Crystalline forms of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3h-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2h-1,2,3-triazol-2-yl)phenol

Abstract

The present invention describes specific crystalline forms of 2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yl)phenol. The present invention further relates to methods for preparing said crystalline forms, pharmaceutical compositions comprising said crystalline forms, and methods of using said crystalline forms and pharmaceutical compositions comprising said crystalline forms to treat Huntington's Disease.

Description

CRYSTALLINE FORMS OF 2-[3-(2,2,6,6-TETRAMETIIYLPIPERIDIN-4-YL)-3H-[ 1 ,2,3] TRIAZOLO [4,5-C] P VRID AZIN-6- YL]-5-(2 IE-1 ,2,3-TRI AZOL-2-YL)PHENOLFIELD OF THE INVENTION

[0001] The present invention is directed to cry stalline forms of 2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1.2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yDphenol. methods of making the same, pharmaceutical compositions comprising the same and methods using the same in treating Huntington's Disease.BACKGROUND

[0002] Polymorphism denotes the existence of more than one crystalline form of a substance. Polymorphs (or crystalline modifications) have an identical chemical structure but often quite different physicochemical properties. Polymorphs include enantiotropic polymorphs and monotropic polymorphs This ability of a chemical substance to crystallize in more than one crystalline form can have a profound effect on the shelf life, solubility, formulation properties, and processing properties of a drug, In addition, the action of a drag can be affected by the polymorphism of the drug molecule Different polymorphs can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity. The occurrence of an unknown crystalline form during manufacture can have a significant impact.

[0003] Understanding and controlling polymorphism, then, gives a decided advantage in bringing new drugs to the marketplace First and foremost, searching for any possible polymorphs for a drug product can be used io dimmish the possibility of contamination during a drug's manufacture or storage by other polymorphic forms. Failure to catch contamination can have life-threatening consequences in some cases Crystallizing an unintended polymorph daring manufacture can mean w eeks or even months of production downtime while scientists find and correct the cause of the new crystalline form or go through another round of testing to obtain approval for the new crystalline form

[0004] Second, understanding which crystalline forms of a drug are possible in certain oases allows researchers to maximize the desired properties of a compound., such as solubility, formulation properties, processing properties, and shelf life. Understanding these fectors early[3-(2,2.6?6-tetramethyipiperidin-4-y I )-3II-[ L2r3]triazolo[4.5*c]py ridazin-6-y 1J-542H- L2r3 - triazol-2-yl)phenolSUMMARY OF THE INVENTION

[0009] The present invention is directed to crystalline forms of 2-p-(2,2,6.6- tetramethy1pipendin"4”yl)-3H-[l>2,3]triazolo(4,5-c|pyridazin"6"yl]-5-(2H- L2,3-tnazoi-2- yl)phenol.

[0010] The present invention is also directed methods of making. isolating and / or characters zing various crystalline forms of 2~[3-(2,2,6,6-teiramethy foiperidm-4-yl)~ ’= i. [1,2,3hriazolo[4,5--c]pyndazin"6"yl]-5--(2H-1,2,3-triazol-2-yl)phenc>l.

[0011] 'Hie present invention also provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of a crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidin-4- yi)’3H-[1,2,3]triazolo[4,5-c]ijyridaz.in-6-yi]-5-(2H’1,2,3-iriaz.ol-2-yi)pbenol of the present invention, and (b> at least one pharmaceutically acceptable carrier.

[0012] The present invention is also directed io a method for treating or ameliorating Huntington’s Disease comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a crystalline form of 2-[3-(2;2,6,6- tetramethylpiperidin-4-yr)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yr[-5-(2H-1,2,3-triazol-2- yi)phenol of the present invention or a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of 2-[3-(2,2,6,64eiramefoyipiperidin-4- yl)’3H-[1,2,3]iriaz.olo[4,5-C]pyndaz.in-6-yl]’5-(2H-1,2,3-triazol-2-yl)phenol of the present invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG 1 depicts the X-ray powder diffraction (XRPD) pattern for crystalline Form A of 2-[3-(2.2,6,6-ietramethylpiperidin-4-yl)-3H-[1.23]triaz0lo[4>5-c]pyridazin-6-yl]-5-(2H-1,2,3- triazi i d s i )phenol according to the present invention.

[0014] FIG 2 depicts the differential scanning calorimetry (DSC) thermogram for crystalline Form A of 2-[3-(2,2.6,6-tetratnethylpiperidin-4-y l)-3H-[1.2,3]triazolo[4,5-c]pyridazin-6-yl]- 5-(2H-1,2,3-triazol-2-yl)phenol according to the present invention

[0015] FIG. 3 depicts the thermogravimetry coupled fourier transform infrared spectroscopy (TG-FTIR) thermogram for crystalline Form A of 2-[3~(2,2,6,64etramedryfoiperidmm~yl)-3M-[1,2,3[tiiazo!o[4,5-c]p5 fidazin-6-yl]-5-(2M-l,2,3-triazol-2-yl)phenol according to tire present invention.

[0016] FIG. 4 depicts the Fourier transform Raman spectroscopy (FT-Raman) spectrum for crystalline Form A of 2-[3-(2.2,6.6-tetramethylpiperidin-4-yl)-3H-[l ,2.3]triazolo[4.5- c]pyridazin-6-yl[-5-(2FI-1,2,3-iriazol-2-yl)phenol according to the present invention

[0017] FIG. 5 depicts the X-ray powder diffraction (XRPDj pattern for crystalline Form B of 2-[3-(2.2.6,6-tetramethylpiperidin-4-yl)-3I-I-[1,2,3]triaz.o1o[4,5-c]pyridazin-6-yi]-5-(2I-I-1,2,3- triazr 4 -2 -yi )phenol according to the present invention

[0018] FIG 6 depicts the differential scanning calorimetry' (DSC) thermogram for crystalline Form B of 2- [3 -(2,2,6, 6-tetramethylpiperidin-4-yl)-3H-[1 ,2,3Jtriazolo[4,5-c[pyridazin-6-yl]-5- (2H-1,2,3-tria2»l-2-yl)phenol according to the present invention.

[0019] FIG. 7 depicts the thermogravimetry coupled fotirier transform infrared spectroscopy (TG-FTIR) thermogram for crystalline Form B of 2-| 3-(2,2,6,6-letramethylpiperidin-4-yl)-3H- [ 1,2,3]lriaz.c4o[4,5-c]pyridaz.in-6-yl]-5-(2H-1,2,3-triaz.c4-2-yl)phenol according to the present invention

[0020] FIG. 8 depicts the fburier transform Raman spectroscopy (FT-Raman) spectrum for crystalline Form B of 2-[3~(2,2,6,6-tetramethylpiperidin-4-yl)-3H-| 1,2,3]tnazolo[4,5- c]pyndazin-6-yl]-5-(2H- 4,2,3-tnazol-2-yl)phenol according to the present invention.

[0021] FIG. 9 depicts the X-ray powder diffraction (XR.PD) pattern tor crystaltitle Form C of 2-[3-(2,2.6.6-tetramethylpiperidin-4-yl)-3H-[1 ,2,3]triazolo[4,5-c]pyridazin-6-yr[-5-(2H- 1 ,2,3- triazoI-2-yl)phenol according to the present invention.

[0022] FIG. 10 depicts the X-ray powder diffraction (XRPD) patern for trihydrate crystalline form HA of 2-|3-(2,2,6,6-teiramethylpiperidm-4-yl)-3H-[ l,2.3]triaz.olo[4.5-c]pyridaz.in-6-yl 5-(2FI-1,2,3-lriaz.ol~2-yl)phenol according to the present invention.

[0023] FIG 1 1 depicts the XRPD patient for solvate form SA of 2-p-(252;6,6- tetramethylpiperidm-4-yr)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-tri azol -2- yl)phenol according to die present invention.

[0024] FIG. 12 depicts the XR.PD patern for solvate form SB of 2-[3-(2,2.6,6- tetramethylpiperidm-4-yl)-3H~[] ,2,3]triaz.olo[4,5-c]pyridazm-6-yl]-5-(2H~1,2,3-iriaz.ol-2- yBphenoi according to the present invention.peak positions and intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for another or an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.

[0033] The terms “solid form” or "‘solid state form” as used herein interchangeably refer to any crystalline and / or amorphous phase of a compound.

[8034] As used herein, the term ‘‘amorphous” refers to a solid form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a. definitive XRPD pattern will's reflections.[00351 As used herein the term “polymorph” refers io crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions forming the crystal

[0036] The term ‘-hydrate” as used herein, refers to a crystalline solid where either water is cooperated in or accommodated by the crystal structure, e.g., is pari of the crystal structure or entrapped into the crystal (water inclusions) Thereby, water can be present in a stoichiometric or nomstoichiometnc amount When water is present in stoichiometric amount, the hydrate may be referred to by adding Greek numeral prefixes. For example, a hydrate may be referred to as a hemibydrate or as a monohydrate depending on hie water / compound stoichiometry. The water content can be measured, for example, by Karl-Fischer-Coulornetry

[0037] 'The terms ‘'dehydrating” or “dehydration” as used herein, describe the at least partial removal of water from the crystal structure of the host molecule.

[0038] The term “solvate” as used herein, refers io a crystalline solid were either one or more organic solvent(s) is / are cooperated in or accommodated by the crystal structure e.g rs / are part of the crystal structure or entrapped into the crystal (water inclusions). Thereby, the one or more organic solvents) can be present in a stoichiometric ornon-stoichiometric amount. When the one or more organic solvents) is / are present in stoichiometric amount(s), the solvate may be referred to by adding Greek numeral prefixes For example, a solvate may be referred to as a hemisoivate or as a monosolvate depending on the solvent(s) / compound stoichiometry. The solvent content can be measured, for example, by GC, NMR, SXRD and / or TGA / MS.

[8839] ’Fhe term "‘pharmaceutically acceptable excipient” as used herein refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. ExcipientsTABLE Aspectrum substantially as shown m FIG. 4TABLE B[0057| In one embodiment, the invention relates to crystalline Form B of 2-[3-(2,2,6,6- tetraniethylpiperidin-4-yl)-3H -[ 1 ,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triaz.ol-2- yDphenol characterized by 3. 4. 5, 6, 7. 8, 9, 10. or more angular positions as provided in Table B. In some embodiments, the angular positions may vary’ by + 0.2. In some embodiments, the angular positions may vary by ± 0.1. In some embodiments, the angular positions mm vary by * 0 05. In some embodiments, the angular positions may vary by ± 0.02.

[0058] in one embodiment, the invention relates to crystalline Form B of 2-[3-(2,2.,6,6~ tetramethylpiperidin-4-yr)-3H”[1,2,3]lriazolo[4,5-c]pyridazin-6-yI]”5-(2H"1,2,3-triazoI-2- yljpbenol characterized by having aXRPD pattern comprising reflections at 2-Theta angles (2 theta values) of:5 2 ± 4.2°, 6 0 * 0.2° and I 5.8 * 6.2°: or5 2 * 0.2°. 6 0 ± 0.2°, 10.5 * 0.2°, 12.6 + 0 2° and 15 8 * 0.2°; or5.2 * 0.2°. 6.0 ± 0 2°, 8.7 * 0.2°, 10.5 * 0.2°, 12.6 + 0.2°, 14.5 * 0.2°, and 15.8 * 0.2°, measured rising Cu-Kalpba radiation

[0059] In another embodiment, crystalline Form B of2-[3-(2,2,6,6-telramethyIpiperidin-4-yl)- 3H-[1,2,3]iriazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol is characterized by having a XRPD pattern comprising at least three, or at least four, or at least five, or all, 2 theta values selected from the group consisting of 5 2 * 0.2°, 6.0 * 0 2°, 8.7 ± 0.2°, 10.5 + 0.2°. 12.0 * 0 2°, 12.6 * 0.2°. 12 9 * 0 2°, 14.5 + 0.2°, 14.8 * 0.2°. 15 0 * 0.2°, 15.8 + 0.2°, 17.4 * 0 2°, 17.6 + 0 2°. 17.8 * 0.2°, 18 0 * 0 2°, 18.4 * 0 2°, 19 0 * 0.2°, 19.2 + 0 2°, 19.9 * 0.2°, 22 7 * 0.2°, 23.3 + 0.2°, 23 7 + 0.2°, 24.0 + 0.2°, 24,5 + 0.2°, 25 0 + 0 2°. 25.4 * 0.2°. 25 8 * 0 2°,26 2 * 0.2°, and 27.6 ± 0.2°, measured using Cu-Katpha radiation.

[0060] Crystalline Form B of 2-[3-(2,2s6,6-teinmiethylpiperidm-4-yl)-3FI-[1,2,3]triazolo[4,5- c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol may be characterized thermally, in one embodiment. Form B is characterized by a DSC thermogram exhibiting a single melting endotherm at 260.3°C (onset at 259 5°C). In another embodiment. Form B is characterized by a DSC thermogram substantially as shown in FIG. 6. In one embodiment. Form A is characterized by a TG-FTIR thermogram exhibiting undergoes mass changes from 7.5 C to 140°C and 140°C to 210°C. followed by decomposition at higher temperatures. In another embodiment, Form B is characterized by a TG-FTIR thermogram substantially as shown in FIG. 7.TABLE CTABLE DTABLE SITABLE S2TABLE S3TABLE S4

[0073] In one embodiment, the invention relates to crystalline form SB of 2-[3-(2, 2,6,6-S2 In some embodiments, the angular positions nw vary by * 0.2 In some embodiments, the angular positions may vary by 0.1. tn some embodiments, the angular positions may vary byHPLC: High performance liquid chromatographyNMR: Nuclear magnetic resonance spectroscopyRH: Relative humidityRT: Room temperatureIGA: Thermo gravimetric analysisXRPD: X-ray powder diffractionThe following examples include illustrations of aspects of the invention. The examples are not to be construed as limitations.General Test ConditionsThe following procedures were employed under each lest condition.Differentia! Scanning Calorimetry (DSC)180861 The DSC instrument used to test the cry stalling forms was the Thermal Analysis Q2000 in closed (hermetically sealed) gold or aluminum crucibles. Samples were filled either under ambient conditions or under nitrogen flow (for 3 to 10 minutes), beating rate of 10 K min-i. and -50c'C to 285°C temperature rangeFourier Transfomi-Raman (FT-Kaman) Spectroscopy

[0087] Instrument Broker MultiRAM (with OPUS 7.0 software); Nd:YAG 1064mm excitation, 100-300 mW nominal laser power, Ge detector. 64-256 scans, 3500-100 cm- 1 spectral range. 2 cm-1 resolution Samples were measured using aluminum sample holders.Tbermogravimetry coupled Fourier Transform Infrared (TG-FT1R) Spectroscopy

[0088] The TG-FTIR spectral range used of samples were recorded with the Netzscb ThermoMicrobalance TG 209 with Bruker FT-IR Spectrometer H S2S or Vector 22 in an Al crucible, nitrogen atmosphere, 10 K min- 1 heating rate, and a 25CC to 300°C or 350' ’C temperature range.X-Ray Powder Diffraction

[0089] The X-ray7powder diffraction (XRPD) patterns described herein, with the exception of Form C, were recorded on a Bruker D8 Advance diffractometer using CuKalpha radiation (wavelength of 1.5406 A), 40 kV / 40 mA. LynxEye detector, Bragg-Brentano reflection geometry, 0.02°2G step size, 37-s step time, 2 5-50°2G range, at room temperature, The

[0091] One of ordinary skill in the art will appreciate that an XRPD pattern may be obtained walk a measurement error that is dependent upon the measurement conditions emukwed. In □articular, it is generally known that intensities in an XRPD pattern may fluctuate deeendma upon measurement conditions employed It should be further understood that relative intensities may also varv depending upon experimental conditions and wavelength oi X-rayExample 1Preparation of crystalline Form A of 2-[3-(2,2,6,6-tetramethy1piperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenolExample 2Solid Stale Stabilitystnbilltv (ire described in T&ble 1TABLE 1TABLE 2Chemical Stability at Accelerated Conditions of Temperature and Humidity at 1 MonthTABLE 3Chemical Stability at Accelerated Conditions of Temperature and Humidity al 6 MonthsExample 3Preparation of crystalline Form B of2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[I,2,3]triazolo|4,5-c]p\'ridazin-6-ylJ-5-(2H-1,2,3-triazol-2-yl)phenolExample 4Preparation of crystalline Form C of 2-[3-(2,2,6,6-tetrameihylpiperidin-4-yI)-3H-[1.2.3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenolspontaneously converts back into Form A upon cooling to ambient temperature. Hie XRPD pattern for Form C is shown in FIG. 9.Example 5Preparation of crystalline Form HA of2-[3-(2,2,6,6-letramethylpiperidin-4-y1)-3H- [1,2,3jtriazolo|4,5-c]pyridazin-6-yll-5-(2H-1,2,3-triazol-2-yl)phenol[0101 1 Frihvdra.te Form 11 \ was obtained bv suspension equib bration oi Form A trom Example 1 in a solvent mixture of 9: 1 (v / v) tetraliydrofuran / FRO at 25°C for 5 to 15 davs. The XRPD pattern for Fenn H\ is shown fo FIG 10.Example 6Preparation of crystalline Form SA of2-[3-(2,2,6,6-tetrametliylpiperidin-4-yl)-3H-[1.2.3]triazolo[4,5-cJpy'ridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol

[0102] Dioxane solvate Form SA was obtained by suspension equilibration of Form A from Example 1 in a solvent mixture of 97'3 (v / v) dioxane / FfrO at 25°C for 15 days The XRPD pattern for Form S > is shown in FIG. 11.ExamplePreparation of crystalline Form SB of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1.2.3]triazolo[ / 4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol10103] Acetic acid disolvale Form SB was obtained bv suspension equilibration of Form A trom Example i m acetic acid ai 2b°V lor 14 days. Rte XRPD pattern lor Form SE D shownExample 8Preparation of crystalline Form Sc of 2-[3-(2,2>6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol Formic acid disolvate Form Sc was obtained by ev aporation oi FormExample 9Preparation of crystalline Form SD of2-[3-(2,2,6,6-tetramelhyipiperidin-4-yl)-3H-[1,2,3]triazo]o[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol

Claims

CLAIMSW e claim:

1. A crystalline form of 2-[3-(2,2,6,6-tetramelhyipiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c] pyridazin-6~y 1] -5-(2H- 1.2, 3 -tri azol -2-yl )phen ol .

2. A crystalline Form A of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3 |triazolo[4,5- cjpyridazin-6-yl]-5-(2H-1.2.3-triazol-2-yl)phenoL3. The crystalline form according to claims 1 or 2 characterized by having an x-ray powder diffraction patern comprising reflections at 2-Theta angles of 4.5 ± 0.2°, 9.0 ± 0.2° and 16.6 ± 0.2°. when measured with Cu-Kalpha radiation.4 The crystalline form according to claims 1 to 3, characterized by having an x-ray powder diffraction patern comprises reflections at 2-Theta angles of 4.5 ± 0.2°, 9.0 ± 0.2°, 16.6 ± 0.2°, 21 . 1 i 0.2° and 25.3 i 0.2° when measured with Cu-Kalpha radiation.

5. A ciysiallmc Form A of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6~yl]-5-(2H-1,2,3-triazol-2~yi)phenoi characterized by having an x-ray powder diffraction patern comprising three, four, five or more 2 theta values selected from the group consisting of 4.5 ± 0.2°, 8 1 ± 0.2°, 9.0 ± 0.2°, 1 1.9 ± 0.2°, 12.2 ± 0.2°, 13.2 ± 0 2°, 13.5 ± 0.2°. 14.2 ± 0.2°, 14.6 ± 0.2°, 15.0 ± 0.2°, 15 3 ± 0.2°, 15.7 ± 0.2°, 16.6 ± 0.2°, 17.0 ± 0.2°, 17.2 ± 0.2°, 17.7 ± 0.2°, 18.0 ± 0.2°, 19.0 ± 0.2°, 19.8 ± 0.2°, 20.0 ± 0.2°, 20.2 ± 0.2°, 20.4 ± 0.2°. 21 . 1 ± 0.2°, 22.8 ± 0.2°, 23.3 ± 0 2°, 23.8 ± 0.2°. 24.3 ± 0.2°, 24.9 ± 0 2°,25.3 ± 0.2°, 25.8 ± 0.2°, 26.3 ± 0.2°, 27. 1 ± 0 2°, 27.3 ± 0 2°, 27.7 ± 0 2°, 28.0 ± 0.2°. and28.4 ± 0.2°, when measured with Cu-Kalpha radiation.

6. A crystalline Form A of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2.3]triazolo[4,5- c]pyridazin-6-yi]-5-(2H-1,2,3-triazol-2-yl)phenol characterized by the x-ray powder diffraction pattern shown in FIG 1.7 The crystalline form according to any one of claims 1 to 6 characterized by having endothermic events at about 193°C and at about 261°C in differential scanning calorimetry (DSC) thermogram profile.

8. Hie crystalline form according to any one of claims 1 to 7 characterized by having a thermogravimetry coupled fouri er transform infrared (TG-FTIR) spectroscopy thermogram showing decomposition occurring at temperatures of about 270°C.

9. The crystalline form according to any one of claims 1 to 8 characterized by having an FT- RAMAN spectrum at least one, more preferably al least two, still more preferably at least four, and most preferably all, of the RAMAN bands at about 3123. 3107, 3075. 2974, 1620, 1610, 1590, 1458, 1397, 1377, 1335, 1319. 1305, 1291, 1266. 1259, 1230, 1188. 1166, 1 138, 1126, 1082, 1064, 1028, 971, 960, 900, 827, 770, 742, 713, 625, 580, 550, 531, 446, 377, 345, 330, 256, 241 , 180, 163, 141, 108. 101 cm -1.

10. A crystalline Form B of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6-yl] -5-(2H-1,2,3-triazol-2-yl)phenol.

11. The crystalline form according to claims 1 and 10 characterized by having an x-ray powder diffraction pattern comprising reflections at 2-Theta angles of 5.2 ± 0.2°, 6.0 ± 0.2° and 15.8 * 0.2°, when measured with Cu-Kalpha radiation.

12. The crystalline form according to claims 1.

10. and 11. characterized by having an x-ray powder diffraction pattern comprises reflections at 2-Theta angles of 5.2 ± 0.2°, 6.0 * 0.2°, 10.5 ± 0.2°, 12.6 ± 0.2° and 15.8 ± 0.2°, when measured with Cu-Kalpha radiation.

13. A crystalline Form B of 2-[3-(2,2,6,6-tetramethylpiperidin-4-y1)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol characterized by having an x-ray powder diffraction pattern comprising three, four, five or more 2 theta values selected from the group consisting of 5.2 ± 0.2°, 6.0 ± 0.2°, 8.7 ± 0.2°, 10.5 * 0.2°, 12.0 ± 0.2°, 12,6 ± 0.2°, 12.9 * 0.2°, 14.5 ± 0.2°, 14.8 * 0.2°, 15.0 * 0.2°, 15.8 ± 0 2°, t 7.4 . 0.2 . 17.6 * 0.2°, 17.8 i 0 2°, 18.0 * 0.2°, 18.4 * 0 2°, 19.0 + 0.2°, 19.2 * 0.2°, 19.9 ± 0.2°, 22.7 i 0.2°, 23.3 * 0.2°, 23.7 ± 0.2°, 24.0 * 0.2°, 24.5 ± 0.2°, 25.0 ± 0.2°, 25.4 * 0.2°. 25.8 ± 0.2°, 26.2 ± 0.2°, and 27.6 * 0.2°, when measured with Cu-Kalpha radiation.

14. A crystalline Form B of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5- c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol characterized by the x-ray powder diffraction pattern shown in FIG.

515. The crystalline form according to any one of claims 1, 10 to 14 characterized by having an endothermic ev ent at about 260°C in differential scanning calorimetry (DSC) thermogram profile.

16. The crystalline form according to any one of claims 1 , 10 to 15 characterized by having a thermogravimetry' coupled fouri er transform infrared (TG-FTIR) spectroscopy thermogram showing mass changes from about 25°C to about 140°C and from about 140°C to about 210°C,17. The cry stalline form according to any one of claims 1, 10 to 16 characterized by having an FT-RAMAN spectrum al least one, more preferably at least two, still more preferably al least four, and most preferably all. of the RAMAN bands al about 3145. 2974, 2931 , 1629, 1611, 1462. 1401, 1376, 1340, 1325, 1307, 1295, 1271, 1215, 1164, 1058, 996, 900, 836, and 706 cm -1.

18. A pharmaceutical composition comprising a crystalline form of claims 1-17, and a pharmaceutically acceptable carrier.

19. A process for the preparation of crystalline Form A of 2-[3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3H~[1,2,3]iriazolo|4,5-cjpyridazm-6-yl]-5-(2H-1,2,3-lriazoi-2-yi)phenol comprising: (a) dissolving 2-[3-(2,2.6,6-tetramethylpiperidin-4-yl)-3H-| 1,2,3jtnazolo[4,5- c]pyridazm-6-yl]-5-(2H-1,2,3-triazol-2~yl)phenol in N,N-dimethy1formamide; (b) adding water; and optionally (c) isolating crystalline Form A of2-[3-(2,2,6,6-tetramethylpiperidin- 4-yl)-3H-[I,2,3|triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol.

20. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a cry stalline form of 2-[3-(2,2,6,6-lelramethylpiperidin-4-yl)-3H-[1,2,3] triazolo[4,5- c]pyridazin-6-yl]-5~(2H-1.2.3-triazol-2-yl)phenol according to any one of Claims 1-19; and (b) at least one pharmaceutically' acceptable carrier, diluent, vehicle or excipient21 . The pharmaceutical composition of Claim 20. wherein the crystalline form is Form A of 2- [3-(2,2,6,6-tetrameihylpiperidin-4-yl)-3H-j 1 ,2,3 jtriazoIo[4,5-c|pyridazin-6-yl]-5-(2H-1 ,2,3-tri azol-2-yl)phenol.

22. A method of treating or ameliorating Huntington’s Disease comprising the step of administering to a subject in need of such treatment a therapeutically' effective amount of a cry' stall ine form of 2-[3-(2,2,6,6-telramethyIpiperidin-4-yl)-3H-[ 1,2,3 ] triazolo[4,5- c]pyridazm-6-yl]-5-(2H-1.2.3-triazol-2-yl)phenol according to any one of Claims 1 -17 or the pharmaceutical composition of claims 20-21.

23. The method of claim 22. wherein the crystalline form is Form A of 2-[3~(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3Jtriazolo|4,5-clpyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yl)phenol.

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