A new crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine

Abstract

Novel crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine and pharmaceutical compositions containing the same are provided. Use of the novel polymorphic forms for the treatment of diseases such as atopic dermatitis (AD), pruritus, and various forms of urticaria, including subtypes of chronic idiopathic urticaria, is also disclosed.

Description

[Technical Field]

[0001] The present invention relates to novel crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, pharmaceutical compositions containing the novel crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, and the use of the novel crystalline forms for the treatment of diseases such as atopic dermatitis (AD), itch, pruritus, and various forms of urticaria, e.g., subtypes of chronic idiopathic urticaria such as cholinergic urticaria. Also provided are methods for preparing the crystalline forms of the present invention. [Background technology]

[0002] U.S. Patent No. 9,586,959 relates to, among other compounds, the compound 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine and its pharmaceutically acceptable salts, as well as pharmaceutical compositions containing same. U.S. Patent No. 9,586,959 discloses methods for preparing various salts of the compound 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0003] 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine exhibits potent histamine 4 receptor antagonistic activity and inhibits histamine-induced infiltration of inflammatory cells, such as mast cells and eosinophils. Therefore, this compound has potent anti-inflammatory and antipruritic effects and may be useful for treating various diseases, including AD, as disclosed in U.S. Patent No. 9,586,959.

[0004] Different crystalline solid forms of a chemical compound may have different physical properties, such as, for example, chemical stability, physical stability, hygroscopicity, melting point, solubility, dissolution rate, morphology, and bioavailability, that affect their suitability as the selected active ingredient of a pharmaceutical product.

[0005] Additionally, chemical substances may exist in multiple different crystalline solid forms, including different polymorphic forms that share the same sum formula (e.g., anhydrate) and different solvates of the same chemical substance that do not share the same sum formula (e.g., hemihydrate, monohydrate, dihydrate, etc.). Such crystalline solid forms have distinct crystal structures and differ in the physical properties described above. Different crystalline solid forms can be characterized by melting points, XRPD patterns, spectral properties (e.g., FT-IR, Raman, and 13 They can be distinguished from one another by their C CP / MAS-NMR and other physical and chemical properties. Chemical substances can also exist in amorphous form.

[0006] Therefore, the actual crystalline form selected plays an important role in the development and manufacture of an active pharmaceutical ingredient. When a single crystalline form is desired, it is important that the crystallization process is robust, reliably produces the desired crystalline form in polymorphically pure form, and does not change crystalline form (e.g., interconvert to different crystalline forms) during the associated manufacturing steps and / or storage.

[0007] Various salts of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine have been identified. Some salts occur as anhydrous salts, while others occur as monohydrates and dihydrates. These salts are unsuitable for pharmaceutical development because they exhibit several polymorphic forms that interconvert when dried or lose moisture at relatively low temperatures.

[0008] The novel crystalline form according to the present invention is a crystalline form of the free base of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-amine. Hereinafter, this novel crystalline form will be referred to as Form A.

[0009] Form A is thermodynamically stable and highly crystalline up to 273°C. Form A was stable in a 4-week stress test at high temperature (60°C) and high humidity (75%). Summary of the Invention

[0010] The present invention relates to Form A, a crystalline form A of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, characterized by one or more XRPD reflections at about (2θ) 7.0, 22.6, and / or 26.3 (±0.2 degrees).

[0011] The present invention also relates to a pharmaceutical composition comprising the aforementioned crystalline form and a pharmaceutically acceptable carrier.

[0012] In one embodiment, the present invention relates to a compound or pharmaceutical composition as described above for treating a disease selected from atopic dermatitis, itching, pruritus and various forms of urticaria, including chronic idiopathic urticaria subtypes. DETAILED DESCRIPTION OF THE INVENTION

[0013] The technical problem underlying the present invention is to avoid the disadvantages of other crystalline and / or amorphous forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, such as crystal forming ability, filtration properties, solubility, thermodynamic properties, stability issues (e.g., due to water absorption), density, and transformations (e.g., interconversion to other polymorphic forms or hydrates / anhydrates) at different humidities and during the crystallization process.

[0014] Hundreds of crystallization experiments have resulted in several polymorphic forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0015] Of these, pure forms A, E and F were obtained, but only form A was stable during mild drying, and attempts to produce pure forms E and F in large quantities were unsuccessful.

[0016] definition As used herein, the term "rt" or "room temperature" indicates that the temperature applied is not critical and that a precise temperature value need not be maintained. Typically, "rt" or "room temperature" is understood to mean a temperature of about 15°C to about 25°C [see, e.g., EU Pharmacopoeia 7.5, 1.2 (2012)].

[0017] The term "solvate," as used herein, refers to a crystalline compound wherein a solvent molecule is incorporated into the crystal lattice of the compound in a stoichiometric or non-stoichiometric manner. When the solvent molecule is water, the term "hydrate" is used herein.

[0018] The type of hydrate depends on the molar ratio of water molecules to 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine molecules.

[0019] The term "monohydrate" means 0.8 to 1.2 moles of water per mole of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0020] An anhydrate is a crystalline form that does not contain any water in the crystal lattice.

[0021] As used herein, the term "non-hygroscopic" refers to a drug substance that exhibits a mass gain of less than 0.2% by weight between about 0% and 80% relative humidity.

[0022] In the context of the present invention, the term "XRPD reflection peak" refers to a specific 2θ position in an XRPD pattern, with a signal-to-noise ratio (calculated according to European Pharmacopoeia article 2.2.46) greater than 3 / 1. "Absence of peaks" is defined as a peak having an intensity of at most 1%, e.g., 0.5% or 0.2%, of the highest peak in the XRPD of a sample of a compound of the invention, i.e., no detectable XRPD peak above the background signal.

[0023] In an XRPD pattern, the main features of the diffraction line profile are the 2θ position, peak height, peak area, and shape (e.g., peak width or asymmetry, characterized by analytical functions, empirical expressions). The 2θ position is the most important factor, since, for example, intensity is affected by sample formulation, and peak width is affected by particle size. In addition to the diffraction peaks, X-ray diffraction experiments also produce a nearly uniform background in the XRPD pattern, onto which the peaks are superimposed. Besides specimen formulation, other factors also affect the background, such as diffuse scattering from the sample holder, air, and instrument, detector noise, and other instrument parameters, such as general radiation from the X-ray tube. The peak-to-background ratio can be increased by minimizing the background and / or selecting a long exposure time.

[0024] Abbreviation DSC: Differential injection calorimeter TGA: Thermogravimetric analysis XRPD: X-ray powder diffraction 13 C CP / MAS NMR: 13 C cross-polarization magic-angle spinning nuclear magnetic resonance SXRD: Single crystal X-ray diffraction [Brief explanation of the drawings]

[0025] [Figure 1A]Figure 1 is the XRPD pattern (3-45° 2θ) of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A. [Figure 1B] FIG. 1 is an XRPD pattern (3-30° 2θ) of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine form A. [Figure 2] 1 is a DSC and TGA curve of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine form A. [Figure 3] FIG. 1 is an ORTREP representation of the absolute crystal structure of crystalline form A of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine form A. [Figure 4] FIG. 13C CP / MAS NMR (14.1 T) spectrum of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, Form A.

[0026] The results of the single crystal structure determination are shown in Table 1. [Table 1]

[0027] Thus, in one embodiment, the present invention relates to 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A.

[0028] In another embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6, and / or 26.3 (±0.2 degrees).

[0029] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A characterized by one or more XRPD reflections at about (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4 and / or 26.3 (±0.2 degrees).

[0030] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6, and 26.3 (±0.2 degrees).

[0031] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A characterized by one or more XRPD reflections at about (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4, and 26.3 (±0.2 degrees).

[0032] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, wherein the crystalline compound has an XRPD pattern essentially similar to the XRPD pattern of Figures 1A and / or 1B.

[0033] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern of FIG. 1A and / or FIG. 1B.

[0034] In one embodiment, crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A has essentially similar DSC and TGA curves as shown in FIG. 2, consisting of an unresolved endothermic-exothermic event with an onset at 273.6±2° C. and a corresponding weight loss included in the TGA curve.

[0035] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, wherein the crystalline compound is a solid having peaks at one or more of 149.1, 148.1, 139.9, 128.0, 119.9, 112.7, 64.6, 63.1, 61.1, 53.6, 51.7, 37.7, and / or 35.4 ppm ± 0.2 ppm. 13 It is characterized by C CP / MAS NMR spectrum.

[0036] In a further embodiment, the present invention relates to the 13 C CP / MAS NMR spectrum essentially similar 13 The present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, characterized by having a C CP / MAS NMR spectrum of:

[0037] In a further embodiment, the present invention relates to the 13 According to C CP / MAS NMR spectrum 13The present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, characterized by having a C CP / MAS NMR spectrum of:

[0038] In a further embodiment, the present invention provides 13 and crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, characterized by having a C CP / MAS NMR spectrum, further characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6, and 26.3 (±0.2 degrees).

[0039] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, wherein the crystalline compound is characterized by having single crystal X-ray crystallography (SXRC) parameters as shown in Table 1.

[0040] In a further embodiment of the present invention, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A is characterized by having single crystal parameters substantially the same as those provided in Table 1.

[0041] In a further embodiment of the present invention, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A has a structure obtained by single crystal X-ray diffraction (SXRD) as shown in FIG.

[0042] In a further embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as described above and a pharmaceutically acceptable carrier.

[0043] In a further embodiment, the present invention relates to said pharmaceutical composition for use in treating a disease selected from atopic dermatitis, itching, pruritus and various forms of urticaria.

[0044] In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, wherein the form of urticaria comprises a subtype of chronic idiopathic urticaria, such as cholinergic urticaria.

[0045] The free base of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine can be prepared as described in US Pat. No. 9,586,959.

[0046] A further aspect of the present invention relates to a pharmaceutical composition comprising a crystalline compound of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition may be in oral dosage form, preferably a tablet and / or a capsule.

[0047] Furthermore, the present invention relates to the use of the crystalline compounds of the present invention for the preparation of solid pharmaceutical preparations.

[0048] In another embodiment, the present invention relates to a solid pharmaceutical composition comprising an effective amount of a crystalline compound of the present invention and a pharmaceutically acceptable carrier, and a method for preparing the same. The present invention also relates to a pharmaceutical composition of the present invention and / or a crystalline compound of the present invention for use in treating any of the diseases or disorders described in U.S. Patent No. 9,586,959, including diseases and disorders such as atopic dermatitis (AD), itch, pruritus, and various types of urticaria.

[0049] The pharmaceutical composition of the present invention containing the crystalline compound of the present invention can further contain one or more pharmaceutically acceptable additives. Such additives are preferably selected from the group consisting of diluents, sweeteners, buffers, glidants, fluidizers, flavoring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants, and thickeners. Other additives known in the field of pharmaceutical compositions can also be used. The pharmaceutical composition can also contain a combination of two or more additives from one of the above groups.

[0050] Suitable binders that can be used in the pharmaceutical compositions of the present invention comprising the crystalline compounds of the present invention further include, for example, alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, dendrimers, and the like. starches such as Pun 1551, modified starches such as sodium carboxymethyl starch, pectin, chitosan, chitin derivatives such as heparin and heparinoids, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylic acid copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of vinyl acetate and polyvinylpyrrolidone, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, e.g., poloxamer and poloxamine, copovidone.

[0051] Suitable diluents that can be used in pharmaceutical compositions of the invention comprising crystalline compounds of the invention further include, for example, calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose additives, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, starch, modified starch, sodium chloride, sucrose, compressible sugar, confectionery sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) (commercially available under the trademark Microcelac®), and a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2) (commercially available under the trademark Prosolv®).

[0052] Suitable glidants that can be used in pharmaceutical compositions of the present invention, including crystalline compounds of the present invention, further include, for example, talc, colloidal silicon dioxide, starch, and magnesium stearate.

[0053] Suitable disintegrants that can be used in the pharmaceutical compositions of the present invention containing the crystalline compounds of the present invention further include, for example, starch, ion exchange resins such as Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gums such as croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginates, and powdered cellulose.

[0054] Suitable lubricants that can be used in pharmaceutical compositions of the present invention, including crystalline compounds of the present invention, further include, for example, magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, and magnesium lauryl sulfate.

[0055] Some formulations, e.g., tablets, may contain components that have XRPD reflection peaks in the same location or region as the crystalline compound of the present invention, or components that have broad peaks. These may mask some of the XRPD pattern or peaks of the crystalline compound of the present invention when XRPD experiments are performed on formulations that contain the crystalline compound of the present invention rather than just the pure crystalline salt. This means that not all of the XRPD reflection peaks of the crystalline compound of the present invention will always be visible when XRPD experiments are performed on dosage forms of the crystalline compound.

[0056] Thus, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein said pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more components that exhibit XRPD reflection peaks, including one or more XRPD reflection peaks that overlap with and mask one or more XRPD reflection peaks of the crystalline compound of the invention.

[0057] For example, strong signals from cellulose components are expected in the 60–110 ppm spectral region, and peaks from stearates are observed in the 15–40 ppm spectral region, along with a carbonyl peak around 172 ppm. 13 The same problem can occur in C CP / MAS NMR.

[0058] Thus, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein said pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) is / are one or more of the crystalline compounds of the present invention. 13 May contain one or more peaks that overlap and mask the C CP / MAS NMR peaks 13 It contains one or more components characterized by a C CP / MAS NMR spectrum.

[0059] The absence of other crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine can be tested by comparing the XRPD pattern of any crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine or a salt thereof with the XRPD pattern of Form A obtained from, for example, Example 1 and shown in Figures 1A and 1B. For purposes of this comparison, the XRPD pattern shown in Figure 1A or 1B can be considered the XRPD pattern of a 100% pure crystalline compound of Form A or Form B of the present invention.

[0060] Description of Test Methods Used to Characterize the Polymorphic Forms Disclosed herein X-ray powder diffraction (XRPD): XRPD patterns were collected using a PANalytical X'pert PRO MPD diffractometer operating at 45 kV and 40 mA using incident CuKα radiation. XRPD patterns were collected over a 2θ range of 3–45° with a step size of 0.0066°, a count time of 148.93 s, and in transmission geometry. The incident beam path contained a 4 mm fixed mask, a 1° fixed anti-scatter slit, and a 1 / 2° fixed divergence slit, along with an elliptically tilted multilayer mirror, to focus the CuKα X-rays from the sample to the detector. The diffraction beam path contained a long anti-scatter extension and a 2 mm anti-scatter slit to minimize background caused by air. Additionally, 0.02 rad Soller slits were placed in both the incident and diffraction beam paths to minimize broadening due to axial divergence.

[0061] For better particle statistics, the sample was placed on a 3 μm thick foil on a 96-well high-throughput plate stage and oscillated in the X direction. Diffraction patterns were collected with a PIXel RTMS detector with an active length of 3.347°, located 240 mm from the sample.

[0062] Thermogravimetric analysis (TGA): TGA experiments were performed using a TA Instruments TGA550 instrument. Approximately 1–10 mg of sample was placed in a ceramic pan for measurement. The sample temperature was increased from 25°C to 500°C at a rate of 10°C / min. Nitrogen was used as the purge gas at a flow rate of 50 mL / min.

[0063] Differential Scanning Calorimetry (DSC): DSC: heating rate 10°C / min under nitrogen atmosphere. For the measurement, approximately 1-2 mg of sample was placed in an open aluminum pan for measurement. Instrument Q20 manufactured by TA Instruments.

[0064] Single crystal X-ray diffraction: Data were collected using a SuperNova dual diffractometer equipped with an Atlas CCD area detector (temperature: 120(2) K; CuKα radiation λ = 1.5418 Å; data collection method: ω scan). Details can be found in Table 1. Programs used for structure interpretation: CrysAlisPro, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlisl71 .NET), ShelXL (Sheldrick, 2008) for structure refinement, and Olex2 (Dolomanov et al., 2009) for ORTEP drawing.

[0065] Solid-state NMR spectroscopy: 13 C CP / MAS NMR spectra were obtained using a 4 mm double alignment ( 1 H- 13 C), recorded at 298 K using a Bruker Avance III HD600 NMR spectrometer (14.1 T) equipped with a CMP probe: contact time 6 ms, recycle delay 64 s, spin speed 14.1 kHz, 256 scans, and high power during an acquisition time of 45.9 ms. 1H decoupling was used. Prior to Fourier transformation, time-domain data (free induction decay) were apodized through 5 Hz Lorentzian line broadening. All spectra were referenced to the chemical shift of the carbonyl group of α-glycine at 176.5 ppm (external sample).

[0066] The error ranges provided in this application for spectroscopic properties, including those set forth in the claims, depend on factors well known to those skilled in the art of spectroscopy and may vary due to, for example, sample preparation, such as particle size distribution, or the composition of the formulation if the crystalline form is part of a formulation, as well as instrumental variations, and other factors. [Example]

[0067] Example 1 11 mg of the free base of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine was placed in a test tube or 4 mL glass vial and 2 mL of a 1:3 CHCl3:THF mixture was added. The solution was heated with a heat gun until all solids were visibly dissolved. The solution was then filtered through a 0.45 μm syringe filter. The filtered solution was placed in a loose-lidded fume cup and placed on a table to allow crystallization while the solvent system slowly evaporated. The resulting crystals were diamond-shaped. The XRPD pattern of Form A is shown in Figures 1A and 1B.

Claims

1. Crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6 and / or 26.3 (±0.2 degrees).

2. 10. The crystalline compound of claim 1 characterized by one or more XRPD reflections at about (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4 and / or 26.3 (±0.2 degrees).

3. 3. The crystalline compound of claim 1 or 2, characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6 and 26.3 (±0.2 degrees).

4. 4. The crystalline compound of any one of claims 1 to 3 characterized by one or more XRPD reflections at about (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4 and 26.3 (±0.2 degrees).

5. 5. The crystalline compound of any one of claims 1 to 4, having an XRPD pattern essentially similar to the XRPD pattern of Figure 1A or Figure 1B.

6. 5. The crystalline compound of any one of claims 1 to 4, having an XRPD pattern according to the XRPD pattern of Figure 1A or Figure 1B.

7. Solids having peaks at one or more of 149.1, 148.1, 139.9, 128.0, 119.9, 112.7, 64.6, 63.1, 61.1, 53.6, 51.7, 37.7 and / or 35.4 ppm ± 0.2 ppm 13 The crystalline compound according to any one of claims 1 to 6, characterized by a C CP / MAS NMR spectrum.

8. In Figure 4 13 C CP / MAS NMR spectrum essentially similar 13 8. The crystalline compound of claim 7, having a C CP / MAS NMR spectrum.

9. In Figure 4 13 According to C CP / MAS NMR spectrum 13 8. The crystalline compound of claim 7, having a C CP / MAS NMR spectrum.

10. 10. The crystalline compound of any one of claims 7 to 9 further characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6 and 26.3 (±0.2 degrees).

11. The crystalline compound according to any one of claims 1 to 10, characterized in that it has single crystal X-ray crystallography (SXRC) parameters as shown in Table 1.

12. 11. The crystalline compound of any one of claims 1 to 10, having single crystal X-ray crystallography (SXRC) parameters substantially the same as those provided in Table 1.

13. 13. The crystalline compound of any one of claims 1 to 12, having essentially similar DSC and TGA curves as shown in Figure 2, consisting of an unresolved endothermic-exothermic event with an onset at 273.6±2°C and a corresponding weight loss included in the TGA curve.

14. A pharmaceutical composition comprising the crystalline salt of any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. A compound or pharmaceutical composition according to any one of claims 1 to 14 for use in the treatment of a disease selected from atopic dermatitis, itching, pruritus and various forms of urticaria.

16. 16. The compound or pharmaceutical composition according to claim 15, wherein the disease is atopic dermatitis.

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