °29, 10.9 (±0.2) °29, and 21.1 (±0.2) °29.

[0070] The Form E polymorph may have an XRPD diffractogram approximately as shown in Table 1 below:

[0071] Table 1 (Table of characteristic XRPD diffractogram peaks for Form E)P39563P39563

[0072] The Form E polymorph may have an XRPD diffractogram approximately as set out in Figure 1.

[0073] The Form E polymorph typically has a DSC profile comprising a single endothermic event. The endothermic event of the Form E polymorph typically has an onset at a temperature in a range from about 115 °C to about 125 °C (e.g. a temperature in a range from about 115°C to about 125 °C, a temperature in a range from about 118 °C to about 122 °C, or at a temperature of about 120 °C).

[0074] The Form E polymorph may have a DSC profile approximately as set out in Figure 2.

[0075] The Form E polymorph typically has a TGA profile comprising two weight losses: a first weight loss of <0.1 %-w / w between 25 and 110 °C and a second weight loss of <0.1 %- w / w between 110 and 210 °C.

[0076] The Form E polymorph may have a TGA profile approximately as set out in Figure 3.

[0077] The Form E polymorph typically has a Raman spectrum comprising at least one peak at one of the positions 696 (±2) cm-1, 1099 (±2) cm-1, or 435 (±2) cm-1, more particularly comprising the peaks at positions 696 (±2) cm-1, 1099 (±2) cm-1, and 435 (±2) cm-1.

[0078] The Form E polymorph may have a Raman Spectrum approximately as set out in Table 2 below:

[0079] Table 2 (Table of characteristic Raman peaks for Form E expressed in cm1)P39563

[0080] The Form E polymorph may have Raman spectrum approximately as set out inFigure 4.

[0081] The Form E polymorph typically has an FTIR spectrum comprising at least three peaks selected from the positions 695 (±2) cm-1, 2925 (±2) cm-1, 976 (±2) cm-1, and 810 (±2) cm-1. More typically, the Form E polymorph has an FTIR spectrum comprising peaks at approximately 695 (±2) cm-1, 2925 (±2) cm-1, 976 (±2) cm-1, and 810 (±2) cm-1.

[0082] The Form E polymorph may have an FTIR spectrum approximately as set out in Table 3 below:

[0083] Table 3 (Table of characteristic FTIR peaks for Form E expressed in cm1)P39563

[0084] The Form E polymorph may have an FTIR spectrum approximately as set out in Figure 5.

[0085] The Form E polymorph typically has a water vapour sorption / desorption curve obtained by dynamic vapour sorption (DVS) that exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 0.1 %-w / w of water sorption. This can be assessed as non-hygroscopic.

[0086] The Form E polymorph may have a DVS isotherm approximately as set out in Figure 6.

[0087] Form C polymorph

[0088] The Form C polymorph is a second particular preferred polymorphic form. It was found to have good solubility and be thermodynamically stable. The Form C polymorph is therefore also suitable for development as a drug product.

[0089] The Form C polymorph typically has an XRPD diffractogram comprising peaks at approximately: 11.8 (±0.2) °29, 20.1 (±0.2) °29, and 23.4 (±0.2) °29. More typically, the Form C polymorph has an XRPD diffractogram comprising peaks at approximately: 11.8 (±0.2) °29, 20.1 (±0.2) °29, 23.4 (±0.2) °29, 16.3 (±0.2) °29, 17.4 (±0.2) °29, and 9.9 (±0.2) °29.

[0090] The Form C polymorph may have an XRPD diffractogram approximately as set out in Table 4 below:

[0091] Table 4 (Table of characteristic XRPD diffractogram peaks for Form C)P39563P39563P39563

[0092] The Form C polymorph may have an XRPD diffractogram approximately as set out in Figure 7.

[0093] The Form C polymorph typically has a DSC profile comprising a single endothermic event. The endothermic event of the Form C polymorph typically has an onset at a temperature in a range from about 120 °C to about 130 °C (e.g. a temperature in a range from about 120 °C to about 130 °C, a temperature in a range from about 123 °C to about 127 °C, or at a temperature of about 125 °C).

[0094] The Form C polymorph may have a DSC profile approximately as set out in Figure 8.

[0095] The Form C polymorph typically has a TGA profile comprising two weight losses: a first weight loss of <0.1 %-w / w between 25 and 100 °C and a second weight loss of <0.1 %- w / w between 110 and 140 °C.

[0096] The Form C polymorph may have a TGA profile approximately as set out in Figure 9.

[0097] The Form C polymorph typically has a water vapour sorption / desorption curve obtained by dynamic vapour sorption (DVS) that exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 0.3 %-w / w of water sorption. This can be assessed as slightly hygroscopic.

[0098] The Form C polymorph may have a DVS isotherm approximately as set out in Figure 10.

[0099] The Form C polymorph typically has a Raman spectrum comprising at least one peak at one of the positions 708 (±2) cm-1, 576 (±2) cm-1, 603 (±2) cm-1, or 1241 (±2) cm-1, more particularly comprising three peaks from the positions 708 (±2) cm-1, 576 (±2) cm-1, 603 (±2) cm-1, and 1241 (±2) cm-1, most particularly, comprising peaks from the positions 708 (±2) cm-1, 576 (±2) cm-1, 603 (±2) cm-1, and 1241 (±2) cm-1.

[0100] The Form C polymorph may have a Raman Spectrum approximately as set out in Table 5 below:

[0101] Table 5 (Table of characteristic Raman peaks for Form C expressed in cm1)P39563

[0102] The Form C polymorph may have a Raman spectrum approximately as set out in Figure 11.

[0103] The Form C polymorph typically has an FTIR spectrum comprising at least one peak at one of the positions 1583 (±2) cm-1, 1305 (±2) cm-1, 1242 (±2) cm-1, or 1067 (±2) cm-1, more particularly comprising three peaks from the positions 1583 (±2) cm-1, 1305 (±2) cm-1, 1242 (±2) cm-1, and 1067 (±2) cm-1, most particularly, comprising peaks from the positions 1583 (±2) cm-1, 1305 (±2) cm-1, 1242 (±2) cm-1, and 1067 (±2) cm-1.

[0104] The Form C polymorph may have an FTIR Spectrum approximately as set out in Table 6 below:

[0105] Table 6 (Table of characteristic FTIR peaks for Form C expressed in cm1)

[0106] The Form C polymorph may have an FTIR spectrum approximately as set out in Figure 12.

[0107] Form A polymorph

[0108] The Form A polymorph is a third particular preferred polymorphic form. It was found to have good solubility.

[0109] The Form A polymorph has an XRPD diffractogram comprising peaks at approximately: 10.4 (±0.2) °29, 12.0 (±0.2) °29 and 23.3 (±0.2) °29. More typically, the Form A polymorph has an XRPD diffractogram comprising peaks at approximately: 10.4 (±0.2) °29, 12.0 (±0.2) °20, 14.3 (±0.2) °20, 19.9 (±0.2) °20, 23.3 (±0.2) °20, and 25.2 (±0.2) °20.

[0110] The Form A polymorph may have an XRPD diffractogram approximately as set out in Table 7 below:

[0111] Table 7 (Table of characteristic XRPD diffractogram peaks for Form C)P39563P39563

[0112] The Form A polymorph may have a simulated X-ray powder diffraction pattern based on the X-ray single crystal diffraction measurement as set out in Figure 13.P39563

[0113] The Form A polymorph typically has a DSC profile comprising a single endothermic event. The endothermic event of the Form C polymorph typically has an onset at a temperature in a range from about 109 °C to about 121 °C (e.g. a temperature in a range from about 116 °C to about 121 °C, a temperature in a range from about 113 °C to about 119 °C, or at a temperature of about 116 °C).

[0114] The Form A polymorph may have a DSC profile approximately as set out in Figure 14.

[0115] The Form A polymorph typically has a TGA profile comprising a mass loss of 0.2 % w / w observed between 25 and 120 °C.

[0116] The Form A polymorph may have a TGA profile approximately as set out in Figure 15.

[0117] The Form A polymorph typically has a water vapour sorption / desorption curve obtained by dynamic vapour sorption (DVS) that exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 0.2 %-w / w of water sorption. This can be assessed as slightly hygroscopic.

[0118] The Form A polymorph may have a DVS isotherm approximately as set out in Figure 16.

[0119] The Form A polymorph may have a Raman Spectrum approximately as set out in Table 8 below:

[0120] Table 8 (Table of characteristic Raman peaks for Form A expressed in cm1)P39563

[0121] The Form A polymorph may have a Raman spectrum approximately as set out in Figure 17.

[0122] The Form A polymorph may have an FTIR Spectrum approximately as set out in Table 9 below:

[0123] Table 9 (Table of characteristic FTIR peaks for Form A expressed in cm1)

[0124] The Form A polymorph may have an FTIR spectrum approximately as set out in Figure 18.

[0125] Form B monohydrate

[0126] The Form B monohydrate may have an XRPD diffractogram approximately as set out in Table 10 below:

[0127] Table 10 (Table of characteristic XRPD diffractogram peaks for Form B)P39563P39563

[0128] The Form B monohydrate may have an XRPD diffractogram approximately as set out in Figure 19.

[0129] The Form B monohydrate typically has a DSC profile comprising a non-baseline separated double peak at 82 °C (peak temperature) and 100 °C (peak temperature).

[0130] The Form B monohydrate may have a DSC profile approximately as set out in Figure 20.

[0131] The Form B monohydrate typically has a TGA profile comprising three weight losses. The first weight loss between 25 and 60 °C represents 0.5 %-w / w. The second weight loss of 2.5 %-w / w between 60 and 90 °C and the third weight loss of 1.9 %-w / w between 90 and 150 °C.

[0132] The Form B monohydrate may have a TGA profile approximately as set out in Figure 21.

[0133] The Form B monohydrate may have a Raman Spectrum approximately as set out in Table 11 below:

[0134] Table 11 (Table of characteristic Raman peaks for Form B expressed in cm1)

[0135] The Form B monohydrate may have a Raman spectrum approximately as set out in Figure 22.P39563

[0136] The Form B monohydrate may have an FTIR Spectrum approximately as set out inTable 12 below:

[0137] Table 12 (Table of characteristic FTIR peaks for Form B expressed in cm1)

[0138] The Form B monohydrate may have an FTIR spectrum approximately as set out in Figure 23.

[0139] The Form B monohydrate typically has a water vapour sorption / desorption curve obtained by dynamic vapour sorption (DVS) that exhibits during the drying step of Form B a conversion mostly into Form A. This is confirmed by an XRPD measurement from the material after the DVS measurement. Form B exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: the reversible water uptake until 90 %-RH with about 0.8 %-w / w represents the conversion of originated Form A (during drying step) into Form B. The conversion of Form A into Form B and back, can be observed during both phases of the sorption. Due to the conversion, no meaningful hygroscopicity can be assessed.

[0140] The Form B monohydrate may have a DVS isotherm approximately as set out in Figure 24.

[0141] Form D polymorphP39563

[0142] The Form D polymorph may have an XRPD diffractogram approximately as set out inTable 13 below:

[0143] Table 13 (Table of characteristic XRPD diffractogram peaks for Form D)P39563P39563

[0144] The Form D polymorph may have an XRPD diffractogram approximately as set out in Figure 25.

[0145] The Form D polymorph typically has a DSC profile comprising a single endothermic event. The endothermic event of the Form D polymorph typically has an onset at a temperature in a range from about 131 °C to about 141 °C (e.g. a temperature in a range from about 131 °CP39563 to about 141 °C, a temperature in a range from about 133 °C to about 139 °C, or at a temperature of about 136 °C).

[0146] The Form D polymorph may have a DSC profile approximately as set out in Figure 26.

[0147] The Form D polymorph typically has a TGA profile comprising a weight loss of 0.2 %-w / w observed between 25 and 140 °C.

[0148] The Form D polymorph may have a TGA profile approximately as set out in Figure 27.

[0149] The Form D polymorph may have a Raman Spectrum approximately as set out in Table 14 below:

[0150] Table 14 (Table of characteristic Raman peaks for Form D expressed in cm1)

[0151] The Form D polymorph may have a Raman spectrum approximately as set out in Figure 28.

[0152] The Form D polymorph may have an FTIR Spectrum approximately as set out inTable 15 below:

[0153] Table 15 (Table of characteristic FTIR peaks for Form D expressed in cm1)P39563

[0154] The Form D polymorph may have an FTIR spectrum approximately as set out in Figure 29.

[0155] The Form C polymorph typically has a water vapour sorption / desorption curve obtained by dynamic vapour sorption (DVS) that exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 0.2 %-w / w of water sorption. This can be assessed as slightly hygroscopic.

[0156] The Form D polymorph may have a DVS isotherm approximately as set out in Figure 30.

[0157] Pattern 11 polymorph

[0158] The Pattern 11 polymorph may have an XRPD diffractogram approximately as set out in Table 16 below:

[0159] Table 16 (Table of characteristic XRPD diffractogram peaks for Pattern 11)P39563P39563

[0160] The Pattern 11 polymorph may have an XRPD diffractogram approximately as set out in Figure 31.P39563

[0161] The Pattern 11 polymorph typically has a DSC profile comprising a single endothermic event. The endothermic event of the Form D polymorph typically has an onset at a temperature in a range from about 107 °C to about 117 °C (e.g. a temperature in a range from about 107 °C to about 117 °C, a temperature in a range from about 109 °C to about 115 °C, or at a temperature of about 112 °C).

[0162] The Pattern 11 polymorph may have a DSC profile approximately as set out in Figure 32.

[0163] The Pattern 11 polymorph typically has a TGA profile comprising two weight losses. First weight loss of 0.2 %-w / w between 25 and 60 °C and a second weight loss of 0.9 %-w / w between 60 and 130 °C.

[0164] The Pattern 11 polymorph may have a TGA profile approximately as set out in Figure 33.

[0165] The Pattern 11 polymorph may have a Raman Spectrum approximately as set out in Table 17 below:

[0166] Table 17 (Table of characteristic Raman peaks for Pattern 11 expressed in cm1)P39563

[0167] The Pattern 11 polymorph may have a Raman spectrum approximately as set out in Figure 34.

[0168] The Pattern 11 polymorph may have an FTIR spectrum approximately as set out in Table 18 below:

[0169] Table 18 (Table of characteristic FTIR peaks for Pattern 11 expressed in cm1)

[0170] The Pattern 11 polymorph may have an FTIR spectrum approximately as set out in Figure 35.

[0171] The Pattern 11 polymorph typically has a water vapour sorption / desorption curve obtained by dynamic vapour sorption (DVS) that exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: during the first cycle, the remaining water / solvent is released with no significant change to Pattern 11. After drying no significant differences between the two cycles can be observed. Both phases of the sorption are continuous until 90 %-RH with about 1.4 %-w / w of water sorption. This can be assessed as slightly hygroscopic.

[0172] The Pattern 11 polymorph may have a DVS isotherm approximately as set out in Figure 36.P39563

[0173] The third aspect of the present invention provides a pharmaceutical composition comprising a crystalline form of the first aspect of the invention or a polymorphic form of the second aspect of the invention, and a pharmaceutically acceptable excipient.

[0174] Pharmaceutically acceptable excipients including adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention, are those conventionally employed in the field of pharmaceutical formulation.

[0175] A fourth aspect of the invention provides a crystalline form of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, for use in medicine, and / or for use in the treatment or prevention of a disease, disorder or condition.

[0176] A fifth aspect of the invention provides the use of a crystalline form of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.

[0177] A sixth aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a crystalline form of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, to thereby treat or prevent the disease, disorder or condition.

[0178] Typically, where the crystalline form of the first aspect of the invention, the polymorphic form of the second aspect of the invention, or the pharmaceutical composition of the third aspect of the invention is used in the treatment or prevention of a disease, disorder and condition, the crystalline form of the first aspect of the invention or the polymorphic form of the second aspect of the invention acts as an NLRP3 inhibitor.

[0179] In one embodiment, the disease, disorder or condition to be treated or prevented is selected from:

[0180] (i) inflammation;

[0181] (ii) an auto-immune disease;

[0182] (iii) cancer;

[0183] (iv) an infection;

[0184] (v) a central nervous system disease;

[0185] (vi) a metabolic disease;

[0186] (vii) a cardiovascular disease;

[0187] (viii) a respiratory disease;

[0188] (ix) a liver disease;

[0189] (x) a renal disease;

[0190] (xi) an ocular disease;

[0191] (xii) a skin disease;

[0192] (xiii) a lymphatic condition;

[0193] (xiv) a psychological disorder;

[0194] (xv) pain; and

[0195] (xvi) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

[0196] Typically, the treatment or prevention of the disease, disorder or condition comprises the administration of the crystalline form of the first aspect of the invention, the polymorphic form of the second aspect of the invention, or the pharmaceutical composition of the third aspect of the invention, to a subject.

[0197] A seventh aspect of the invention provides a method of inhibiting NLRP3, the method comprising the use of a crystalline form of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the third aspect of the invention, to inhibit NLRP3. In one embodiment of the seventh aspect of the present invention, the method is performed ex vivo or in vitro.

[0198] Unless stated otherwise, in any of the fourth to seventh aspects of the invention, the subject may be a human or other animal. Typically, the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse etc. Most typically, the subject is a human.

[0199] Any of the medicaments employed in the present invention can be administered by oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway (aerosol), rectal, vaginal or topical (including transdermal, buccal, mucosal and sublingual) administration.

[0200] Typically, the mode of administration selected is that most appropriate to the disorder, disease or condition to be treated or prevented.

[0201] For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.Experimental part

[0202] Examples

[0203] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

[0204] RH means relative humidity.

[0205] X-Ray Powder Diffraction (XRPD), Thermogravimetric Analysis (TGA), and Differential Scanning Calorimetry (DSC) techniques referred to in the examples were carried out under the following conditions:

[0206] High Resolution X-Ray Powder Diffraction (XRPD)

[0207] High resolution X-ray powder diffraction patterns were recorded at ambient conditions in transmission geometry. X-ray diffraction patterns were recorded on a STOE STADI P diffractometer with CuKal radiation (1.5406 A) at 20°C and a Mythen position sensitive detector. The samples (approximately 10 to 50 mg) were prepared between thin polymer films and were usually analysed without further processing (e.g. grinding or sieving) of the substance.

[0208] X-Ray Single Crystal Diffraction

[0209] X-ray single crystal diffraction is employed to measure and elucidation of the crystals structure of crystalline forms. A single crystal is mounted in a loop and cooled to approximately 100 K in a nitrogen stream or measured at ambient temperature. Data are collected on a XtaLAB Synergy-i diffractometer (Rigaku) with Cu-radiation (1.54184 A). Data are processed with the Oxford Diffraction CRYSALIS -software. The crystal structure is solved and refined with the software Olex2 (OlexSys Ltd, Durham, England).

[0210] Thermogravimetric Analysis (TGA)P39563

[0211] Thermogravimetric analyses were performed on a Mettler -Toledo thermogravimetric analyzer TGA / DSC1, TGA / DSC3+. For the thermogravimetric analyses, approximately 5 to 15 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the perforation lids were automatically pierced resulting in approx. 0.5 mm pin holes. The samples were then heated under a flow of nitrogen of about 50 mL / min applying a heating rate of 5 K / min up to a maximum temperature of typically 350 °C.

[0212] Differential Scanning Calorimetry (DSC)

[0213] The DSC-thermograms were recorded using a Mettler-Toledo differential scanning calorimeter DSC 1 / 2 or TA Instruments Discovery series. System suitability tests and calibrations are carried out according to the internal standard operating procedure. For the measurements, approximately 2 to 6 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the perforation lids were pierced resulting in approx. 0.5 mm pin holes. In order to measure the sample under pressure, closed lids can also be used. The samples were then heated under a flow of nitrogen of about 100 mL / min applying a heating rate of typically 1 -20 K / min, usually 10 K / min to a maximum temperature of typically 180-350 °C (depending on decomposition temperature).

[0214] Moisture Sorption / Desorption

[0215] Moisture sorption / desorption data was collected on a DVS Advantage, a DVS Adventure, or a DVS Intrinsic (SMS Surface Measurements Systems) moisture balance system. The sorption / desorption isotherms were measured stepwise in a range from 0 %-RH to 90 %- RH at typically 25 °C. A weight change of typically <0.001 % / min was chosen as criterion to switch to the next level of relative humidity (with a maximum equilibration time of typically 24 hours, if the weight change criterion was not met). The data were corrected for the initial moisture content of the samples by taking the weight after drying of the samples at 0 %-RH as zero point.

[0216] The hygroscopicity of a given substance was characterized (by close analogy with the European Pharmacopoeia) by the increase in mass when the relative humidity was raised from 0 %-RH to 90 %-RH:

[0217] non-hygroscopic: weight increase Dm < 0.2%

[0218] slightly hygroscopic: weight increase 0.2% < Dm < 2.0%P39563

[0219] hygroscopic: weight increase 2.0% < Dm < 15.0%

[0220] very hygroscopic: weight increase Dm > 15.0%

[0221] deliquescent: sufficient liquid is adsorbed to form a liquid

[0222] European Pharmacopoeia 8thEdition (2014), Chapter 5.11.

[0223] IR Spectroscopy

[0224] The ATR FTIR spectra were recorded without any sample preparation using aThermoNicolet iS5 FTIR spectrometer with ATR accessory. The spectral range is between 4000 cm'1and 650 cm'1, resolution 4 cm'1and 32 co-added scans were collected. Happ-Genzel apodization was applied. Using ATR FTIR will cause the relative intensities of infrared bands to differ from those seen in a transmission FTIR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FTIR, the bands at lower wavenumber are more intense than those at higher wavenumber.

[0225] Peakpicking was performed using Thermo Scientific Omnic 9.6 software using the automated ‘Find Peaks’ function. The ‘threshold’ and ‘sensitivity’ were manually adjusted to get a representative number of peaks.

[0226] Raman Spectroscopy

[0227] The FT-Raman spectrum was collected in the spectral range of 4000-50 cm'1with a Bruker MultiRam FT-Raman spectrometer, equipped with a NdYAG 1064 nm laser and a liquid nitrogen cooled Germanium detector. The laser power was set to 300mW, 4 cm'1resolution was used and 512 scans were co-added. The apodization used was Blackman-Harris 4-term.

[0228] Peakpicking was performed using Thermo Scientific Omnic 9.6 software using the automated ‘Find Peaks’ function. The ‘threshold’ and ‘sensitivity’ were manually adjusted to get a representative number of peaks.

[0229] Synthesis and Crystallization Protocol

[0230] 5-[3 -[[(3R)-l-Ethyl-3 -piperidyl] amino] -5 -methyl- 1,2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol may be synthesized as set out in WO2022253936.

[0231] Example 1 : 5-[3-[[(3R)-l-Ethvl-3-piperidvl1amino1-5-methyl-1.2.4-triazin-6-vl1-2.3- dihydrobenzofuran-4-ol Form E

[0232] 105.6 mg of a Mixture of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4- triazin-6-yl]-2,3- dihydrobenzofuran-4-ol Form C and Form D was suspended in 0.75 mL of acetone. After 1 day stirring at 20 °C the suspension was seeded with material from samplesP39563 that contain beside known also unknown crystal forms of the compound. After one additional day stirring time the seeding was repeated. After 10 additional days a sub -sample of the suspension was analyzed. Surprisingly, a new crystal form (Form E) had formed that did not match any other known crystal forms.

[0233] Form E can be reproduced by cooling crystallization, but with seeding with Form E.

[0234] Alternatively, 200 mg of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4- triazin-6-yl]-2,3- dihydrobenzofuran-4-ol Form C was suspended in 1.5 mL of 2-propanol. Clear solution at 65 °C, set to 40 °C and seeded with Form E. Cooled to 15 °C in 8 h. The suspension was filter-centrifuged.

[0235] The XRPD, DSC, TGA, Raman, and IR spectra are shown in Figures 1 -5, respectively. Dynamic Vapor Sorption showed Form E to be non-hygroscopic.

[0236] Example 2: 5-[3-[[(3R)-l-Ethvl-3-piperidvl1amino1-5-methyl-L2.4-triazin-6-vl1-2.3- dihydrobenzofuran-4-ol Form C

[0237] 198.1 mg of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol was dissolved in 3.4 mL of toluene. Then, 2.8 mL of n-heptane was added. No precipitation was observed. After stirring for 4 days at 22 °C / 100 rpm, only a very small amount of precipitation was observed. The thin suspension was further stirred at 22 °C. After 2 days of stirring, the suspension was filter-centrifuged. The solid was dried for approximately 1 day in a vacuum tray dryer at 50 °C / 5 mbar.

[0238] XRPD, DSC, TG, Raman and IR spectra are shown in Figures 7-9, 11 and 12, respectively. Dyanmic Vapor Sorption showed Form C to be slightly hygroscopic.

[0239] Example 3 : 5 -[3 -[[(3R)- 1 -Ethyl-3 -piperidyllaminol-5-methyl- 1.2.4-triazin-6-yl1 -2.3 - dihydrobenzofuran -4-ol Form A

[0240] Roughly 1 mg of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]- 2,3- dihydrobenzofuran -4-ol was filled into a small vial. The solid was suspended in 200 pl of tetrahydrofuran. The vial was closed and vortexed for 10 seconds. A solution was observed. The vial was opened again and placed into a bigger vial filled with 1 mL of n-heptane. The bigger vial was closed. Crystallization by vapor diffusion. Yellow block crystals observed.P39563

[0241] A simulated XRPD spectrum, based on the X-ray single crystal diffraction measurement, DSC, TG, Raman and IR spectra similar to those in Figures 13-15, 17 and 18, respectively, were observed. Dynamic Vapor Sorption showed Form A to be slightly hygroscopic.

[0242] Example 4: 5-[3-[[ 3R)-l-Ethvl-3-piperidvl]amino]-5-methvl-1.2.4-triazin-6-yl]-2.3- dihydrobenzofuran-4-ol Form B

[0243] 209.8 mg of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol Form C was suspended in a mixture of methyl ethyl ketone and water (aw: 0.5) (1.5 mL). The suspension was stirred for 5 days at 22 °C. 1 mL of the suspension was filter-centrifuged. Sample was analyzed as Form B.

[0244] The XRPD, DSC, TG, Raman and IR spectra for Form B are shown in Figures 19-23 respectively.

[0245] Example 5 : 5 -[3 -[[(3R)- 1 -Ethyl-3 -piperidyllaminol-5-methyl- 1.2.4-triazin-6-yl1 -2.3 - dihydrobenzofuran -4-ol Form D

[0246] 5-[3 -[[(3R)-1 -Ethyl-3 -piperidyl] amino] -5 -methyl- 1,2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol was suspended in 300 pl of ethanol / water (95 / 5 v / v). The suspension was stirred at 65 °C / 100 rpm. The suspension was seeded with spatula tips each of 5 -[3-[[(3R)- l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4-triazin-6-yl]-2,3- dihydrobenzofuran-4-ol Form C, Form A and Pattern 11. After 5 days of stirring a thick suspension was observed. The solvent of the remaining suspension was completely evaporated after 2 additional days at 65 °C. The solid was dried overnight at RT / 400 mbar under a light flow of air.

[0247] The XRPD, DSC, TG, Raman and IR spectra for Form D are shown in Figures 25 -29 respectively. Dynamic Vapor Sorption showed Form D to be slightly hygroscopic.

[0248] Example 6: 5 -[3 -[[(3R)-1 -Ethyl-3 -piperi dyl]amino]-5-methyl- 1,2, 4-triazin-6-yl] -2,3- dihydrobenzofuran-4-ol Pattern 11P39563

[0249] 5-[3 -[[(3R)-l-Ethyl-3 -piperidyl] amino] -5 -methyl- 1,2, 4-triazin-6-yl]-2, 3- dihydrobenzofuran-4-ol was dissolved in a mixture of 3.8 mL of -butanol and 2.8 mL of n- heptane. The solvent was evaporated at 65 °C for 4 days.

[0250] The XRPD, DSC, TG, Raman and IR spectra for Pattern 11 are shown in Figures 31 -35 respectively. Dynamic Vapor Sorption showed Pattern 11 to be slightly hygroscopic.

[0251] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

P39563CLAIMSWhat is claimed is:

1. A crystalline polymorphic form of 5-[3-[[(3R)-l-Ethyl-3-piperidyl]amino]-5-methyl-l,2,4- triazin-6-yl]-2,3- dihydrobenzofuran-4-ol, or a hydrate or solvate thereof.

2. The crystalline polymorphic form of claim 1, wherein the crystalline polymorphic form is Form E, characterized by having an XRPD diffractogram (CuKal radiation) comprising peaks at 11.5 (±0.2) °20, 21.4 (±0.2) °20, and 17.8 (±0.2) °20.

3. The crystalline polymorphic form of claim 2, having an XRPD diffractogram (CuKal radiation) comprising peaks at: 11.5 (±0.2) °29, 21.4 (±0.2) °29, 17.8 (±0.2) °29, 12.2 (±0.2) °20, 10.9 (±0.2) °20, and 21.1 (±0.2) °20.

4. The crystalline polymorphic form of any one of claims 2 to 3, having a DSC profile comprising a single endothermic event having an onset at a temperature in a range from about 115 °C to about 125 °C at a heating rate of 10 K / min.

5. The crystalline polymorphic form of any one of claims 2 to 4, characterized by an FTIR spectrum comprising at least three peaks selected from the positions 695 (±2) cm-1, 2925 (±2) cm-1, 976 (±2) cm-1, and 810 (±2) cm-1.

6. The crystalline polymorphic form of any one of claims 2 to 5, characterized by an FTIR spectrum comprising peaks at the positions 695 (±2) cm-1, 2925 (±2) cm-1, 976 (±2) cm-1, and 810 (±2) cm-1.

7. The crystalline polymorphic form of any one of claims 2 to 6, characterized by a Raman spectrum comprising the peaks at positions 696 (±2) cm-1, 1099 (±2) cm-1, and 435 (±2) cm-1.

8. The crystalline polymorphic form of claim 1, wherein the crystalline polymorphic form is Form C, characterized by having an XRPD diffractogram (CuKal radiation) comprising peaks at 11.8 (±0.2) °20, 20.1 (±0.2) °20, and 23.4 (±0.2) °20.

9. The crystalline polymorphic form of claim 8, having an XRPD diffractogram (CuKal radiation) comprising peaks at: 11.8 (±0.2) °29, 20.1 (±0.2) °29, 23.4 (±0.2) °29, 16.3 (±0.2) °20, 17.4 (±0.2) °20, and 9.9 (±0.2) °20.P3956310. The crystalline polymorphic form of any one of claims 8-9, having a DSC profile comprising a single endothermic event having an onset at a temperature in a range from about 120 °C to about 130 °C at a heating rate of 10 K / min.

11. The crystalline polymorphic form of any one of claims 8-10, characterized by an FTIR spectrum comprising at least three peaks selected from the positions 1583 (±2) cm-1, 1305 (±2) cm-1, 1242 (±2) cm-1, and 1067 (±2) cm-1.

12. The crystalline polymorphic form of any one of claims 8-11, characterized by a Raman spectrum comprising the peaks at positions 708 (±2) cm-1, 576 (±2) cm-1, 603 (±2) cm-1, and 1241 (±2) cm-1.

13. A pharmaceutical composition comprising a crystalline polymorphic form of any one of claims 1 to 12, and a pharmaceutically acceptable excipient.

14. The crystalline polymorphic form of any one of claims 1 to 12, for use in medicine.

15. The crystalline polymorphic form of any one of claims 1 to 12, for use in the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.

16. The crystalline polymorphic form of any one of claims 1 to 12, for use in the treatment or prophylaxis of a disease, disorder or condition selected from Parkinson’s Disease or Alzheimer’s Disease.47

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