Solid forms of a gamma-secretase modulator

Abstract

The present invention provides novel crystalline solid forms of (R)-7-(3,5-difluorophenoxy)-N-((1R,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-amine. Moreover, the invention relates to pharmaceutical compositions comprising said novel solid forms, to processes for making them and to their use as pharmaceutically active compounds.

Description

[0001] Case P39657

[0002] SOLID FORMS OF A GAMMA- SECRET ASE MODULATOR

[0003] Field of the invention

[0004] The present invention relates to novel solid forms of (R)-7-(3,5-difluorophenoxy)-N-((lR,5S,8s)- 3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-amine. Moreover, the invention relates to pharmaceutical compositions comprising said novel solid forms, to processes for making them and to their use as pharmaceutically active compounds.

[0005] Background

[0006] W02020 / 120521A1, the entire contents of which are incorporated herein by reference, discloses (R)-7-(3 , 5 -difluorophenoxy)-N-(( 1 R, 5 S, 8 s)-3 -(6-methoxypyridazin-4-yl)-3 - azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine (hereinafter referred to as “compound (I)”) which is a novel highly potent gamma-secretase modulator (GSM) for the treatment of Alzheimer’s disease (AD).

[0007] There is a need for new compounds and solid forms thereof, formulations, treatments and therapies to treat diseases and disorders associated with the deposition of P-amyloid in the brain. Solid forms are different polymorphic or amorphous solid forms of the same compound.

[0008] Different polymorphic solid forms typically have a different crystal structure due to a different packing of the molecules in the lattice. Solid forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If a solid form is not held constantly during clinical studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a specific solid form of a compound in high purity when the compound is used in clinical studies or commercial products, since any impurities may produce undesired effects. Certain solid forms may also display enhanced stability or may be more readily manufactured in high purity in large quantities, and are more suitable for inclusion in pharmaceutical formulations.

[0009] For pharmaceutical development and commercialization, there is a need to identify solid forms of compound (I) having desirable properties such as high crystallinity, high purity, and favorable physical stability, chemical stability, aqueous solubility and mechanical properties.

[0010] The novel solid forms of compound (I) according to the invention show significantly improved stability compared with the corresponding amorphous form of compound (I). Developing novel crystalline forms of compound (I) with good processability and acceptable aqueous solubility is crucial for its pharmaceutical development, but remains challenging. Some novel solid forms fundamentally enhance the potential of compound (I) in drug development and improve its suitability for new dosage forms.

[0011] In view of the above, there is an unmet need for new solid forms of compound (I), which ultimately allow it to be employed as a drug for the treatment and / or prevention of diseases associated with the deposition of P-amyloid in the brain, such as Alzheimer’s disease. summary of the invention

[0012] The present invention relates generally to novel crystalline forms of (R)-7-(3,5- difhrorophenoxy)-N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[ 1 ,2-b] [ 1 ,2,4]triazol-2-amine (compound (I)) as described herein, as well as processes for making the same, methods of using the same and pharmaceutical compositions comprising the same.

[0013] It has now surprisingly been found that crystalline polymorphic Form C and Form L of compound (I) are the most stable solid forms. Forms C and L also have favorable physicochemical properties such as for instance bioavailability and pharmacokinetics may hence provide for a single dose administration per day. shows an X-ray powder diffraction pattern of the amorphous form of (R)-7-(3,5- difhrorophenoxy)-N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-

[0014] 6,7-dihydro-5H-pyrrolo[ 1 ,2-b] [ 1 ,2,4]triazol-2-amine. shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0015] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form A.

[0016] Figure 3 shows a DSC thermogram of (R)-7-(3,5 difluorophenoxy)-N -(( 1 R, 5 S, 8 s)-3 -(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-amine crystalline form, also known as Form A. shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0017] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form B, in ethyl acetate. Figure 5 shows an X-ray powder diffraction pattern of (R)-7 (3,5 difluorophenoxy)-N-

[0018] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form C.

[0019] Fi ure 6 shows a DSC thermogram of (R) (3,5 difluorophenoxy)-N -(( 1 R, 5 S, 8 s)-3 -(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-amine crystalline form, also known as Form C. shows a DVS isotherm plot of (R)-7-(3,5-difhrorophenoxy)-N-((lR,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-amine crystalline form, also known as Form C.

[0020] Figure 8 shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0021] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form D.

[0022] Figure 9 shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0023] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form E. shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0024] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form F. shows an X-ray powder diffraction pattern of (R)-7-(3,5 difluorophenoxy)-N-

[0025] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form G.

[0026] Figure 12 shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0027] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form H. shows an X-ray powder diffraction pattern of (R)-7-(3,5 difluorophenoxy)-N-

[0028] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form I.

[0029] Figure 14 shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0030] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form J. shows an X-ray powder diffraction pattern of (R)-7 (3,5 difluorophenoxy)-N-

[0031] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form K. shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0032] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as Form L.

[0033] Figure 17 shows a DSC thermogram of (R) (3,5 difluorophenoxy)-N-(( 1 R, 5 S, 8 s)-3 (6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-amine crystalline form, also known as Form L.

[0034] Figure 18 shows a DVS isotherm plot of (R)- ■7-(3 5 difluorophenoxy)-N-(( 1 R, 5 S, 8 s)-3 -(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-amine crystalline form, also known as Form L. shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0035] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as “Pattern 2”. Figure 20 shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0036] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as “Pattern 6”.

[0037] Figure 21 shows an X-ray powder diffraction pattern of (R)-7-(3,5 difluorophenoxy)-N-

[0038] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as “Pattern 9”. shows an X-ray powder diffraction pattern of (R) (3,5 difluorophenoxy)-N-

[0039] ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine crystalline form, also known as “Pattern 12”.

[0040] Detailed description of the invention

[0041] Definitions

[0042] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0043] The term “amorphous” refers to solid materials that lack the long-range order that is characteristic of a crystalline solid.

[0044] The term "characteristic peak" refers to the presence of a powder X-ray diffraction peak that definitively identifies (R)-7-(3,5-difluorophenoxy)-N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)- 3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine as the referenced crystalline form (selected from Forms A to L and Patterns 2, 6, 9 and 12).

[0045] The term “optional” or “optionally” denotes that a subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0046] 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.

[0047] The term "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions forming the crystal. In general, reference throughout this specification will be to a polymorph of (R)-7-(3,5- difhiorophenoxy)-N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)- 6,7-dihydro-5H-pyrrolo[ 1 ,2-b] [ 1 ,2,4]triazol-2-amine (compound (I)).

[0048] 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).

[0049] The term “hydrate” refers herein to a solvate comprising a compound of formula (I) and a stoichiometric or non-stoichiometric amount of water.

[0050] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. The effective amount will be selected based on the particular patient and the disease level. It is understood that “an effect amount” or “a therapeutically effective amount” varies from subject to subject, due to variation in metabolism of drug, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. In one embodiment, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study. In some embodiments, the term “effective amount” or “therapeutically effective amount,” is used in reference to the crystalline and amorphous forms described herein being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated.

[0051] The term “XRPD” refers the analytical method of X-Ray Powder Diffraction. The repeatability of the angular values is in the range of 2Theta ±0.2°. The term “approximately” given in combination with an angular value denotes the repeatability which is in the range of 2Theta ±0.2°. 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, preferred orientations cause a change in the intensity distribution. Preferred orientation effects are particularly pronounced with crystalline APIs of relatively large particle size.

[0052] The following abbreviations are used in the present text:

[0053] DSC Differential scanning calorimetry

[0054] DVS Dynamic vapor sorption

[0055] FaSSIF Fasted state simulated intestinal fluid

[0056] FeSSIF Fed state simulated intestinal fluid

[0057] SGF Simulated gastric fluid

[0058] NMR Nuclear magnetic resonance

[0059] Pos. Position

[0060] Rel. Int. Relative Intensity

[0061] RH Relative Humidity

[0062] TGA Thermal gravimetric analysis

[0063] XRPD X-ray powder diffraction Crystalline polymorphic forms

[0064] In one aspect, the present invention provides a crystalline solid form of compound (I), wherein the crystalline solid forms are Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Pattern 2, Pattern 6, Pattern 9, Pattern 12, or a combination thereof.

[0065] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 20.1°±0.2° and 21.3°±0.2°.

[0066] In one embodiment, Form A exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 10.3°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 21.3°±0.2° and 23.8°±0.2°.

[0067] In one embodiment, Form A exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 9.9°±0.2°, 10.0°±0.2°, 10.3°±0.2°, 10.6°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.4°±0.2°, 12.8°±0.2°, 13.4°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.3°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 23.4°±0.2°, 23.8°±0.2°, 24.8°±0.2°, 25.8°±0.2° and 27.0°±0.2°.

[0068] In one embodiment, Form A exhibits an XRPD pattern shown in Figure 2. In one embodiment, Form A exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with onset temperature at 105 °C ± 3 °C.

[0069] In one embodiment, Form A exhibits a DSC thermogram as shown in Figure 3.

[0070] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.8°±0.2°, 10.3°±0.2°, 11.6°±0.2°, and 18.1°±0.2°.

[0071] In one embodiment, Form B exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.8°±0.2°, 10.3°±0.2°, 11.6°±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.8°±0.2°, 18.1°±0.2°, 18.4°±0.2° and 20.2°±0.2.

[0072] In one embodiment, Form B exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.8°±0.2°, 10.3°±0.2°, 11.6°±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.8°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.2°±0.2, 20.6°±0.2, 21.0°±0.2 and 21.3°±0.2.

[0073] In one embodiment, Form B exhibits an XRPD pattern shown in Figure 4.

[0074] In one embodiment, Form B is an isopropyl acetate solvate or an ethyl acetate solvate.

[0075] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°,

[0076] 10.9°±0.2°, 12.7°±0.2°, 16.8°±0.2° and 20.8°±0.2°.

[0077] In one embodiment, Form C exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 12.7°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 19.1°±0.2°, and 20.8°±0.2°.

[0078] In one embodiment, Form C exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 12.7°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 20.8°±0.2°, 22.4°±0.2° and 23.7°±0.2°.

[0079] In one embodiment, Form C exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 11.2°±0.2°, 12.0°±0.2°, 12.7°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 19.1°±0.2°,

[0080] 19.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 22.8°±0.2°, 23.4°±0.2°,

[0081] 23.7°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 27.2°±0.2°, 27.5°±0.2°, 28.2°±0.2°, 28.5°±0.2°, 28.9°±0.2°,

[0082] 29.2°±0.2°, 31.6°±0.2° and 32.4°±0.2°.

[0083] In one embodiment, Form C exhibits an XRPD pattern shown in Figure 5.

[0084] In one embodiment, Form C exhibits a DSC thermogram comprising endothermic peak with onset temperature at 130 °C ± 3 °C.

[0085] In one embodiment, Form C exhibits a DSC thermogram as shown in Figure 6. In one embodiment, Form C exhibits a DVS Isotherm Plot as shown in Figure 7.

[0086] In one embodiment, Form C is a non-hydrate form or a hydrate form.

[0087] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.8°±0.2°, 10.9°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 19.0°±0.2°and 20.4°±0.2°.

[0088] In one embodiment, Form D exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 8.8°±0.2°, 10.9°±0.2°, 14.1°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 22.5°±0.2°, 23.4°±0.2°, 24.2°±0.2° and 25.1°±0.2°.

[0089] In one embodiment, Form D exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 7.9°±0.2°, 8.8°±0.2°, 10.1°±0.2°, 10.9°±0.2°, 11.6°±0.2°, 14.1°±0.2°, 14.6°±0.2°, 14.8°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 16.4°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 20.2°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.1°±0.2°, 22.5°±0.2°, 23.1°±0.2°, 23.4°±0.2°, 23.9°±0.2°, 24.2°±0.2°, 25.1°±0.2°, 26.4°±0.2°, 26.7°±0.2°, 27.3°±0.2°, 27.7°±0.2°, 28.4°±0.2°, 29.0°±0.2°, 29.6°±0.2°, 31.3°±0.2°, 31.5°±0.2° and 31.8°±0.2°.

[0090] In one embodiment, Form D exhibits an XRPD pattern shown in Figure 8.

[0091] In one embodiment, Form D is an ethanol solvate of compound (I).

[0092] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°,

[0093] 9.8°±0.2°, 11.5°±0.2°, 17.7°±0.2° and 19.5°±0.2°.

[0094] In one embodiment, Form E exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 9.8°±0.2°, 11.5°±0.2°, 12.1°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.7°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 22.7°±0.2°, 23.2°±0.2° and 24.4°±0.2°.

[0095] In one embodiment, Form E exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 9.8°±0.2°, 10.5°±0.2°, 11.5°±0.2°, 12.1°±0.2°, 12.9°±0.2°, 16.0°±0.2°, 16.7°±0.2°, 17.0°±0.2°, 17.7°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 21.3°±0.2°, 21.6°±0.2°, 22.7°±0.2°, 23.2°±0.2°, 24.4°±0.2°, 24.7°±0.2°, 25.5°±0.2°, 26.5°±0.2° and 28.9°±0.2°.

[0096] In one embodiment, Form E exhibits an XRPD pattern as shown in Figure 9.

[0097] In one embodiment, Form E is an acetone solvate, a tetrahydrofuran solvate or an isopropanol solvate of compound (I).

[0098] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.6°±0.2°, 10.7°±0.2°, 13.8°±0.2°, 17.1°±0.2°, 18.8°±0.2° and 20.3°±0.2.

[0099] In one embodiment, Form F exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.6°±0.2°, 10.7°±0.2°, 11.9°±0.2°, 13.8°±0.2°, 15.2°±0.2°, 17.1°±0.2°, 18.8°±0.2°, 19.8°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 22.5°±0.2°, 23.4°±0.2° and 24.1°±0.2°.

[0100] In one embodiment, Form F exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.2°±0.2°, 7.8°±0.2°, 8.6°±0.2°, 9.4°±0.2°, 10.0°±0.2°, 10.7°±0.2°, 11.6°±0.2°, 11.9°±0.2°, 13.8°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 16.2°±0.2°, 16.7°±0.2°, 17.1°±0.2°, 17.3°±0.2°, 18.3°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 19.8°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 22.5°±0.2°, 23.4°±0.2°, 23.8°±0.2°, 24.1°±0.2°, 24.9°±0.2°, 26.9°±0.2°, and 27.9°±0.2°.

[0101] In one embodiment, Form F exhibits an XRPD pattern as shown in Figure 9.

[0102] In one embodiment, Form F is an n-propanol solvate of compound (I).

[0103] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 10.8°±0.2°, 13.1°±0.2°, 17.6°±0.2° and 20.0°±0.2°. In one embodiment, Form G exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 10.8°±0.2°, 13.1°±0.2°, 15.7°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 20.0°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.2°±0.2°, 24.0°±0.2° and 28.5°±0.2°.

[0104] In one embodiment, Form G exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.9°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 12.0°±0.2°, 12.6°±0.2°, 13.1°±0.2°, 14.9°±0.2°, 15.3°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 17.8°±0.2°, 19.0°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, 20.7°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.2°±0.2°, 24.0°±0.2°, 26.9°±0.2° and 28.5°±0.2°.

[0105] In one embodiment, Form G exhibits an XRPD pattern as shown in Figure 11.

[0106] In one embodiment, Form G is a toluene solvate of compound (I).

[0107] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.2°±0.2°, 10.8°±0.2°, 12.6°±0.2°, 17.7°±0.2° and 18.8°±0.2°.

[0108] In one embodiment, Form H exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.2°±0.2°, 10.8°±0.2°, 12.6°±0.2°, 15.0°±0.2°, 17.1°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 20.9°±0.2°, 21.7°±0.2°, 23.3°±0.2° and 27.6°±0.2°. In one embodiment, Form H exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.2°±0.2°, 9.9°±0.2°, 10.4°±0.2°, 10.8°±0.2°, 11.8°±0.2°, 12.6°±0.2°, 15.0°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.5°±0.2°, 17.7°±0.2°, 18.1°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 20.9°±0.2°, 21.2°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 25.6°±0.2°, 25.9°±0.2°, 26.7°±0.2°, 27.0°±0.2° and 27.6°±0.2°.

[0109] In one embodiment, Form H exhibits an XRPD pattern as shown in Figure 12.

[0110] In one embodiment, Form H is an isopropyl acetate solvate or a methyl isobutyl ketone solvate of compound (I).

[0111] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form I that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, l l.l°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 17.4°±0.2° and 18.7°±0.2.

[0112] In one embodiment, Form I exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, l l.l°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 17.0°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 18.9°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.1°±0.2°, 22.1°±0.2° and 22.5°±0.2°.

[0113] In one embodiment, Form I exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.2°±0.2°, 9.0°±0.2°, 10.1°±0.2°, l l.l°±0.2°, 11.6°±0.2°, 12.0°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 15.7°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.1°±0.2°, 22.1°±0.2°, 22.5°±0.2°.

[0114] In one embodiment, Form I exhibits an XRPD pattern as shown in Figure 13.

[0115] In one embodiment, Form l is a methanol solvate of compound (I).

[0116] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form J that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.4°±0.2°, 10.6°±0.2°, 13.8°±0.2°, 16.7°±0.2°, and 17.5°±0.2°.

[0117] In one embodiment, Form J exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.4°±0.2°, 10.6°±0.2°, 11.5°±0.2°, 12.0°±0.2°, 13.8°±0.2°, 15.2°±0.2°, 16.3°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.8°±0.2°, and 20.4°±0.2°.

[0118] In one embodiment, Form J exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.6°±0.2°, 8.4°±0.2°, 10.6°±0.2°, 11.5°±0.2°, 12.0°±0.2°, 13.8°±0.2°, 14.5°±0.2°, 14.7°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.3°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 20.9°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 23.1°±0.2°, 23.4°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 29.1°±0.2°, 29.7°±0.2°, and 30.6°±0.2°.

[0119] In one embodiment, Form J exhibits an XRPD pattern as shown in Figure 14. In one embodiment, Form J is an isopropanol solvate of compound (I).

[0120] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form K that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 10.1°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.2°±0.2° and 19.1°±0.2°.

[0121] In one embodiment, Form K exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.7°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 13.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 20.7°±0.2°, 22.4°±0.2°, and 23.2°±0.2°.

[0122] In one embodiment, Form K exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.7°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 11.6°±0.2°, 13.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 20.3°±0.2°, 20.7°±0.2°, 21.2°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 23.2°±0.2°, 23.9°±0.2°, 24.8°±0.2°, 25.3°±0.2° and 25.6°±0.2°.

[0123] In one embodiment, Form K exhibits an XRPD pattern as shown in Figure 15.

[0124] In one embodiment, Form K is an isopropanol solvate of compound (I).

[0125] In a further aspect, the present invention provides a solid form of compound (I), wherein the solid form is crystalline polymorphic Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.7°±0.2°,

[0126] 14.4°±0.2°, 17.2°±0.2°, 21.7°±0.2° and 25.6°±0.2°.

[0127] In one embodiment, Form L exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.7°±0.2°, 13.3°±0.2°, 14.4°±0.2°, 16.4°±0.2°, 17.2°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 21.7°±0.2°, 25.6°±0.2° and 28.8°±0.2°.

[0128] In one embodiment, Form L exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 11.7°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 14.4°±0.2°, 16.4°±0.2°, 17.2°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 21.7°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 26.8°±0.2° and 28.8°±0.2°.

[0129] In one embodiment, Form L exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 7.0°±0.2°, 9.0°±0.2°, 11.7°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 14.4°±0.2°, 16.4°±0.2°, 16.9°±0.2°, 17.2°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 20.6°±0.2°, 21.1°±0.2°, 21.7°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 22.8°±0.2°, 23.6°±0.2°, 24.7°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 26.8°±0.2°, 27.6°±0.2°, 27.9°±0.2°, 28.8°±0.2°, 30.9°±0.2°, 31.2°±0.2°, 33.2°±0.2°, 36.5°±0.2°, 37.5°±0.2° and 38.0°±0.2°.

[0130] In one embodiment, Form L exhibits an XRPD pattern shown in Figure 16.

[0131] In one embodiment, Form L exhibits a DSC thermogram comprising endothermic peak with onset temperature at 170 °C ± 3 °C.

[0132] In one embodiment, Form L exhibits a DSC thermogram as shown in Figure 17. In one embodiment, Form L exhibits a DVS Isotherm Plot as shown in Figure 18.

[0133] In one embodiment, the solid form of compound (I) exhibits an XRPD pattern as described herein, wherein Cu-Ka radiation was used as radiation source for the measurement.

[0134] With regard to general solid formulation development, the melting point of a synthetic substance should not be below 80 °C (Stefan Balbach, 2004, Pharmaceutical evaluation of early development candidates “the 100 mg-approach”, International Journal of Pharmaceutics 275 (2004) 1-12). Form C of compound (I) with the onset melting point at approximately 130 °C, Form L of compound (I) with the onset melting point at approximately 170 °C and Form A of compound (I) with the onset melting point at approximately 105 °C are preferred with respect to solid formulation development of this invention.

[0135] Preparation of Crystalline Forms

[0136] In one aspect, the present invention provides processes for preparing the crystalline and amorphous forms described herein, wherein said processes are as outlined in the Examples.

[0137] It is noted that solvents, temperatures and other reaction conditions presented in the Examples may vary.

[0138] In a further aspect, the present invention provides crystalline and amorphous forms described herein, when obtained by the processes described in the Examples.

[0139] In a further embodiment, the solid form of compound (I) is produced by a method comprising the steps of: a) suspending Form B of the present invention in a solvent; preferably the solvent is n- heptane / water; b) stirring and cooling the suspension; preferably the stirring is performed at 55-60 °C for about 1 hour and then at about 25 °C for about 2 hours, and the cooling is performed in about 2 hours; c) filtering the suspension; d) washing the wet cake; preferably the wet cake is washed with n-heptane; and e) drying the wet cake in vacuum; preferably the drying is performed at 45-50 °C; or the solid form is produced by a method comprising the steps of: a) suspending Form A of the present invention in a solvent; preferably the solvent is n- heptane; b) concentrating the suspension under vacuum; preferably this step is performed at 25 - 45 °C; c) adding additional solvent to the suspension; preferably the additional solvent is n- heptane; d) further concentrating the suspension under vacuum; preferably this step is performed at 25 - 45 °C; e) adding water to the suspension; preferably this step is performed at about 60 °C; f) stirring the suspension; preferably the stirring is performed at about 60 °C overnight; g) filtering the suspension; preferably this step is performed at about 60 °C; h) washing the wet cake; preferably the wet cake is washed with n-heptane; and i) drying wet cake; preferably the drying is performed at about 60 °C.

[0140] Pharmaceutical

[0141] The solid forms of compound (I) can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g., in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

[0142] The solid forms of compound (I) can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.

[0143] Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc. Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.

[0144] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0145] The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of solid forms of compound (I) should be appropriate, although the above upper limit can also be exceeded when necessary.

[0146] 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.

[0147] The following embodiments illustrate typical compositions of the present invention, but serve merely as representative thereof.

[0148] Composition A

[0149] A solid form of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

[0150] Per tablet

[0151] Active ingredient 200 mg

[0152] Microcrystalline cellulose 155 mg

[0153] Corn starch 25 mg

[0154] Talc 25 mg

[0155] Hydroxypropylmethylcellulose 20 mg

[0156] Total 425 mg Composition B

[0157] A solid form of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

[0158] Per capsule

[0159] Active ingredient 100.0 mg

[0160] Corn starch 20.0 mg

[0161] Lactose 95.0 mg

[0162] Talc 4.5 mg

[0163] Magnesium stearate 0.5 mg

[0164] Total 220.0 mg

[0165] Indications

[0166] Also an object of the present invention is a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable thereof, for use as therapeutically active substance.

[0167] As described above, crystalline solid forms of compound (I) are useful as gamma-secretase modulators.

[0168] In one aspect, the present invention provides a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42-amyloidosis.

[0169] In one aspect, the present invention provides a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0170] In one embodiment, the present invention provides a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable thereof, for use in the therapeutic and / or prophylactic treatment of Alzheimer’s disease.

[0171] In a further aspect, the present invention provides the use of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42- amyloidosis.

[0172] In a further aspect, the present invention provides the use of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0173] In one embodiment, the present invention provides the use of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of Alzheimer’s disease.

[0174] In a further aspect, the present invention provides the use of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42-amyloidosis.

[0175] In a further aspect, the present invention provides the use of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

[0176] In one embodiment, the present invention provides the use of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of Alzheimer’s disease.

[0177] In a further aspect, the present invention provides a method for the therapeutic and / or prophylactic treatment of neurodegenerative diseases associated with Ap42-amyloidosis which method comprises administering an effective amount of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0178] In a further aspect, the present invention provides a method for the therapeutic and / or prophylactic treatment of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, amyloid-mediated brain disorders caused by head injuries e.g. chronic traumatic encephalopathy and amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome., which method comprises administering an effective amount of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0179] In one embodiment, the present invention provides a method for the therapeutic and / or prophylactic treatment of Alzheimer’s disease which method comprises administering an effective amount of a crystalline solid form of compound (I) as described herein, or a pharmaceutically acceptable salt thereof. Examples

[0180] The invention will be better understood by reference to the following experiments and examples. They should not, however, be construed as limiting the scope of the invention.

[0181] HPLC method for chemical purity and assay test

[0182] HPLC conditions are disclosed here in Table 1.

[0183] Table 1 : HPLC conditions for chemical purity and assay test Characterization methods

[0184] X-ray Powder Diffraction

[0185] X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a PANalytical Empyrean powder diffractometer with Cu-Ka radiation. The diffractometer was equipped with a primary Focusing Mirror and a PIXcel detector. Tube voltage was 40 kV and tube current was 40 mA. Scan range was from 4 to 40 degree 2-theta. The test was with a step size of 0.0263 degree 2-theta in approximately 454 seconds.

[0186] Differential Scanning Calorimetry (DSC)

[0187] DSC curves were recorded using a TA differential scanning calorimeter Q2500. System suitability tests were performed with Indium as reference substance and calibrations were carried out using Indium and Zinc as reference substances.

[0188] For the measurements, approximately 1 to 6 mg of sample were placed in aluminum pans, accurately weighed and hermetically closed with perforation lids. Prior to measurement, the lids were automatically pierced resulting in approx. 1.5 mm pin holes. The samples were then heated under a flow of nitrogen of about 50 mL / min using heating rates of usually 10 K / min.

[0189] Thermal Gravimetric Analysis (TGA)

[0190] TGA was performed on a Mettler-Toledo™ thermogravimetric analyzer (TGA / DSC 3+). System suitability tests were performed with Hydranal as reference substance and calibrations using Aluminum and Indium as reference substances.

[0191] For the thermogravimetric analyses, approx. 5 to 10 mg of sample were placed in aluminum pans, accurately weighed. The samples were then heated under a flow of nitrogen of about 50 mL / min using a heating rate of 10 K / min.

[0192] Moisture Sorption / Desorption (DVS)

[0193] Moisture sorption / desorption data was collected on a DVS Advantage, a DVS Resolution, 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. 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: non-hygroscopic: weight increase Dm < 0.2%, slightly hygroscopic: weight increase 0.2% < Dm < 2.0%, hygroscopic: weight increase 2.0% < Dm < 15.0%, very hygroscopic: weight increase Dm > 15.0%, deliquescent: sufficient liquid is adsorbed to form a liquid; European Pharmacopoeia - 8th Edition (2014), Chapter 5.11.

[0194] Example 1: Preparation of amorphous (R)-7-(3,5-difluorophenoxy)-N-((lR,5S,8s)-3-(6- methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazol-2-amine (“Form Amorphous”)

[0195] (R)-7-(3 , 5 -difluorophenoxy)-N-(( 1 R, 5 S, 8 s)-3 -(6-methoxypyridazin-4-yl)-3 - azabicyclo[3.2. l]octan-8-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol-2-amine was prepared according to Example 1 of W02020 / 120521 Al and then lyophilized as outlined below. In a sealed tube, to a solution of the intermediate 2-bromo-7-(3,5-difluorophenoxy)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole (0.25 mmol) in 2-MeTHF (7 ml) was added 1.0 equivalent of the intermediate (lR,5S,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-amine. The reaction mixture was degassed and NaOtBu (1.5 eq.) was added at room temperature and the stirring continued for 10 minutes before tBu-Xphos (0.06 eq.) and Pd2(dba)s (0.03 eq.) were added. The reaction mixture was heated at 70-80 °C until completion of the reaction (usually between 1 and 3 hours) and concentrated under vacuum. A separation was done by preparative chiral HPLC, followed by a lyophilization of the solvent, to afford (R)-7-(3,5-difluorophenoxy)- N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine as a white solid.

[0196] The resulting solid was identified as an amorphous solid (“Form Amorphous”) by XRPD.

[0197] Characteristic XRPD diffractogram of Form Amorphous is shown in Figure 1. Example 2: Preparation of crystalline Form B of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0198] Form Amorphous (Example 1) (39.93 mg) was dissolved in 6.5 volumes (0.26 mL) of ethyl acetate and heated to 60 °C and kept for 5 min. The solution was cooled to 20 °C at the rate of 1 °C / min. After the dropwise addition of 19.5 volumes (0.78 mL) of n-heptane, the suspension was agitated overnight.

[0199] Alternatively, a suspension of 50 mg of Form A (Example 3) in 200 pL of isopropyl acetate was slurried at 25 °C overnight and then filtered.

[0200] The resulting solid was identified as Form B by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 2. Characteristic XRPD diffractogram of Form B is shown in Figure 4.

[0201] Table 2: Characteristic XRPD peaks of Form B

[0202] Form B was obtained as an ethyl acetate solvate or isopropyl acetate solvate.

[0203] Example 3: Preparation of crystalline Form A of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine Form B (Example 2) (1 g) was dried at 50 °C under vacuum for 16 hours. A sample of the solid was tested for XRPD and DSC.

[0204] The resulting solid was identified as Form A by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 3. Characteristic XRPD diffractogram of Form A is shown in Figure 2.

[0205] Table 3: Characteristic XRPD peaks of Form A

[0206] NMR data suggests no residual solvent suggesting that Form A is a neat crystal form.

[0207] The DSC thermogram shown in Figure 3 indicates Form A has an endothermic event at around 105 °C (onset temperature).

[0208] Characterization method: DSC analysis: TA Q2500, 30-300 °C, heating rate 10 °C / min. Example 4: Preparation of crystalline Form C of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0209] Form B (Example 2) (890 g) was suspended in n-heptane / water (6 L / 0.06 L) and stirred at 55- 60 °C for 1 hour. Then the suspension was cooled to 25 °C in 2 hours and kept stirring for 2 hours. After filtration and washing with n-heptane (2 L), the wet cake was dried in vacuum at 45- 50 °C for 16 hours.

[0210] Alternatively, Form A (Example 3) (9.98 kg, 1.00 eq.) was charged in a 160 L reactor and n- heptane (146 L) was added. The suspension was concentrated under vacuum at 25 - 45 °C to 110 L. n-Heptane (35 L) was added and the suspension was concentrated under vacuum at 25 - 45 °C to 110 L. Water (0.73 L) was added to the suspension at 60 °C and the suspension stirred overnight at this temperature. The suspension was filtered at 60 °C and the product rinsed with n- heptane (50 L). The product was dried at 60 °C to give 9.18 kg (Form C) as a white solid.

[0211] The resulting solid was identified as Form C by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 4. Characteristic XRPD diffractogram of Form C is shown in Figure 5.

[0212] Table 4: Characteristic XRPD peaks of Form C

[0213] The DSC thermogram shown in Figure 6 indicates Form C has an endothermic event at around 130 °C (onset temperature).

[0214] Characterization method: DSC analysis TA Q2500, 30-200 °C, heating rate 10 °C / min.

[0215] Form C integrates water into the crystal lattice as shown by water vapor sorption. The vapor sorption takes place in two distinct phases at around 25 °C: for the first phase in the sorption part, there is a plateau at 70% RH with about 0.5 eq. of water sorption (DVS isotherm plot shown in Figure 7), accompanied by a slight peak shift in the XRPD towards the smaller 2-theta angles, which is characteristic of an expansion of the crystal lattice. The second phase of the sorption part is continuous and no further peak shift is observed in the XRPD pattern. This observation was confirmed by humidity dependent XRPD. On desorption in Figure 7, a hysteresis is observed, indicating a water retention. Therefore, Form C can be a non-hydrate form at low RH and a hydrate at over 10% RH.

[0216] Example 5: Preparation of crystalline Form D of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0217] Form A (Example 3) (50 mg) was suspended in ethanol (200 pL) and agitated at 25 °C for 4 days. The solid was filtered and dried. The resulting solid was identified as Form D by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 5. Characteristic XRPD diffractogram of Form D is shown in Figure 8.

[0218] Table 5: Characteristic XRPD peaks of Form D

[0219] Form D was obtained as an ethanol solvate. Example 6: Preparation of crystalline Form E of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine Form A (Example 3) (50 mg) was suspended in a solvent mixture acetone / n-heptane (100 pL / 100 pL) and heated to 50 °C to obtain a clear solution. The solution was cooled to 20 °C at the rate of 0.2 °C / min. Solid precipitated out and the suspension was agitated at 20 °C overnight. The solid was filtered and dried.

[0220] The resulting solid was identified as Form E by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 6. Characteristic XRPD diffractogram of Form E is shown in Figure 9.

[0221] Table 6. Characteristic XRPD peaks of Form E Form E was obtained in acetone, tetrahydrofuran or isopropanol. Form E was obtained as an acetone solvate, a tetrahydrofuran solvate, or an isopropanol solvate. Example 7: Preparation of crystalline Form F of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0222] Form A (Example 3) (50 mg) was suspended in ^-propanol (100 pL) and heated to 50 °C to obtain a clear solution. The solution was cooled to 20 °C at the rate of 0.2 °C / min. Solid precipitated out and the suspension was agitated at 20 °C overnight. The solid was filtered and dried. The resulting solid was identified as Form F by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 7. Characteristic XRPD diffractogram of Form F is shown in Figure 10.

[0223] Table 7: Characteristic XRPD peaks of Form F

[0224] Form F was obtained as an n-propanol solvate.

[0225] Example 8: Preparation of crystalline Form G of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0226] Form A (Example 3) (50 mg) was suspended in toluene (200 pL) and heated to 60 °C to obtain a clear solution. The solution was cooled to 20 °C at the rate of 0.2 °C / min. Solid precipitated out and the suspension was agitated at 20 °C overnight. The solid was filtered and dried.

[0227] The resulting solid was identified as Form G by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 8. Characteristic XRPD diffractogram of Form G is shown in Figure 11. Table 8: Characteristic XRPD peaks of Form G

[0228] Form G was obtained as a toluene solvate.

[0229] Example 9: Preparation of crystalline Form H of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine Form A (Example 3) (150 mg) was suspended in methyl isobutyl ketone (200 pL). And the suspension was heated to 50 °C to obtain a clear solution. The solution was cooled to 20 °C at the rate of 0.2 °C / min. Solid precipitated out and the suspension was agitated at 20 °C overnight. The solid was filtered and dried.

[0230] The resulting solid was identified as Form H by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 9. Characteristic XRPD diffractogram of Form H is shown in Figure 12. Table 9: Characteristic XRPD peaks of Form H

[0231] Form H was obtained in methyl isobutyl ketone or isopropyl acetate. Form H was obtained as an isopropyl acetate solvate or a methyl isobutyl ketone solvate.

[0232] Example 10: Preparation of crystalline Form I of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine Form A (Example 3) (100 mg) was suspended in methanol (200 pL) and agitated at 25 °C overnight. The solid was filtered and dried. A sample of the solid was taken for XRPD test. The resulting solid was identified as Form I by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 10. Characteristic XRPD diffractogram of Form I is shown in Figure 13. Table 10: Characteristic XRPD peaks of Form I

[0233] Form I was obtained as a methanol solvate.

[0234] Example 11: Preparation of crystalline Form J of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine Form A (Example 3) (100 mg) was dissolved in isopropanol (300 pL) at 60 °C and cooled to 20 °C at the rate of 1 °C / min. N-heptane (900 pL) was charged dropwise into the suspension and kept slurring overnight. The solid was filtered and dried.

[0235] The resulting solid was identified as Form J by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 11. Characteristic XRPD diffractogram of Form J is shown in Figure 14. Table 11 : Characteristic XRPD peaks of Form J

[0236] Form J was obtained as an isopropanol solvate.

[0237] Example 12: Preparation of crystalline Form K of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine Form A (Example 3) (200 mg) was dissolved in isopropanol (800 pL) at 55 °C and cooled to 40 °C naturally. The suspension was cooled to room temperature naturally and kept stirring for 2 days. The solid was filtered and dried. The resulting solid was identified as Form K by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 12. Characteristic XRPD diffractogram of Form K is shown in Figure 15.

[0238] Table 12: Characteristic XRPD peaks of Form K

[0239] Form K was a more stable crystalline form compared to Form J. Form K was obtained as an isopropanol solvate. Example 13: Preparation of crystalline Form L of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0240] Form C (Example 4) (255 mg, jet-milled) was introduced in a glass vial closed with a screw cap fitted with a septum. The vial was inserted into an aluminum block placed on a heating plate.

[0241] The aluminum block, fitted with a temperature sensor, was heated to 145-150 °C. After 1 hour 45 minutes at 145-150 °C, the glass vial was left to return to room temperature naturally. The solid obtained was removed from the glass vial by scraping with a spatula. During the entire preparation process, a slight flow of nitrogen was introduced via a needle inserted into the septum, which was itself equipped with a second needle to allow the gas flow to be evacuated.

[0242] A sample of the resulting solid was tested for XRPD, DSC and DVS. The resulting solid was identified as Form L by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 13. Characteristic XRPD diffractogram of Form L is shown in Figure 16. NMR data suggest no residual solvent suggesting that Form L is a neat crystal form.

[0243] Table 13: Characteristic XRPD peaks of Form L The DSC thermogram shown in Figure 17 indicates Form L has an endothermic event at 170 °C (onset temperature).

[0244] Characterization method: DSC analysis: TA Q2500, 30-200 °C, heating rate 10 °C / min.

[0245] Form L exhibits a DVS isotherm comprising the vapor sorption in two distinct phases: no differences between the two cycles were observed. Both phases of the sorption are continuous until 90% RH with about 0.4% of water sorption (DVS isotherm plot shown in Figure 18).

[0246] Example 14: Preparation of crystalline Form “Pattern 2” of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazol-2-amine

[0247] Form Amorphous (Example 1) (1 g) was dissolved in 2 volumes (2 mL) of toluene and agitated at room temperature. Solid precipitated out after 20 minutes. The solid was filtered and dried. The resulting solid was identified as Pattern 2 by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 14. Characteristic XRPD diffractogram of Pattern 2 is shown in Figure 19. NMR data shows no residual solvent suggesting that Pattern 2 was obtained as a non-solvated solid form.

[0248] Table 14: Characteristic XRPD peaks of Pattern 2

[0249] Example 15: Preparation of crystalline Form “Pattern 6” of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0250] Form Amorphous (Example 1) (1 g) was dissolved in 2 volumes (2 mL) of 1 -propanol and agitated at room temperature. Solid precipitated out after 5 minutes. 5 mL of 1 -propanol was then added in 1 mL aliquots. The suspension was agitated and thermocycled for 72 hours using the following temperature cycle: hold at 40 °C for 1 hour, ramp to 5 °C at the rate of 0.1 °C / min, hold at 5 °C for 1 hour, ramp to 40 °C at the rate of 0.1 °C / min. After 72 hours, the solid was filtered and dried.

[0251] The resulting solid was identified as Pattern 6 by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 15. Characteristic XRPD diffractogram of Pattern 6 is shown in Figure 20. NMR data shows traces of residual 1 -propanol suggesting that Pattern 6 was obtained as a nonsolvated solid form with small solvent accessible voids.

[0252] Table 15: Characteristic XRPD peaks of Pattern 6

[0253] Example 16: Preparation of crystalline Form “Pattern 9” of (R)-7-(3,5-difluorophenoxy)-N- ((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b] [l,2,4]triazol-2-amine

[0254] Form Amorphous (Example 1) (1 g) was dissolved in 1 mL of 2-methyl THF. The solution immediately precipitated out and resulted in a thick suspension. 4 mL of 2-methyl THF was then added in 1 mL aliquots. The suspension was agitated and thermocycled for 24 hours using the following temperature cycle: hold at 40 °C for 1 hour, ramp to 5 °C at the rate of 0.1 °C / min, hold at 5 °C for 1 hour, ramp to 40 °C at the rate of 0.1 °C / min. After 24 hours, the solid was filtered and dried. The resulting solid was identified as Pattern 9 by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 16. Characteristic XRPD diffractogram of Pattern 9 is shown in Figure 21.

[0255] NMR data shows traces of residual 2-methyl THF suggesting that Pattern 9 was obtained as a non-solvated solid form with small solvent accessible voids. Table 16: Characteristic XRPD peaks of Pattern 9 Example 17: Preparation of crystalline Form “Pattern 12” of (R)-7-(3,5-difluorophenoxy)- N-((lR,5S,8s)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazol-2-amine

[0256] Form C (Example 4) (1 g) was suspended in 3 volumes (3 mL) of acetonitrile and agitated at room temperature. Solid precipitated out after 5 minutes. As there was no obvious excess solvent, the solid was dried without preliminary filtration.

[0257] The resulting solid was identified as Pattern 12 by XRPD. Major peaks and their relative intensities in the XRPD pattern are shown in Table 17. Characteristic XRPD diffractogram of Pattern 12 is shown in Figure 22. NMR data shows traces of residual acetonitrile suggesting that Pattern 12 was obtained as a nonsolvated solid form with small solvent accessible voids.

[0258] Table 17: Characteristic XRPD peaks of Pattern 12

[0259] Example 18: Solubility and stability study

[0260] Apparent solubility was determined by suspending 15 mg of Form A (Example 3) and Form C (Example 4) in different bio-relevant media including FaSSIF and FeSSIF. The suspensions were equilibrated at 37 °C for 4 hours or at 25 °C for 24 hours. The suspensions were then filtered through a 0.22 pm PVDF filter into a 2-mL HPLC vial. The quantitation of the filtrate was conducted by HPLC with reference to a standard solution. The solubility results of selected novel solid forms in this invention are shown in Table 18 and Table 19. The filtered solids were dried. The samples of the solids were tested for XRPD.

[0261] Table 18: Solubility of different solid forms at 37 °C Table 19: Solubility of different solid forms at 25 °C

[0262] Characterization method:

[0263] XRPD: PANalytical Empyrean X-ray powder diffractometer with Cu-Ka radiation. Tube voltage was 40 kV and tube current was 40 mA. Scan range was from 4 to 40 degree 2-theta. The test was with a step size of 0.0263 degree 2-theta in 7.5 min.

[0264] It can be seen from Table 18 and Table 19 that, in FaSSIF, after slurried for 4 hours at 37 °C and for 24 hours at 25 °C, Form A changed into Form C, whereas Form C stayed unchanged. Thus, Form C shows no absorption variation risk.

[0265] In the test condition of 1.2 million Lux.hours, Form C is more stable than Form A as shown in Table 20. Furthermore, we have found that Form C exists in a non-hydrate form at low RH and in a hydrate form at over 10% RH.

[0266] Table 20: Photostability of the Solid State Example 19: Comparative stability assessment of Form C and Form L

[0267] For each experiment in this set of competitive slurries, a powder mixture of equal parts of Form C and Form L were suspended in 1 mL of a mixture of water and acetone.

[0268] The quantity of solid suspended (100 mg to 500 mg) was adapted, by successive addition of 50 mg portions, to the experimental conditions of each experiment in order to obtain a stirrable suspension.

[0269] The water / acetone mixtures were made as follows: 7 volumes of water for 93 volumes of acetone (aw= 0.59), 40 volumes of water for 60 volumse of acetone (aw= 0.78), 95 volumes of water for 5 volumes of acetone (aw= 0.97). The water activity was measured at room temperature before adding the mixture of solid forms (starting water activity).

[0270] A sample of the suspension was taken every 3 days, filtered, and the residual solid from filtration taken wet for XRPD test. Each experiment was stopped after complete transformation into Form L. In the case of the experiment carried out at 0-2 °C and a water activity aw= 0.97, the experiment was stopped after 21 days when the ratio between Form C and Form L had not changed for 6 days.

[0271] Table 21. Stability assessment of Form C and Form L

[0272] Competitive slurry experiments carried out at three temperatures (0-2 °C, 25 °C, 50 °C) and 3 water activities (aw= 0.59, aw= 0.78, aw= 0.97) showed a clear superiority of the stability of Form L compared to Form C.

Claims

CLAIMS1. A solid form of compound (I),wherein the solid form is a crystalline polymorphic selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L and mixtures thereof.

2. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 20.1°±0.2° and 21.3°±0.2°.3 The solid form according to claim 2, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 10.3°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 21.3°±0.2° and 23.8°±0.2°.

4. The solid form according to claim 2 or 3, wherein the solid form that exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 9.9°±0.2°, 10.0°±0.2°, 10.3°±0.2°, 10.6°±0.2°, 11.0°±0.2°, 11.6°±0.2°, 12.4°±0.2°, 12.8°±0.2°, 13.4°±0.2°, 14.5°±0.2°, 15.2°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 19.6°±0.2°, 20.1°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.3°±0.2°,21.6°±0.2°, 22.0°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 23.4°±0.2°, 23.8°±0.2°, 24.8°±0.2°, 25.8°±0.2° and 27.0°±0.2°.

5. The solid form according to any one of claims 2 to 4, wherein the solid form exhibits an XRPD pattern shown in Figure 2.

6. The solid form according to any one of claims 2 to 5, wherein the solid form exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with onset temperature at 105 °C ± 3 °C.

7. The solid form according to any one of claims 2 to 6, wherein the solid form exhibits a DSC thermogram as shown in Figure 3.

8. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.8°±0.2°, 10.3°±0.2°, 11.6°±0.2°, and 18.1°±0.2°.

9. The solid form according to claim 8, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.8°±0.2°, 10.3°±0.2°, 11.6°±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.8°±0.2°, 18.1°±0.2°, 18.4°±0.2° and 20.2°±0.2.

10. The solid form according to claim 8 or 9, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.8°±0.2°, 10.3°±0.2°, 11.6°±0.2°, 14.8°±0.2°, 16.8°±0.2°, 17.8°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.2°±0.2, 20.6°±0.2, 21.0°±0.2 and 21.3°±0.2.

11. The solid form according to any one of claims 8 to 10, wherein the solid form exhibits an XRPD pattern shown in Figure 4.

12. The solid form according to any one of claims 8 to 11, wherein the solid form is an isopropyl acetate solvate or an ethyl acetate solvate.

13. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, 10.9°±0.2°, 12.7°±0.2°, 16.8°±0.2° and 20.8°±0.2°.

14. The solid form according to claim 13, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 12.7°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 19.1°±0.2°, and 20.8°±0.2°.

15. The solid form according to claim 13 or 14, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 12.7°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 20.8°±0.2°, 22.4°±0.2° and 23.7°±0.2°.

16. The solid form according to any one of claim 13 to 15, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, 10.2°±0.2°, 10.9°±0.2°, 11.2°±0.2°, 12.0°±0.2°, 12.7°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 22.8°±0.2°, 23.4°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.2°±0.2°, 27.2°±0.2°, 27.5°±0.2°, 28.2°±0.2°, 28.5°±0.2°, 28.9°±0.2°, 29.2°±0.2°, 31.6°±0.2° and 32.4°±0.2°.

17. The solid form according to any one of claims 13 to 16, wherein the solid form exhibits an XRPD pattern shown in Figure 5.

18. The solid form according to any one of claims 13 to 17, wherein the solid form exhibits a DSC thermogram comprising endothermic peak with onset temperature at 130 °C ± 3 °C.

19. The solid form according to any one of claims 13 to 18, wherein the solid form exhibits a DSC thermogram as shown in Figure 6.

20. The solid form according to any one of claims 13 to 19, wherein the solid form exhibits a DVS Isotherm Plot as shown in Figure 7.

21. The solid form according to any one of claims 13 to 20, wherein the solid form is a nonhydrate form or a hydrate form.

22. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.8°±0.2°, 10.9°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 19.0°±0.2°and 20.4°±0.2°.

23. The solid form according to claim 22, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 8.8°±0.2°, 10.9°±0.2°, 14.1°±0.2°, 15.5°±0.2°, 17.2°±0.2°, 19.0°±0.2°, 20.4°±0.2°, 22.5°±0.2°, 23.4°±0.2°, 24.2°±0.2° and 25.1°±0.2°.

24. The solid form according to claim 22 or 23, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 7.9°±0.2°, 8.8°±0.2°, 10.1°±0.2°, 10.9°±0.2°, 11.6°±0.2°, 14.1°±0.2°, 14.6°±0.2°, 14.8°±0.2°, 15.5°±0.2°, 15.9°±0.2°, 16.4°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 20.2°±0.2°, 20.4°±0.2°, 20.8°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.1°±0.2°, 22.5°±0.2°, 23.1°±0.2°, 23.4°±0.2°, 23.9°±0.2°, 24.2°±0.2°, 25.1°±0.2°, 26.4°±0.2°, 26.7°±0.2°, 27.3°±0.2°, 27.7°±0.2°, 28.4°±0.2°, 29.0°±0.2°, 29.6°±0.2°, 31.3°±0.2°, 31.5°±0.2° and 31.8°±0.2°.

25. The solid form according to any one of claims 22 to 24, wherein the solid form exhibits an XRPD pattern shown in Figure 8.

26. The solid form according to any one of claims 22 to 25, wherein the solid form is an ethanol solvate of compound (I).

27. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 9.8°±0.2°, 11.5°±0.2°, 17.7°±0.2° and 19.5°±0.2°.

28. The solid form according to claim 27, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 9.8°±0.2°, 11.5°±0.2°, 12.1°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.7°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 22.7°±0.2°, 23.2°±0.2° and 24.4°±0.2°.

29. The solid form according to claim 27 or 28, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 6.6°±0.2°, 9.8°±0.2°, 10.5°±0.2°, 11.5°±0.2°, 12.1°±0.2°, 12.9°±0.2°, 16.0°±0.2°, 16.7°±0.2°, 17.0°±0.2°, 17.7°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 21.3°±0.2°, 21.6°±0.2°, 22.7°±0.2°, 23.2°±0.2°, 24.4°±0.2°, 24.7°±0.2°, 25.5°±0.2°, 26.5°±0.2° and 28.9°±0.2°.

30. The solid form according to any one of claims 27 to 29, wherein the solid form exhibits an XRPD pattern as shown in Figure 9.

31. The solid form according to any one of claims 27 to 30, wherein the solid form is an acetone solvate, a tetrahydrofuran solvate or an isopropanol solvate of compound (I).

32. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.6°±0.2°, 10.7°±0.2°, 13.8°±0.2°, 17.1°±0.2°, 18.8°±0.2° and 20.3°±0.2.

33. The solid form according to claim 32, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.6°±0.2°, 10.7°±0.2°, 11.9°±0.2°, 13.8°±0.2°, 15.2°±0.2°, 17.1°±0.2°, 18.8°±0.2°, 19.8°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 22.5°±0.2°, 23.4°±0.2° and 24.1°±0.2°.

34. The solid form according to claim 32 or 33, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.2°±0.2°, 7.8°±0.2°, 8.6°±0.2°, 9.4°±0.2°, 10.0°±0.2°, 10.7°±0.2°, 11.6°±0.2°, 11.9°±0.2°, 13.8°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 15.8°±0.2°, 16.2°±0.2°, 16.7°±0.2°, 17.1°±0.2°, 17.3°±0.2°, 18.3°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 19.8°±0.2°, 20.3°±0.2°, 21.2°±0.2°, 22.1°±0.2°, 22.5°±0.2°, 23.4°±0.2°, 23.8°±0.2°, 24.1°±0.2°, 24.9°±0.2°, 26.9°±0.2°, and 27.9°±0.2°.

35. The solid form according to any one of claims 34 to 33, wherein the solid form exhibits an XRPD pattern as shown in Figure 9.

36. The solid form according to any one of claims 32 to 35, wherein the solid form is an n- propanol solvate of compound (I).

37. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 10.8°±0.2°, 13.1°±0.2°, 17.6°±0.2° and 20.0°±0.2°.

38. The solid form according to claim 37, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 10.8°±0.2°, 13.1°±0.2°, 15.7°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 20.0°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.2°±0.2°, 24.0°±0.2° and 28.5°±0.2°.

39. The solid form according to claim 37 or 38, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.3°±0.2°, 9.9°±0.2°, 10.8°±0.2°, 11.5°±0.2°, 12.0°±0.2°, 12.6°±0.2°, 13.1°±0.2°,14.9°±0.2°, 15.3°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 17.8°±0.2°, 19.0°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, 20.7°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 23.2°±0.2°, 24.0°±0.2°, 26.9°±0.2° and 28.5°±0.2°.

40. The solid form according to any one of claims 37 to 39, wherein the solid form exhibits an XRPD pattern as shown in Figure 11.

41. The solid form according to any one of claims 37 to 40, wherein the solid form is a toluene solvate of compound (I).

42. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.2°±0.2°, 10.8°±0.2°, 12.6°±0.2°, 17.7°±0.2° and 18.8°±0.2°43. The solid form according to claim 42, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.2°±0.2°, 10.8°±0.2°, 12.6°±0.2°, 15.0°±0.2°, 17.1°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 20.9°±0.2°, 21.7°±0.2°, 23.3°±0.2° and 27.6°±0.2°.

44. The solid form according to claim 42 or 43, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.2°±0.2°, 9.9°±0.2°, 10.4°±0.2°, 10.8°±0.2°, 11.8°±0.2°, 12.6°±0.2°, 15.0°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.5°±0.2°, 17.7°±0.2°, 18.1°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 20.9°±0.2°, 21.2°±0.2°, 21.7°±0.2°, 22.1°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 25.6°±0.2°, 25.9°±0.2°, 26.7°±0.2°, 27.0°±0.2° and 27.6°±0.2°.

45. The solid form according to any one of claims 42 to 44, wherein the solid form exhibits an XRPD pattern as shown in Figure 12.

46. The solid form according to any one of claims 42 to 45, wherein the solid form is an isopropyl acetate solvate or a methyl isobutyl ketone solvate of compound (I).

47. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form I that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, l l.l°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 17.4°±0.2° and 18.7°±0.2.

48. The solid form according to claim 47, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.0°±0.2°, l l.l°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 17.0°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 18.9°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.1°±0.2°, 22.1°±0.2° and 22.5°±0.2°.

49. The solid form according to claim 47 or 48, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.2°±0.2°, 9.0°±0.2°, 10.1°±0.2°, l l.l°±0.2°, 11.6°±0.2°, 12.0°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 15.7°±0.2°, 16.4°±0.2°, 17.0°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 20.3°±0.2°, 20.8°±0.2°, 21.1°±0.2°, 22.1°±0.2°, 22.5°±0.2°,50. The solid form according to any one of claims 47 to 49, wherein the solid form exhibits an XRPD pattern as shown in Figure 13.

51. The solid form according to any one of claims 47 to 50, wherein the solid form is a methanol solvate of compound (I).

52. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form J that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.4°±0.2°, 10.6°±0.2°, 13.8°±0.2°, 16.7°±0.2°, and 17.5°±0.2°53. The solid form according to claim 52, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.4°±0.2°, 10.6°±0.2°, 11.5°±0.2°, 12.0°±0.2°, 13.8°±0.2°, 15.2°±0.2°, 16.3°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.8°±0.2°, and 20.4°±0.2°.

54. The solid form according to claim 52 or 53, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.6°±0.2°, 8.4°±0.2°, 10.6°±0.2°, 11.5°±0.2°, 12.0°±0.2°, 13.8°±0.2°, 14.5°±0.2°, 14.7°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.3°±0.2°, 16.7°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.3°±0.2°, 19.5°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 20.9°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 23.1°±0.2°, 23.4°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 25.5°±0.2°, 26.7°±0.2°, 29.1°±0.2°, 29.7°±0.2°, and 30.6°±0.2°.

55. The solid form according to any one of claims 52 to 54, wherein the solid form exhibits an XRPD pattern as shown in Figure 14.

56. The solid form according to any one of claims 52 to 55, wherein the solid form is an isopropanol solvate of compound (I).

57. A solid form of compound (I),wherein the solid form is crystalline polymorphic Form K that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 10.1°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.2°±0.2° and 19.1°±0.2°58. The solid form according to claim 57, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.7°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 13.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 20.7°±0.2°, 22.4°±0.2°, and 23.2°±0.2°.

59. The solid form according to claim 57 or 58, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.7°±0.2°, 7.9°±0.2°, 9.1°±0.2°, 10.1°±0.2°, 11.6°±0.2°, 13.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°,6018.2°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 20.3°±0.2°, 20.7°±0.2°, 21.2°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 23.2°±0.2°, 23.9°±0.2°, 24.8°±0.2°, 25.3°±0.2° and 25.6°±0.2°.

60. The solid form according to any one of claims 57 to 59, wherein the solid form exhibits an XRPD pattern as shown in Figure 15.

61. The solid form according to any one of claims 57 to 60, wherein the solid form is an isopropanol solvate of compound (I).

62. A solid form of compound (I),(I), wherein the solid form is crystalline polymorphic Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.7°±0.2°, 14.4°±0.2°, 17.2°±0.2°, 21.7°±0.2° and 25.6°±0.2°63. The solid form according to claim 62, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.7°±0.2°, 13.3°±0.2°, 14.4°±0.2°, 16.4°±0.2°, 17.2°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 21.7°±0.2°, 25.6°±0.2° and 28.8°±0.2°.

64. The solid form according to claim 62 or 63, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 11.7°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 14.4°±0.2°, 16.4°±0.2°, 17.2°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 21.1°±0.2°, 21.7°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 26.8°±0.2° and 28.8°±0.2°.

65. The solid form according to any one of claims 62 to 64, wherein the solid form exhibits an XRPD pattern with characteristic peaks expressed in degrees 2-theta at 7.0°±0.2°, 9.0°±0.2°, 11.7°±0.2°, 13.3°±0.2°, 13.6°±0.2°, 14.4°±0.2°, 16.4°±0.2°, 16.9°±0.2°, 17.2°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 19.3°±0.2°, 20.6°±0.2°, 21.1°±0.2°, 21.7°±0.2°, 22.2°±0.2°, 22.5°±0.2°, 22.8°±0.2°, 23.6°±0.2°, 24.7°±0.2°,6125.2°±0.2°, 25.6°±0.2°, 26.8°±0.2°, 27.6°±0.2°, 27.9°±0.2°, 28.8°±0.2°, 30.9°±0.2°, 31.2°±0.2°, 33.2°±0.2°, 36.5°±0.2°, 37.5°±0.2° and 38.0°±0.2°.

66. The solid form according to any one of claims 62 to 65, wherein the solid form exhibits an XRPD pattern shown in Figure 16.

67. The solid form according to any one of claims 62 to 66, wherein the solid form exhibits aDSC thermogram comprising endothermic peak with onset temperature at 170 °C ± 3 °C.

68. The solid form according to any one of claims 62 to 67, wherein the solid form exhibits a DSC thermogram as shown in Figure 17.

69. The solid form according to any one of claims 62 to 68, wherein the solid form exhibits a DVS Isotherm Plot as shown in Figure 18.

70. A pharmaceutical composition comprising the solid form of any one of the claims 1 to 69 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

71. A solid form of any one of claims 1 to 69 for use as a medicament.

72. A solid form of any one of claims 1 to 69 for use in the treatment or prophylaxis of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

73. The use of a solid form of any one of claims 1 to 69 for the treatment or prophylaxis of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

74. The use of a solid form of any one of claims 1 to 69 or the pharmaceutical composition of claim 70 for the manufacture of a medicament for the treatment or prophylaxis Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica,chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome.

75. A method for the treatment or prophylaxis of Alzheimer’s disease, cerebral amyloid angiopathy, cochlear synaptopathy, hearing loss, hearing loss associated with neurodegeneration, hereditary cerebral hemorrhage with amyloidosis-Dutch type(HCHWA-D), multi-infarct dementia, dementia pugilistica, chronic traumatic encephalopathy, amyloidosis after traumatic brain injury, neurodegeneration triggered by traumatic brain injury, amyloidosis or Down syndrome, which method comprises administering a therapeutically effective amount of a solid form as defined in any one of claims 1 to 69 or the pharmaceutical composition of claim 70 to a patient in need thereof.

76. A solid form, use or method according to any one of the preceding claims wherein the solid form is administered orally under fed conditions, in particular wherein the administration takes place within about 1 hour after the intake of a meal, more particular within about 30 minutes after the intake of a high -fat meal.

77. A solid form, use or method according to any one of the preceding claims wherein the solid form is administered orally under fastened conditions, in particular wherein the administration takes place in the morning and at least about 10 hour after the intake of a meal, more particular in the morning and at least about 8 hours after the intake of a meal.

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