Crystal form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-C]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol

Abstract

The present invention describes a specific crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. The present invention further relates to a method for preparing the crystalline form, a pharmaceutical composition comprising the crystalline form, and a method for using the crystalline form and the pharmaceutical composition comprising the crystalline form to treat Huntington's disease.

Description

[Technical Field] 【0001】 The present invention relates to the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, a method for producing the same, a pharmaceutical composition containing the same, and a method for using the same in the treatment of Huntington's disease. [Background technology] 【0002】 Polymorphism refers to the existence of two or more crystalline forms of a substance. Polymorphisms (or crystalline modifications) have the same chemical structure but often possess very different physicochemical properties. Polymorphisms include tautomorphisms and monomorphisms. This ability of chemical substances to crystallize in two or more crystalline forms can significantly affect the shelf life, solubility, formulation properties, and processing properties of drugs. Furthermore, the action of a drug can be affected by polymorphisms of the drug molecule. Different polymorphisms result in different rates of uptake into the body, potentially leading to lower or higher biological activity than desired. In extreme cases, undesirable polymorphisms may even be toxic. The occurrence of unknown crystalline forms during manufacturing can have significant consequences. 【0003】 Understanding and controlling polymorphisms provides a significant advantage in bringing new drugs to market. Firstly, exploring all possible polymorphisms for a drug product can be used to reduce the likelihood of contamination during the manufacture or storage of the drug by other polymorphic forms. Failure to capture contamination can, in some cases, lead to life-threatening consequences. Crystallization of an unintended polymorph during manufacturing can mean a production shutdown of several weeks or even months while scientists discover and correct the cause of the new crystal form, or undergo another round of testing to obtain approval for the new crystal form. 【0004】 Secondly, understanding which crystalline form of a drug is possible under specific circumstances allows researchers to maximize desired properties of the compound, such as solubility, formulation properties, processing properties, and shelf life. Understanding these factors early in the development of new drugs can mean producing drugs that are more active, more stable, or less expensive to manufacture. 【0005】 Huntington's disease (HD) is a rare hereditary neurodegenerative disorder caused by mutations in the huntingtin (HTT) gene. The disorder results in behavioral, cognitive, and motor impairments. These symptoms gradually reduce an individual's quality of life and ultimately lead to death within 15 to 25 years of the onset of apparent clinical motor symptoms. Each child of a parent with a mutation in the huntingtin gene has a 50% chance of inheriting the mutation. It is estimated that approximately 1 in 10,000 people carry the mutated huntingtin gene. Current HD therapies manage the severity of symptoms, but there are currently no approved treatments that slow the progression of the disease. 【0006】 The international application, published as International Publication No. 2020 / 005873, identifies a genus of compounds that may be used in the treatment of Huntington's disease (HD), a method for producing them, and a pharmaceutically acceptable formulation thereof, which is incorporated herein by reference in its entirety. One such compound is of the formula [ka] It is 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. 【0007】 Knowledge of the potential polymorphisms of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is useful in the development of a suitable dosage form, because if a single polymorphism is not available during clinical or stability studies, the exact dosage form being used or studied may not be comparable between lots. If selected, it is important that the polymorphism is prepared reproducibly and remains unchanged over long periods in the developed dosage form. 【0008】 International Publication No. 2020 / 005873A1 of the Brochure does not provide information on possible crystalline modifications of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol. Therefore, novel crystalline forms of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol could facilitate the development of the compound's drug product in the treatment of Huntington's disease. The present invention provides such a novel crystalline form, for example, the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. [Overview of the Initiative] 【0009】 The present invention relates to the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. 【0010】 The present invention is directed to a method for generating, isolating and / or characterizing various 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. 【0011】 The 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-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol of the present invention; and (b) at least one pharmaceutically acceptable carrier. 【0012】 The present invention is also directed to a method of treating or ameliorating Huntington's disease, comprising 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-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol of the present invention or a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form 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 of the present invention. 【Brief Description of the Drawings】 【0013】 [Figure 1] Figure 1 shows an X-ray powder diffraction (XRPD) pattern for crystalline 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-yl)phenol according to the present invention. [Figure 2]Figure 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 3] Figure 3 shows a thermogravimetric integrated Fourier transform infrared (TG-FTIR) thermogram of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 4] Figure 4 shows the Fourier transform Raman (FT-Raman) spectrum of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 5] Figure 5 shows the X-ray powder diffraction (XRPD) pattern for crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 6] Figure 6 shows a differential scanning calorimetry (DSC) thermogram of crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 7]Figure 7 shows a thermogravimetric integrated Fourier transform infrared (TG-FTIR) thermogram of crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 8] Figure 8 shows the Fourier transform Raman (FT-Raman) spectrum of crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 9] Figure 9 shows the X-ray powder diffraction (XRPD) pattern for crystalline form C of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 10] Figure 10 shows the X-ray powder diffraction (XRPD) pattern for the trihydrate crystal form HA of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 11] Figure 11 shows the XRPD pattern for the solvate form SA of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 12] Figure 12 shows the XRPD pattern for the solvate form SB of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 13] Figure 13 shows the XRPD pattern for the solvate form Sc of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Figure 14] Figure 14 shows the XRPD pattern for the solvate form SD of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to the present invention. [Modes for carrying out the invention] 【0014】 In the context of this invention, the following definitions have the meanings shown unless otherwise explicitly stated. 【0015】 References to values ​​or parameters "about" in this specification include (and shall be described) variations directed toward the value or parameter itself. For example, a statement referring to "about X" includes a statement of "X". 【0016】 When used herein, the terms "a" or "an" mean one or more unless otherwise clearly indicated by the context. 【0017】 As used herein, the terms "room temperature" or "RT" refer to temperatures in the range of 20 to 30°C. 【0018】 As used herein, the term "reflection" in relation to X-ray powder diffraction (XRPD) refers to a peak in an X-ray diffractogram caused at a specific diffraction angle (Bragg angle) by constructive interference from X-rays scattered by parallel planes of atoms in a solid material, which are distributed in a regular, repeating pattern with long-range positional order. Such solid materials are classified as crystalline materials, while amorphous materials are defined as solid materials that lack long-range order and exhibit only short-range order, resulting in widespread scattering. According to the literature, long-range order extends, for example, over approximately 100 to 1000 atoms, while short-range order extends over only a few atoms (see "Fundamentals of Powder Diffraction and Structural Characterization of Materials" by Vitalij K. Pecharsky and Peter Y Zavalij, Kluwer Academic Publishers, 2003, p. 3). 【0019】 The crystalline morphology of the present invention may be referred to herein as characterized by graph data, e.g., XRPD, “shown in the drawings.” Those skilled in the art will understand that factors such as variations in the type of instrument, sample orientation, sample concentration, and sample purity can lead to small variations in such data, e.g., variations in precise peak position and peak intensity, when presented in graph form. However, the comparison of the graph data in the drawings herein with graph data generated for another or unknown solid morphology, and the assurance that the two sets of graph data relate to the same crystalline morphology, is well within the knowledge of those skilled in the art. 【0020】 The terms “solid form” or “solid state form” as used interchangeably herein refer to any crystalline and / or amorphous phase of a compound. 【0021】 As used herein, the term "amorphous" refers to the solid form of a compound that is not crystalline. Amorphous compounds do not possess long-range order and do not exhibit XRPD patterns with distinct reflections. 【0022】 As used herein, the term "polymorph" refers to a crystalline form having the same chemical composition but with a different spatial arrangement of molecules, atoms, and / or ions that form the crystal. 【0023】 As used herein, the term "hydrate" refers to a crystalline solid in which water cooperates within or adapts to the crystalline structure, for example, being part of the crystalline structure or trapped within the crystal (water inclusion). Thus, water may exist in stoichiometric or non-stoichiometric amounts. When water is present in stoichiometric amounts, the hydrate may be named by adding a Greek number prefix. For example, the hydrate may be named a hemihydrate or monohydrate depending on the water / compound stoichiometry. The water content may be measured, for example, by Karl Fischer coulometry. 【0024】 When used herein, the terms "dehydration" or "dewatering" describe the at least partial removal of water from the crystalline structure of a host molecule. 【0025】 The term "solvate," as used herein, refers to a crystalline solid in which one or more organic solvents cooperate in or adapt to a crystalline structure, e.g., are part of a crystalline structure or are trapped in a crystal (water-enclosed). Thus, one or more organic solvents may be present in stoichiometric or non-stoichiometric amounts. If one or more organic solvents are present in stoichiometric amounts, the solvate may be named by adding a Greek numerical prefix. For example, a solvate may be named a half-solvate or monosolvate depending on the solvent / compound stoichiometry. Solvent content may be measured, for example, by GC, NMR, SXRD, and / or TGA / MS. 【0026】 The term "pharmaceutically acceptable excipient," as used herein, refers to a substance that does not exhibit significant pharmacological activity at a given dose and is added to a pharmaceutical composition in addition to the active pharmaceutical component. Excipients may, among other functions, serve as a vehicle, diluent, release agent, disintegrant, solubilizer, absorption enhancer, stabilizer, or manufacturing aid. 【0027】 Excipients may include fillers (diluents), binders, disintegrants, lubricants, and flow enhancers. 【0028】 The terms “filler” or “diluent,” as used herein, refer to substances that may be used to dilute the active pharmaceutical ingredient before delivery. Diluents and fillers may also function as stabilizers. 【0029】 As used herein, the term “binder” refers to a substance that binds together an active pharmaceutical ingredient and a pharmaceutically acceptable excipient in order to maintain the adherent and discrete portions. 【0030】 The terms "disintegrant" or "disintegrating agent," as used herein, refer to a substance that, when added to a solid pharmaceutical composition, promotes its degradation or disintegration after administration, thereby enabling the release of the active pharmaceutical component as efficiently as possible to facilitate its rapid dissolution. 【0031】 As used herein, the term "lubricant" refers to a substance added to a powder blend to prevent the compressed powder mass from sticking to the equipment during the tableting or capsuleing process. They can help expel tablets from the mold and improve powder flow. 【0032】 As used herein, the term "flow enhancer" refers to a substance used for tablet and capsule formulations to improve the flow properties during tablet compression and to produce an anticoagulant effect. 【0033】 One aspect of the present invention provides distinguishable crystalline forms of the compound 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. These “crystalline forms” (or “crystal form” or “crystal modification” or “polymorph” or “polymorph” (if these terms are used interchangeably herein)) differ with respect to thermodynamic stability, physical parameters, X-ray structure and preparation method. 【0034】 Polymorphs exist in two categories: interconvertible and monoconvertible. An "interconvertible" polymorph is one that can be interconverted depending on temperature at a given pressure or pressure at a given temperature (called the transition temperature or pressure). Relative thermodynamic stability is reversed above and below the transition temperature or pressure. If a polymorph is more stable regardless of temperature, it is a "monoconvertible." Classically, polymorphism refers to the ability of a compound to crystallize into two or more distinguishable crystalline species (having the same chemical structure but very different physicochemical properties), whereas the term pseudopolymorph is typically applied to solvate and hydrate crystalline forms. However, for the purposes of this invention, both true polymorphs and pseudopolymorphs, i.e., both hydrate and solvate forms, are included in the range of "crystalline forms." Also, "amorphous" refers to a disordered solid state. It should be noted that different samples of a particular crystalline form may share the same major X-ray powder diffraction (XRPD) "peaks" or "reflections," but variations in the powder pattern may exist with respect to minor peaks. Furthermore, with respect to the XRPD peak value (degrees), the term "approximately" usually means within 0.3°, more preferably within 0.2°, and most preferably within 0.1° of a given value. Alternatively, the term "approximately" means within the allowable standard error (in this context and all contexts) as considered by those skilled in the art. 【0035】 In one embodiment, a crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is provided, referred to as crystalline form A. 【0036】 In another embodiment, crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is characterized by the XRPD pattern in Figure 1. The angular positions of characteristic peaks in the XRPD pattern for form A are listed in Table A. 【0037】 [Table 1] 【0038】 In one embodiment, the present invention relates to crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions provided in Table A. 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 may vary by ±0.05. In some embodiments, the angular positions may vary by ±0.02. 【0039】 In one embodiment, the present invention measures using Cu-K alpha radiation. 4.5±0.2°, 9.0±0.2°, and 16.6±0.2°; or 4.5±0.2°, 9.0±0.2°, 16.6±0.2°, 21.1±0.2° and 25.3±0.2°; or This relates to crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by having an XRPD pattern that includes reflections at 2-theta angles (2-theta values) of 4.5±0.2°, 9.0±0.2°, 13.2±0.2°, 13.5±0.2°, 14.2±0.2°, 15.3±0.2°, 16.6±0.2°, 18.0±0.2°, 19.8±0.2°, 21.1±0.2°, 25.3±0.2°, 25.8±0.2° and 26.3±0.2°. 【0040】 In another embodiment, the crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol was measured using Cu-K alpha radiation to 4.5±0.2°, 8. 1±0.2°, 9.0±0.2°, 11.9±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 Characterized by having an XRPD pattern that includes at least three, at least four, at least five, or all 2-theta values ​​selected from the group consisting of 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°, and 28.4±0.2°. 【0041】 Crystalline morphology A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol can be thermally characterized. In one embodiment, morphology A is characterized by a DSC thermogram showing three endothermic temperatures, namely a small endothermic temperature at 193.4°C (starting at 189.4°C) and two large overlapping endothermic temperatures at 261.2°C (starting at 260.6°C) and 261.7°C (starting at 260.6°C). In another embodiment, morphology A is characterized by a DSC thermogram substantially as shown in Figure 2. In one embodiment, morphology A is characterized by a TG-FTIR thermogram showing decomposition at a temperature of approximately 270°C. In another embodiment, morphology A is characterized by a TG-FTIR thermogram, substantially as shown in Figure 3. 【0042】 Crystal morphology A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol can also be characterized by Raman spectroscopy. In one embodiment, morphology A is approximately 3123, 3107, 3075, 2974, 1620, 1610, 1590, 1458, 1397, 1377, 1335, 1319, 1305, 1291, 1266, 1259, 1230, 1188, 1166, 1138, 1126, 1082, 1064, 1028, 971, 960, 900, 827, 770, 742 It is characterized by an FT-Raman spectrum having at least one, more preferably at least two, even more preferably at least four, and most preferably all of the Raman bands at 713, 625, 580, 550, 531, 446, 377, 345, 330, 256, 241, 180, 163, 141, 108, and 101 cm⁻¹. In another embodiment, form A is characterized by an FT-Raman spectrum substantially as shown in Figure 4. 【0043】 In one embodiment, a crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is provided, referred to as crystalline form B. 【0044】 In another embodiment, crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is characterized by the XRPD pattern in Figure 5. The angular positions of characteristic peaks in the XRPD pattern for form B are listed in Table B. 【0045】 [Table 2] 【0046】 In one embodiment, the present invention relates to crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions 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 may vary by ±0.05. In some embodiments, the angular positions may vary by ±0.02. 【0047】 In one embodiment, the present invention measures using Cu-K alpha radiation. 5.2±0.2°, 6.0±0.2°, and 15.8±0.2°; or 5.2±0.2°, 6.0±0.2°, 10.5±0.2°, 12.6±0.2° and 15.8±0.2°; or This relates to crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by having an XRPD pattern that includes reflections at 2-theta angles (2-theta values) of 5.2±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°. 【0048】 In another embodiment, the crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol was measured using Cu-K alpha radiation and yielded the following values: 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°, 1 Characterized by having an XRPD pattern that includes at least three, at least four, at least five, or all 2-theta values ​​selected from the group consisting of 7.6±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°. 【0049】 Crystalline morphology B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol can be thermally characterized. In one embodiment, morphology B is characterized by a DSC thermogram showing a single melting endotherm at 260.3°C (starting at 259.5°C). In another embodiment, morphology B is characterized by a DSC thermogram substantially as shown in Figure 6. In one embodiment, morphology A is characterized by a TG-FTIR thermogram showing mass changes from 25°C to 140°C and from 140°C to 210°C, followed by decomposition at higher temperatures. In another embodiment, morphology B is characterized by a TG-FTIR thermogram substantially as shown in Figure 7. 【0050】 Crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol can also be characterized by Raman spectroscopy. In one embodiment, form B is characterized by an FT-Raman spectrum having at least one, more preferably at least two, even more preferably at least four, and most preferably all of the Raman bands at approximately 3145, 2974, 2931, 1629, 1611, 1462, 1401, 1376, 1340, 1325, 1307, 1295, 1271, 1215, 1164, 1058, 996, 900, 836, and 706 cm⁻¹. In another embodiment, form B is characterized by an FT-Raman spectrum, substantially as shown in Figure 8. 【0051】 In one embodiment, a crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is provided, referred to as crystalline form C. Form C was isolated by heating form A to 225°C. Form C spontaneously reverts back to form A upon cooling to ambient temperature. In another embodiment, crystalline form C of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is characterized by the XRPD pattern in Figure 9. The angular positions of characteristic peaks in the XRPD pattern for form C are listed in Table C. 【0052】 [Table 3] 【0053】 In one embodiment, the present invention relates to the crystalline form C of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions provided in Table C. 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 may vary by ±0.05. In some embodiments, the angular positions may vary by ±0.02. 【0054】 In one embodiment, the present invention measures using Cu-K alpha radiation. 4.0±0.2°, 7.9±0.2°, and 13.5±0.2°; or 4.0±0.2°, 7.9±0.2°, 13.5±0.2°, 14.4±0.2° and 17.7±0.2°; or 4.0±0.2°, 7.9±0.2°, 12.0±0.2°, 12.6±0.2°, 13.5±0.2°, 14.4±0.2°, 14.7±0.2°, 15.2±0.2°, 15.6±0.2°, 16.0±0.2°, 17.7±0.2°, 19.0±0.2°, 19.6±0.2°, 24.9±0.2° and 25.8±0.2° This relates to the crystalline form C of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by having an XRPD pattern that includes reflection at a 2-theta angle (2-theta value). 【0055】 In another embodiment, the crystalline morphology C of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol was measured using Cu-K alpha radiation and yielded the following values: 4.0±0.2°, 7.9±0.2°, 12.0±0.2°, 12.6±0.2°, 13.5±0.2°, 14.4±0.2°, 14.7±0.2°, 15.2±0.2°, 15.6±0.2°, 16.0±0.2°, 16.4±0.2°, and 16.9±0. Characterized by having an XRPD pattern that includes at least three, at least four, at least five, or all 2-theta values ​​selected from the group consisting of 0.2°, 17.7±0.2°, 18.1±0.2°, 19.0±0.2°, 19.6±0.2°, 20.0±0.2°, 20.4±0.2°, 21.2±0.2°, 22.0±0.2°, 22.6±0.2°, 22.8±0.2°, 23.5±0.2°, 24.2±0.2°, 24.9±0.2°, 25.8±0.2°, 26.4±0.2°, and 26.8±0.2°. 【0056】 In one embodiment, the trihydrate crystal form H AThe crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, referred to as morphology H, is provided. A It was isolated in a suspension equilibrium study of form A in a solvent mixture of 9:1 (v / v) tetrahydrofuran / H2O. In another embodiment, the crystalline form H of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol A This is characterized by the XRPD pattern in Figure 10. Morphology H A The angular positions of characteristic peaks in the XRPD pattern for this are listed in Table D. 【0057】 [Table 4] 【0058】 In one embodiment, the present invention relates to the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions provided in Table D. A Regarding this, in some embodiments, the angular position may vary by ±0.2. In some embodiments, the angular position may vary by ±0.1. In some embodiments, the angular position may vary by ±0.05. In some embodiments, the angular position may vary by ±0.02. 【0059】 In one embodiment, the present invention measures using Cu-K alpha radiation. 7.8±0.2°, 13.2±0.2°, and 25.4±0.2°; or 7.8±0.2°, 13.2±0.2°, 14.5±0.2°, 25.4±0.2° and 26.7±0.2°; or The crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol is characterized by having an XRPD pattern that includes reflections at 2-theta angles (2-theta values) of 7.8±0.2°, 8.2±0.2°, 11.5±0.2°, 12.4±0.2°, 13.2±0.2°, 14.5±0.2°, 14.7±0.2°, 15.0±0.2°, 15.8±0.2°, 16.4±0.2°, 25.4±0.2° and 26.7±0.2°. A Regarding. 【0060】 In another embodiment, the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol H A The following measurements were taken using Cu-K alpha radiation, yielding values ​​of 7.8±0.2°, 8.2±0.2°, 11.5±0.2°, 12.4±0.2°, 13.0±0.2°, 13.2±0.2°, 13.7±0.2°, 13.9±0.2°, 14.5±0.2°, 14.7±0.2°, 15.0±0.2°, 15.8±0.2°, 16.4±0.2°, 17.3±0.2°, 18.5±0.2°, 18.8±0.2°, 19.6±0.2°, 19.8±0.2°, 20.6±0.2°, 20.9±0.2°, 21.7±0.2°, 22.1±0.2°, 22.4±0.2°, and 2 Characterized by having an XRPD pattern that includes at least three, at least four, at least five, or all 2-theta values ​​selected from the group consisting of 4.5±0.2°, 25.4±0.2°, 25.7±0.2°, 25.9±0.2°, 26.2±0.2°, 26.7±0.2°, 27.0±0.2°, 27.6±0.2°, 28.1±0.2°, 28.9±0.2°, 29.3±0.2°, 29.6±0.2°, 30.1±0.2°, 31.7±0.2°, 32.9±0.2°, 33.3±0.2°, and 33.6±0.2°. 【0061】 In addition, several solvates were discovered during the equilibrium suspension and evaporation studies of crystalline 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-yl)phenol. The dioxane solvate form S A , and the acetic acid disolvate form S B were isolated in suspension equilibrium studies using their respective solvents. The formic acid disolvate form S C was isolated in the evaporation study, and the formic acid monosolvate form S C was obtained by drying form S D . The solvate forms S A , S B , S C , and S D can be characterized by their XRPD patterns as shown in Figures 11 to 14, respectively. 【0062】 The angular positions of the characteristic peaks in the XRPD patterns for the solvate forms S A , S B , S C , and S D are listed in Tables S1, S2, S3, and S4, respectively. 【0063】 【Table 5】 【0064】 【Table 6】 【0065】 【Table 7】 【0066】 【Table 8】 【0067】 In one embodiment, the present invention relates to the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions provided in Table S1. A Regarding this, in some embodiments, the angular position may vary by ±0.2. In some embodiments, the angular position may vary by ±0.1. In some embodiments, the angular position may vary by ±0.05. In some embodiments, the angular position may vary by ±0.02. 【0068】 In one embodiment, the present invention relates to the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions provided in Table S2. B Regarding this, in some embodiments, the angular position may vary by ±0.2. In some embodiments, the angular position may vary by ±0.1. In some embodiments, the angular position may vary by ±0.05. In some embodiments, the angular position may vary by ±0.02. 【0069】 In one embodiment, the present invention relates to the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions provided in Table S3. C Regarding this, in some embodiments, the angular position may vary by ±0.2. In some embodiments, the angular position may vary by ±0.1. In some embodiments, the angular position may vary by ±0.05. In some embodiments, the angular position may vary by ±0.02. 【0070】 In one embodiment, the present invention relates to the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by 3, 4, 5, 6, 7, 8, 9, 10 or more angular positions provided in Table S4. D Regarding this, in some embodiments, the angular position may vary by ±0.2. In some embodiments, the angular position may vary by ±0.1. In some embodiments, the angular position may vary by ±0.05. In some embodiments, the angular position may vary by ±0.02. 【0071】 Crystallographic forms of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol (Forms A, B, C, H A S A S B S C , and S D Various methods can be used to achieve this. Such methods are as shown above and in the examples provided below, and include equilibration with a solvent, crystallization at room temperature, crystallization from a high-temperature saturated solution, precipitation by addition of a solvent, evaporation with a solvent, vapor diffusion with a solvent, and drying / desolvation. 【0072】 Another embodiment of the present invention relates to (a) a therapeutically effective amount of the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol according to one of the prior embodiments of the present invention; and (b) a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient. 【0073】 In one embodiment, the pharmaceutical composition is one comprising (a) a therapeutically effective amount of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol according to one of the prior embodiments of the present invention; and (b) a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient. 【0074】 The terms “therapeutic effective amount” or “effective amount” of Compound 1, as used herein, refer to the amount of the inventive crystalline form of the present invention that, when administered to a subject in need, would induce a biological or medical response in that subject. In another embodiment, the term refers to the amount of the inventive crystalline form of the present invention that, when administered to a subject, would be effective in at least partially improving a pathological condition, disorder, or disease. The amount of a given compound of the present invention that would be therapeutically effective would vary depending on factors such as the disease state and its severity, and the identity of the subject in need, but the amount can be routinely determined by those skilled in the art. 【0075】 "At least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient" may be readily selected by those skilled in the art and will be determined by the desired mode of administration. Exemplary examples of preferred modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal. The pharmaceutically active compositions of the present invention may take any pharmaceutically active form that is recognized as suitable by those skilled in the art. Suitable pharmaceutically active forms include solid, semi-solid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. 【0076】 Another aspect of the present invention relates to a method for treating or improving Huntington's disease, comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol of the present invention to a subject requiring such treatment. 【0077】 The terms “to treat,” “to treat,” “treatment,” or “therapy,” as used herein, refer to obtaining a beneficial or desired outcome, such as a clinical outcome. Beneficial or desired outcomes may include, but are not limited to, stabilizing or improving the progression of stages of hemodialysis (e.g., compared to a placebo). One aspect of a treatment is, for example, that the treatment should have minimal adverse effects on the patient, such as that the agent used should have a high level of safety without causing adverse side effects. In another aspect, the term “method for treatment,” as used herein, refers to “a method for treatment.” 【0078】 In one embodiment, the present invention relates to a method for treating or improving Huntington's disease, comprising the step of administering a therapeutically effective amount of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol of the present invention to a subject in need of such treatment. In another embodiment, the present invention relates to a method for treating or improving Huntington's disease, comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol of the present invention to a subject in need of such treatment. As described above, exemplary modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal administration. Administration of the crystalline form can be achieved by administering the pharmaceutical composition of the present invention or by any other effective means. 【0079】 Specific embodiments of the present invention will now be described by reference to the following examples. These examples are disclosed merely to illustrate the present invention and should not be construed as limiting the scope of the invention in any way. [Examples] 【0080】 The following abbreviations are used throughout this disclosure in relation to chemical and biological terminology. DSC: Differential Scanning Calorimetry FT-IR: Fourier Transform Infrared HPLC: High-Performance Liquid Chromatography NMR: nuclear magnetic resonance spectroscopy RH: Relative humidity RT: room temperature TGA: Thermogravimetric analysis XRPD: X-ray Powder Diffraction 【0081】 The following examples include illustrative aspects of the present invention. These examples should not be construed as limiting. 【0082】 General test conditions The following procedure was used under each test condition. 【0083】 Differential Scanning Calorimetry (DSC) The DSC instrument used to test the crystal morphology was a Thermal Analysis Q2000 in a closed (sealed) gold or aluminum crucible. Samples were packed under ambient conditions or under a nitrogen stream (3–10 minutes) (heating rate of 10 K min⁻¹ and temperature range of -50°C to 285°C). 【0084】 Fourier transform-Raman (FT-Raman) spectroscopy Instrument: Bruker MultiRAM (equipped with OPUS 7.0 software); Nd:YAG 1064nm excitation, nominal laser power of 100-300mW, Ge detector, 64-256 scans, spectral range of 3500-100cm⁻¹, resolution of 2cm⁻¹. Samples were measured using an aluminum sample holder. 【0085】 Integrated Fourier Transform Infrared (TG-FTIR) Spectroscopy of Thermogravimetric Analysis The TG-FTIR spectral range of the samples used was recorded using a Netzsch Thermo-Microbalance TG209 equipped with a Bruker FT-IR Spectrometer IFS28 or Vector22 in an Al crucible, under a nitrogen atmosphere, at a heating rate of 10 K min-1, and at a temperature range of 25°C to 300°C or 350°C. 【0086】 X-ray powder diffraction Except for form C, the X-ray powder diffraction (XRPD) patterns described herein were recorded at room temperature using a Bruker D8 Advance diffractometer with CuK alpha rays (wavelength 1.5406 Å), 40 kV / 40 mA, LynxEye detector, Bragg-Brentano reflection configuration, 0.02°²θ step size, 37 sec step time, and a ²θ range of 2.5–50°. Powder samples were measured in a silicon single crystal sample holder with a depth of 0.1 mm. No special procedures were used in sample preparation except for applying slight pressure to obtain a flat surface. Ambient air was used for all measurements. 【0087】 X-ray powder diffraction (XRPD) patterns described for morphology C were recorded at 225°C using a PANalytical X'Pert PRO-MPD with CuK alpha (wavelength 1.5406 Å), 45 kV / 40 mA, PIXCEL detector, Bragg-Brentano reflection configuration, 0.0131°²θ step size, 87.72 sec step time, and a ²θ range of 3.0–33.0°. Powder samples were measured in a 0.4 mm deep nickel-coated copper sample holder without any special treatment other than applying slight pressure to obtain a flat plane. Samples were measured in a Parr TTK-450 chamber using an ambient air atmosphere. The sample was not rotated during measurement. Variable divergence slits and anti-scattering slits were used at a distance of 9.0 mm on either side of the sample, and solar slits were 0.04 radians on both sides. A heating rate of 2 K min⁻¹ was used, and the temperature was kept constant for 15 minutes, as required for each measurement. 【0088】 Those skilled in the art will understand that XRPD patterns may be obtained with measurement errors depending on the measurement conditions used. In particular, it is generally known that the intensity in an XRPD pattern may vary depending on the measurement conditions used. It should also be understood that the relative intensity may also vary depending on the experimental conditions and the wavelength of the X-ray radiation used. The agreement of the two-theta diffraction angles between the sample and the reference is within 0.2° for the same crystal morphology, and the degree of such measurement error should be considered in relation to the diffraction angles as described above. Consequently, it should be understood that the crystal morphology of the present invention is not limited to crystal morphology that provides an X-ray diffraction pattern completely identical to the XRPD pattern shown in the accompanying drawings disclosed herein. Any crystal morphology that provides an XRPD pattern substantially identical to that disclosed in the accompanying drawings falls within the scope of the present invention. The ability to verify the substantial identity of the XRPD pattern is within the capabilities of those skilled in the art. 【0089】 Example 1 Preparation of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol The starting material, 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, was prepared according to Example 37 of International Publication No. 2020 / 005873. The starting material (245 mg) and N,N-dimethylformamide (10 mL) were placed in a vial. After warming to 90°C, a clear solution was obtained. The mixture was cooled to 60°C, and then water (5 mL) was added dropwise. The resulting suspension was stirred at 60°C for 15 minutes and at room temperature for 1 hour, and then filtered. The solid cake was washed with 20 mL of water and dried at room temperature under complete vacuum to obtain 228 mg of the product, identified as morphology A by XRPD analysis, as a yellow solid. 【0090】 The XRPD pattern and FT-Raman spectrum for morphology A are shown in Figures 1 and 4, respectively. The DSC thermogram shows that morphology A exhibits three endothermic phases, namely a small endothermic phase at 193.4°C (starting at 189.4°C) and two large overlapping endothermic phases at 261.2°C (starting at 260.6°C) and 261.7°C (starting at 260.6°C), as shown in Figure 2. The TG-FTIR thermogram shows that morphology A begins to decompose at a temperature of approximately 270°C, as shown in Figure 3. 【0091】 Example 2 Solid State Stability In the solid state, samples of crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol were subjected to accelerated temperature and humidity conditions (25°C / 60%RH open, 40°C / 75%RH closed, and 40°C / 75%RH open) for up to 6 months. The HPLC conditions used for chemical stability are listed in Table 1. 【0092】 [Table 9] 【0093】 HPLC results (as shown in Tables 2 and 3) indicate that form A is chemically stable for up to 6 months under accelerated temperature and humidity conditions without any significant increase in process impurities (RRT 0.89, 0.98, 1.02, 1.04, and 1.17) or formation of degradation products. 【0094】 [Table 10] 【0095】 [Table 11] 【0096】 Form A was also found by DSC, TGA, and XRPD to be physically stable and unchanged from the initial state for 6 months under accelerated temperature and humidity conditions (25°C / 60%RH open, 40°C / 75%RH closed, and 40°C / 75%RH open). 【0097】 Example 3 Preparation of crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol The starting material, 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, was prepared according to Example 37 of International Publication No. 2020 / 005873. The starting material (118 mg) and ethyl acetate (40 mL) were placed in a vial. After heating and refluxing, a clear solution was obtained. The mixture was cooled to room temperature, stirred for 2 hours, and then filtered. The solid was dried at room temperature under complete vacuum to obtain 86 mg of the product, identified as morphology B by XRPD analysis, as a yellow solid. 【0098】 Alternatively, form B was obtained by suspension equilibrium of form A from Example 1 using a variety of solvents: methyl acetate for 15 days at 25°C, pyridine for 15 days at 25°C, dichloromethane for 12 days at 10°C, ethyl acetate for 7 days at 40°C, methyl ethyl ketone for 7 days at 40°C, 2-methyltetrahydrofuran for 7 days at 40°C, toluene for 7 days at 40°C, acetone for 12 days at 5°C, isopropyl acetate for 4 days at 60°C, and 2-methyltetrahydrofuran for 4 days at 60°C. 【0099】 The XRPD pattern and FT-Raman spectrum for morphology B are shown in Figures 5 and 8, respectively. The DSC thermogram shows that morphology B exhibits a single fusion endothermic reaction at 260.3°C (starting at 259.5°C), as shown in Figure 6. The TG-FTIR thermogram shows that morphology A undergoes mass changes from 25°C to 140°C and from 140°C to 210°C, as shown in Figure 7, followed by decomposition at higher temperatures. 【0100】 Example 4 Preparation of the crystalline form C of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol Morphology C was obtained by heating morphology A from Example 1 to 225°C. Morphology C spontaneously reverts back to morphology A when cooled to ambient temperature. The XRPD pattern for morphology C is shown in Figure 9. 【0101】 Example 5 Crystal form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol H A Preparation Form A from Example 1 is suspended in a 9:1 (v / v) tetrahydrofuran / H2O solvent mixture at 25°C for 5-15 days, resulting in trihydrate form H A Obtained. Morphology H A The XRPD pattern for this is shown in Figure 10. 【0102】 Example 6 Crystal form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol S A Preparation Form A from Example 1 is suspended in a 97:3 (v / v) dioxane / H2O solvent mixture for 15 days at 25°C, and form S of the dioxane solvate is obtained by the equilibrium of the suspension of form A. A Obtained. Form S A The XRPD pattern for this is shown in Figure 11. 【0103】 Example 7 Crystal form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol S B Preparation Form S of acetic acid disolvate obtained by suspension equilibrium of Form A from Example 1 in acetic acid at 25°C for 14 days. B Obtained. Form S B The XRPD pattern for this is shown in Figure 12. 【0104】 Example 8 Crystal form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol S C Preparation Evaporation of form A from Example 1 in formic acid under ambient conditions yields formic acid disolvate form S. C Obtained. Form S C The XRPD pattern for this is shown in Figure 13. 【0105】 Example 9 Crystal form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol S D Preparation Morphology S from Example 7 C By drying under vacuum at 40°C for 5 hours, formic acid monosolvate form S D Obtained. Form S D The XRPD pattern for this is shown in Figure 14.

Claims

[Claim 1] Crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. [Claim 2] Crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. [Claim 3] The crystalline morphology according to claim 1 or 2, characterized by having an X-ray powder diffraction pattern that includes reflections at two theta angles of 4.5 ± 0.2°, 9.0 ± 0.2°, and 16.6 ± 0.2° when measured with Cu-K alpha rays. [Claim 4] The crystalline morphology according to any one of claims 1 to 3, characterized by having an X-ray powder diffraction pattern that includes reflections at two theta angles of 4.5±0.2°, 9.0±0.2°, 16.6±0.2°, 21.1±0.2° and 25.3±0.2° when measured with Cu-K alpha rays. [Claim 5] When measured with Cu-K alpha radiation, the values ​​were 4.5±0.2°, 8.1±0.2°, 9.0±0.2°, 11.9±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°, and 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± Crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by having an X-ray powder diffraction pattern containing three, four, five or more 2-theta values ​​selected from the group consisting of 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°, and 28.4±0.2°. [Claim 6] Crystal morphology A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by the X-ray powder diffraction pattern shown in Figure 1. [Claim 7] The crystalline morphology according to any one of claims 1 to 6, characterized by having endothermic events at approximately 193°C and approximately 261°C in differential scanning calorimetry (DSC) thermogram profiles. [Claim 8] The crystalline form according to any one of claims 1 to 7, characterized by having a thermogravimetric integrated Fourier transform infrared (TG-FTIR) spectroscopy thermogram showing decomposition occurring at a temperature of approximately 270°C. [Claim 9] Approximately 3123, 3107, 3075, 2974, 1620, 1610, 1590, 1458, 1397, 1377, 1335, 1319, 1305, 1291, 1266, 1259, 12 30, 1188, 1166, 1138, 1126, 1082, 1064, 1028, 971, 960, 900, 827, 770, 742, 713, 625, 580, 550, 531, 4 The crystalline form according to any one of claims 1 to 8, characterized by having FT-Raman spectra in at least one, more preferably at least two, even more preferably at least four, and most preferably all of the Raman bands at 46, 377, 345, 330, 256, 241, 180, 163, 141, 108, and 101 cm⁻¹. [Claim 10] Crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. [Claim 11] The crystalline morphology according to claim 1 or 10, characterized by having an X-ray powder diffraction pattern that includes reflections at two theta angles of 5.2 ± 0.2°, 6.0 ± 0.2°, and 15.8 ± 0.2° when measured with Cu-K alpha rays. [Claim 12] The crystalline morphology according to any one of claims 1, 10, and 11, characterized by having an X-ray powder diffraction pattern that includes reflections at two 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-K alpha rays. [Claim 13] When measured with Cu-K alpha radiation, the values ​​were 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°, Crystalline form B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by having an X-ray powder diffraction pattern containing three, four, five or more 2-theta values ​​selected from the group consisting of 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°. [Claim 14] Crystal morphology B of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, characterized by the X-ray powder diffraction pattern shown in Figure 5. [Claim 15] The crystalline morphology according to any one of claims 1, 10 to 14, characterized by having an endothermic event at approximately 260°C in the differential scanning calorimetry (DSC) thermogram profile. [Claim 16] The crystalline form according to any one of claims 1, 10 to 15, characterized by having a thermogravimetric integrated Fourier transform infrared (TG-FTIR) spectroscopy thermogram showing mass changes from approximately 25°C to approximately 140°C and from approximately 140°C to approximately 210°C. [Claim 17] A crystalline form according to any one of claims 1, 10 to 16, characterized by having an FT-Raman spectrum in at least one, more preferably at least two, even more preferably at least four, and most preferably all of, the Raman bands at approximately 3145, 2974, 2931, 1629, 1611, 1462, 1401, 1376, 1340, 1325, 1307, 1295, 1271, 1215, 1164, 1058, 996, 900, 836, and 706 cm⁻¹. [Claim 18] A pharmaceutical composition comprising the crystalline form and a pharmaceutically acceptable carrier described in any one of claims 1 to 17. [Claim 19] A process for preparing crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, wherein (a) 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-( A process comprising: (b) dissolving 2H-1,2,3-triazole-2-yl)phenol in N,N-dimethylformamide; (b) adding water; and (c) optionally isolating crystalline form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. [Claim 20] (a) a therapeutically effective amount of the crystalline form of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol as described in any one of claims 1 to 19; and (b) a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient. [Claim 21] The pharmaceutical composition according to claim 20, wherein the crystalline form is form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol. [Claim 22] A method for treating or improving Huntington's disease, comprising the step of administering a therapeutically effective amount of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol in crystalline form as described in any one of claims 1 to 17, or a pharmaceutical composition as described in any one of claims 20 to 21, to a subject in need of such treatment. [Claim 23] The method according to claim 22, wherein the crystalline form is form A of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol.

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