Novel crystalline forms of 1-(8-bromopyrido [2, 3-e] [1, 2, 4] triazolo [4, 3-a] pyrazin-4-yl)-n-methylazetidine-3-amine monosuccinate

Abstract

Provided are novel crystalline forms of 1-(8-bromopyrido [2, 3-e] [1, 2, 4] triazolo [4, 3-a] pyrazin-4-yl)-N-methylazetidine-3-amine 1-(8-bromopyrido [2, 3-e] [1, 2, 4] triazolo [4, 3-a] pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate and pharmaceutical compositions comprising the same. Also disclosed is the use of the novel polymorphs for the treatment of diseases, such as atopic dermatitis (AD), pruritus, pruritus and various forms of urticaria, such as the chronic idiopathic urticaria subtype.

Description

SUMMARY OF THE INVENTION

[0002] The present invention relates to a novel crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate, a pharmaceutical composition comprising the novel crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate, and to the use of the novel crystalline form for treating diseases such as atopic dermatitis (AD), pruritus, pruritus, and various forms of urticaria, such as chronic idiopathic urticaria subtypes, such as cholinergic urticaria. Also provided herein is a method for preparing the crystalline form of the present invention. Background of the Invention

[0004] U.S. Patent No. 9586959 particularly relates to 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 and pharmaceutical compositions containing the same. The patent discloses the preparation of 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.

[0005] 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine exhibits a strong histamine 4 receptor inhibitory effect and shows an inhibitory effect on the infiltration of inflammatory cells (such as mast cells and eosinophils) induced by histamine. Therefore, the compound has a strong anti-inflammatory and anti-itching effect and can therefore be used to treat a series of diseases, such as those disclosed in U.S. Pat. No. 9586959, including AD.

[0006] Different crystalline solid forms of a compound may have different physical properties, such as, for example, chemical stability, physical stability, hygroscopicity, melting point, solubility, dissolution rate, morphology, and bioavailability, which make them more or less suitable as selected active ingredients in a pharmaceutical product.

[0007] In addition, chemical entity can exist with several different crystalline solid forms, and these forms include different polymorphs (such as anhydrous substances) with the same total molecular formula (sum formula) and different solvates (such as hemihydrates, monohydrates and dihydrates) of the same chemical entity that do not share the same total molecular formula. Such crystalline solid forms have different crystal structures, and physical properties are different. Different crystalline solid forms can be distinguished from each other by, for example, melting point, XRPD spectrum, spectrum characteristics (such as FT-IR, Raman and SS-NMR) and other physical and chemical properties. Chemical entity can also exist in amorphous form.

[0008] Therefore, the actual crystalline form selected plays an important role in the development and manufacture of the active pharmaceutical ingredient. If a single crystalline form is desired, it is important that the crystallization process is robust and reliably produces the desired crystalline form in polymorphically pure form and that the crystalline form does not change (e.g., interconvert to a different crystalline form) during the relevant manufacturing process and / or during storage.

[0009] A variety of different 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 are present as anhydrous forms, others are present as monohydrates and dihydrates, each salt is present in multiple polymorphs that interconvert upon drying or lose water at relatively low temperatures, and therefore they are not suitable for development as drugs.

[0010] The new crystalline form according to the present invention is a crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine monosuccinate. The new crystalline form is referred to as Form B hereinafter. SUMMARY OF THE INVENTION

[0012] The present invention relates to crystalline Form B of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate, characterized by one or more XRPD reflections at about (2θ) 7.5, 16.8 and / or 21.8 (±0.2 degrees).

[0013] The present invention also relates to a pharmaceutical composition comprising the above crystal form and a pharmaceutically acceptable carrier.

[0014] In one embodiment, the invention relates to a compound or a pharmaceutical composition as described above for use in the treatment of a disease selected from atopic dermatitis, pruritus, pruritus and various forms of urticaria including the chronic idiopathic urticaria subtype. DETAILED DESCRIPTION OF THE INVENTION

[0016] The technical problem on which the present invention is based is to overcome 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 the ability to form crystals, filterability, solubility, thermodynamic properties, stability problems (e.g. due to water absorption), density and transformations at different humidities and during the crystallization process (e.g. interconversion into other polymorphs or hydrates / anhydrates).

[0017] The experiment produced 14 different polymorphs of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate. Some were not isolated in pure form and some converted to other forms upon mild drying.

[0018] Form B has excellent crystallinity, stability and thermal properties.

[0019] definition

[0020] As used herein, the term "rt" or "room temperature" indicates that the temperature applied is not critical and that an exact temperature value does not have to be maintained. Typically, "rt" or "room temperature" is understood to mean a temperature of about 15°C to about 25°C [see, e.g., European Pharmacopoeia 7.5, 1.2 (2012)].

[0021] As used herein, the term "solvate" describes a crystalline compound in which a solvent molecule is incorporated into the crystal lattice of the compound in a stoichiometric or non-stoichiometric manner. If the solvent molecule is water, the term "hydrate" is used herein.

[0022] 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.

[0023] 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.

[0024] Anhydrates are crystalline forms that do not contain any water in the crystal lattice.

[0025] As used herein, the term "non-hygroscopic" indicates that the mass of the drug substance increases by less than 0.2% by weight between about 0% and 80% relative humidity.

[0026] In the context of the present invention, the term "XRPD reflection peak" refers to a specific 2θ position in the XRPD pattern where the signal-to-noise ratio (calculated according to European Pharmacopoeia 2.2.46) is greater than 3 / 1. "Peak absence" is defined herein 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 XRPD peak is detectable above the background signal.

[0027] In the XRPD spectrum, the main features of the diffraction line curve are 2θ position, peak height, peak area and shape (characterized by, for example, peak width or asymmetry, analytical function, empirical expression). The 2θ position is the most important factor, because, for example, the intensity will be affected by the sample preparation, and the peak width will be affected by the particle size. In addition to the diffraction peaks, the X-ray diffraction experiment also produces a more uniform or less uniform background in the XRPD spectrum, with the peaks superimposed on it. In addition to sample preparation, other factors also affect the background, such as the sample holder, diffuse scattering from air and equipment, other instrument parameters (such as detector noise, general radiation from the X-ray tube, etc.). The peak-to-background ratio can be increased by minimizing the background and / or by selecting an extended exposure time.

[0028] abbreviation

[0029] DSC: Differential Scanning Calorimetry

[0030] DVS: Dynamic Vapor Sorption

[0031] TGA: Thermogravimetric analysis

[0032] XRPD: X-ray powder diffraction

[0033] 13 C CP / MAS NMR: 13 C cross-polarization magic angle spinning NMR

[0034] SXRD: Single Crystal X-ray Diffraction BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1A :XRPD pattern of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate form B (3-45° 2θ)

[0037] Figure 1B :XRPD pattern of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate form B (3-30° 2θ)

[0038] Figure 2: DSC and TGA curves of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate form B.

[0039] Figure 3 : 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate form B 13 C CP / MAS NMR (14.1T) spectrum.

[0040] 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 monosuccinate.

[0041] In another embodiment, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate characterized by one or more XRPD reflections at about (°2θ) 18.0, 24.4 and / or 27.6 (±0.2 degrees).

[0042] In additional embodiments, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate characterized by one or more XRPD reflections at approximately (°2θ) 7.5, 16.8, 18.0, 21.8, 24.4 and / or 27.6 (±0.2 degrees).

[0043] In additional embodiments, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate characterized by XRPD reflections at approximately (°2θ) 18.0, 24.4 and 27.6 (±0.2 degrees).

[0044] In additional embodiments, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate characterized by XRPD reflections at approximately (°2θ) 7.5, 16.8, 18.0, 21.8, 24.4 and 27.6 (±0.2 degrees).

[0045] In another embodiment, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate, wherein the crystalline compound has a substantially similar Figure 1A Or the XRPD pattern in 1B.

[0046] In another embodiment, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate, wherein the crystalline compound has a Figure 1A Or the XRPD pattern in 1B.

[0047] In another embodiment, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate, wherein the crystalline compound is characterized by having a solid phase having a peak at one or more of 178.0, 177.0, 152.1, 147.7, 146.9, 140.3, 137.8, 129.3, 113.5, 63.3, 57.9, 57.1, 51.2, 35.8, 33.6, 30.9, 27.4 and / or 13.3 ppm (±0.2 ppm). 13 CCP / MAS NMR spectroscopy.

[0048] In another embodiment, the present invention is directed to a crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosolvate characterized by having a substantially similar Figure 3 In 13 C CP / MAS NMR spectroscopy 13 C CP / MAS NMR spectroscopy.

[0049] In a further embodiment, the invention relates to a crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosolvate characterized in that it has Figure 3 In 13 CCP / MAS NMR spectroscopy 13 C CP / MAS NMR spectroscopy.

[0050] In another embodiment, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate having a DSC and TGA curve consisting of two unseparated endothermic events with an onset at 179.0±2°C and a corresponding weight loss in the TGA curve.

[0051] In another embodiment, the present invention is directed to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate having a substantially similar Figure 2 The DSC and TGA curves of the curves shown in .

[0052] In some embodiments, Form B is a propanol solvate, suitably a 1-propanol solvate.

[0053] In a further embodiment, the present invention relates to a pharmaceutical composition comprising the crystalline compound as described above and a pharmaceutically acceptable carrier.

[0054] In a further embodiment, the invention relates to a pharmaceutical composition as above for use in the treatment of a disease selected from atopic dermatitis, pruritus, pruritus and various forms of urticaria.

[0055] In a specific embodiment, the present invention relates to the pharmaceutical composition as above, wherein the form of urticaria comprises a chronic idiopathic urticaria subtype, such as cholinergic urticaria.

[0056] Another aspect of the present invention relates to a pharmaceutical composition comprising the crystalline compound of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition may be in an oral dosage form, preferably a tablet and / or capsule.

[0057] Furthermore, the present invention relates to the use of the crystalline compound of the present invention for preparing a solid medicament.

[0058] 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 to a method for preparing the same. In addition, the present invention relates to a pharmaceutical composition of the present invention and / or a crystalline compound of the present invention for use in treating any disease or disorder mentioned in U.S. Pat. No. 9,586,959, including diseases and disorders such as atopic dermatitis (AD), pruritus, pruritus, and any of the various types of urticaria.

[0059] The pharmaceutical composition of the present invention comprising the crystalline compound of the present invention may also comprise one or more pharmaceutically acceptable excipients. Such excipients are preferably selected from the group consisting of diluents, sweeteners, buffers, glidants, flow agents, flavoring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners. Other excipients known in the field of pharmaceutical compositions may also be used. In addition, the pharmaceutical composition may comprise a combination of two or more excipients also within one of the members of the above-mentioned groups.

[0060] Suitable binders that can be used in the pharmaceutical composition of the present invention comprising the crystalline compound of the present invention also include, for example, alkyl celluloses such as methyl cellulose, hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose, hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose, carboxyalkyl celluloses such as carboxymethyl cellulose, alkali metal salts of carboxyalkyl celluloses such as sodium carboxymethyl cellulose, carboxyalkyl alkyl celluloses such as carboxymethyl ethyl cellulose, carboxyalkyl cellulose esters, starches such as starch 1551, modified starches such as sodium carboxymethyl starch, pectin, chitin derivatives such as Chitosan, heparin and heparinoids, polysaccharides such as alginic acid, its alkali metal salts and ammonium salts, carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylate copolymers, polyvinyl alcohol, polyvinyl pyrrolidone, copolymers of polyvinyl pyrrolidone with vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, for example poloxamers and poloxamines, copovidone.

[0061] Suitable diluents that can be used in the pharmaceutical composition of the present invention comprising the crystalline compound of the present invention also include, for example, calcium carbonate, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, calcium phosphate, calcium sulfate, microcrystalline cellulose (including silicified microcrystalline cellulose), powdered cellulose, dextrates, dextrin, glucose excipients, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, starch, modified starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) (which can be used as commercially available), a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2) (available as (commercially available).

[0062] Suitable glidants that may be used in the pharmaceutical composition of the present invention comprising the crystalline compound of the present invention also include, for example, talc, colloidal silicon dioxide, starch and magnesium stearate.

[0063] Suitable disintegrants that can be used in the pharmaceutical composition of the invention comprising the crystalline compound of the invention also include, for example, starch, ion exchange resins (e.g., Amberlite), cross-linked polyvinyl pyrrolidone, modified cellulose gum (e.g., cross-linked sodium carboxymethylcellulose), sodium starch glycolate, sodium carboxymethylcellulose, sodium lauryl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginates, and powdered cellulose.

[0064] Suitable lubricants that may also be used in the pharmaceutical composition of the present invention comprising the crystalline compound of the present invention also include, for example, magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, and magnesium lauryl sulfate.

[0065] Some preparations, such as tablets, may contain ingredients that have XRPD reflection peaks or broad peaks in the same position or region as the crystalline compound of the present invention. When an XRPD experiment is performed on a preparation containing the crystalline compound of the present invention rather than a single pure crystalline salt, these ingredients may hide some XRPD patterns or peaks of the crystalline compound of the present invention. This means that when an XRPD experiment is performed on a preparation of the crystalline compound, all XRPD reflection peaks of the crystalline compound of the present invention cannot always be seen.

[0066] Therefore, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein and a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein the pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more ingredients exhibiting such XRPD reflection peaks, wherein the XRPD reflection peaks include one or more XRPD reflection peaks that overlap with and hide one or more XRPD reflection peaks of the crystalline compound of the invention.

[0067] The same problem can arise with solid state NMR, where, for example, strong signals from the cellulose component would be expected in the spectral region of 60-110 ppm, and peaks from stearate would be seen in the spectral region of 15-40 ppm - as well as a carbonyl peak around 172 ppm.

[0068] Thus, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein and a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein the pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more of the following: 13 C CP / MAS NMR spectrum of the components, 13C CP / MAS NMR spectra may include one or more of the following: 13 C CP / MAS NMR peaks overlap and hide one or more of the crystalline compounds of the invention 13 C CP / MAS NMR peak.

[0069] The XRPD pattern collected for 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 can be compared with, for example, that obtained from Example 1 and Figure 1A or Form B shown in 1B to test whether other crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine exist. For such a comparison, Figure 1A The XRPD pattern shown in or 1B can be regarded as the XRPD pattern of a 100% pure crystalline compound of Form B of the present invention.

[0070] Description of the test methods used to characterize the polymorphs disclosed herein

[0071] X-ray powder diffraction (XRPD)

[0072] With PANalytical X'pert PRO MPD diffractometer, use incident Cu Kα radiation, and run at 45kV and 40mA, collect XRPD spectrum.XRPD spectrum is collected in 2θ range of 3 to 45 degrees, step length is 0.0066°, counting time is 148.93s, and in transmission geometry.In the incident beam path, place elliptically graded multilayer mirror (ellipticallygraded multilayer mirror) and 4mm fixed mask, 1° fixed anti-scatter slit and 1 / 2° fixed divergence slit, so that Cu Kα X-ray line is focused through sample and on detector.On the diffraction beam path, place long anti-scatter extension and 2mm anti-scatter slit, to minimize the background produced by air.In addition, 0.02 radian (rad) Soller slit (Soller slit) is placed on the incident and diffraction beam paths, to minimize the broadening caused by axial divergence.

[0073] The sample was placed on a 3 μm thick foil on a 96 high throughput well plate stage and oscillated in the X direction for better particle statistics. The diffraction patterns were collected using a PIXel RTMS detector with an effective length of 3.347° and located 240 mm from the sample.

[0074] Thermogravimetric analysis (TGA):

[0075] TGA experiments were performed using a TGA550 instrument from TA Instruments. About 1-10 mg of sample was loaded into a ceramic pan for measurement. The sample temperature was increased from 25 to 500° C. at 10° C. / min. Nitrogen was used as the purge gas at a flow rate of 50 mL / min.

[0076] Differential Scanning Calorimetry (DSC)

[0077] DSC: Heating rate 10°C / min under nitrogen atmosphere. Approximately 1-2 mg of sample is loaded into an open aluminum pan for measurement. Instrument Q20 from TA Instruments.

[0078] Single crystal X-ray diffraction

[0079] Data were collected using a SuperNova dual diffractometer with an Atlas CCD area detector (temperature: 120(2)K; Cu Kα radiation). Data collection method: ω scan). Additional details can be found in Table 1. Program(s) used to solve the structure: CrysAlisPro, Agilent Technologies, version 1.171.37.34 (CrysAlis171.NET release May 22, 2014), ShelXL (Sheldrick, 2008) was used to refine the structure, and Olex2 (Dolomanov et al., 2009) was used for ORTEP mapping.

[0080] Solid-state NMR spectroscopy

[0081] During the acquisition time of 45.9 ms, a contact time of 6 ms, a recycle delay of 64 s, a rotation rate of 14.1 kHz, 128 scans and high power were used. 1 H decoupling, equipped with 4mm dual tuned ( 1 H- 13 C) Recorded at 298K on a Bruker AvanceIII HD 600 NMR spectrometer (14.1T) with a CMP probe 13 C CP / MAS NMR spectroscopy. Time domain data (free induction decay) were apodized by Lorentzian line broadening at 5 Hz before Fourier transformation. All spectra were referenced to the chemical shift of the carbonyl group in α-glycine at 176.5 ppm (external sample).

[0082] The given error ranges for spectral features in this application, including in the claims, may be more or less dependent on factors well known to those skilled in the art of spectroscopy and may, for example, depend on sample preparation such as particle size distribution, or if a crystalline form is part of a preparation, on the composition of the preparation, as well as instrumental fluctuations and other factors. Example

[0083] Example 1

[0084] 60 mg of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine monosuccinate was dissolved in 4 mL of EtOH:H2O (99:1) mixture. The sample solution was filtered through a 0.45 μm filter and 5 drops of EtOH:H2O [99:1] were added.

[0085] The solution was carefully added to a 5 mm NMR tube filled with an equal volume of heptane, which has a lower density. The tube was sealed with a polyethylene cap and left undisturbed in a fume cupboard. XRPD is shown in Figure 1A and 1B middle.

Claims

1. Crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine-3-amine monosuccinate, characterized in that One or more XRPD reflections at about (° 2θ) 18.0, 24.4 and / or 27.6 (± 0.2 degrees).

2. The crystalline compound according to claim 1, characterized in that One or more XRPD reflections at about (° 2θ) 7.5, 16.8, 18.0, 21.8, 24.4 and / or 27.6 (± 0.2 degrees).

3. The crystalline compound according to any one of claims 1 to 2, characterized in that XRPD reflections at approximately (° 2θ) 18.0, 24.4 and 27.6 (± 0.2 degrees).

4. The crystalline compound according to claim 1-3, characterized in that XRPD reflections at approximately (° 2θ) 7.5, 16.8, 18.0, 21.8, 24.4 and 27.6 (± 0.2 degrees).

5. The crystalline compound of any one of claims 1-4, wherein the crystalline compound has an XRPD pattern substantially similar to the XRPD pattern in Figure 1A or 1B.

6. The crystalline compound according to any one of claims 1-4, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern in Figure 1A or 1B.

7. The crystalline compound of any one of claims 1-6, wherein the crystalline compound is characterized by having a solid phase having a peak at one or more of 178.0, 177.0, 152.1, 147.7, 146.9, 140.3, 137.8, 129.3, 113.5, 63.3, 57.9, 57.1, 51.2, 35.8, 33.6, 30.9, 27.4, and / or 13.3 ppm ± 0.2 ppm. 13 C CP / MAS NMR spectroscopy.

8. The crystalline compound according to claim 7, characterized in that Having a substantially similar 13 C CP / MASNMR spectroscopy 13 C CP / MAS NMR spectroscopy.

9. The crystalline compound according to claim 7, characterized in that According to FIG. 3 13 C CP / MAS NMR spectroscopy 13 C CP / MAS NMR spectroscopy.

10. The crystalline compound according to any one of claims 7 to 9, further characterized in that One or more XRPD reflections at about (°2θ) (°2θ) 18.0, 24.4 and 27.6 (±0.2 degrees).

11. The crystalline compound according to any one of claims 1-10, having a DSC and TGA curve consisting of two unseparated endothermic events with an onset at 179.0±2°C and a corresponding weight loss in the TGA curve.

12. The crystalline compound according to any one of claims 1 to 11, having DSC and TGA curves substantially similar to those shown in Figure 2.

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

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

15. The compound or pharmaceutical composition for use according to claim 14, wherein the disease is atopic dermatitis.

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