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 hemisuccinate

Abstract

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 hemisuccinate is provided, as well as pharmaceutical compositions containing the same. Also disclosed is the use of the novel crystalline form for the treatment of diseases such as atopic dermatitis (AD), itch, pruritus, and various forms of urticaria, including chronic idiopathic urticaria subtype.

Description

[Technical field]

[0001] The present disclosure 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 hemisuccinate, pharmaceutical compositions containing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate, and the use of the novel crystalline forms for the treatment of 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 are methods for preparing the crystalline forms of the present invention. [Background technology]

[0002] US Patent No. 9,586,959 relates, among other compounds, 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 pharma- ceutically acceptable salts and pharmaceutical compositions containing same. The document discloses the preparation of a number of 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 a strong histamine 4 receptor inhibitory effect and suppresses histamine-induced infiltration of inflammatory cells such as mast cells and eosinophils. Therefore, this compound has a strong anti-inflammatory and anti-itch effect, and is therefore useful for the treatment of various diseases, including AD, as disclosed in Patent Document 1.

[0004] Different crystalline solid forms of a chemical compound may have distinct physical properties, such as chemical stability, physical stability, hygroscopicity, melting point, solubility, dissolution rate, morphology and bioavailability, that make them more or less suitable as a selected active ingredient of a pharmaceutical product.

[0005] Also, a chemical may exist in several different crystalline solid forms, including different polymorphic forms (e.g., anhydrates) that share the same unified formula, and different solvates (e.g., hemihydrate, monohydrate, and dihydrate) of the same chemical that do not share the same unified formula. Such crystalline solid forms have different crystal structures and vary in physical properties. Different crystalline solid forms can be distinguished from each other by, for example, melting points, XRPD patterns, spectral properties (e.g., FT-IR, Raman, and SS-NMR), and other physical and chemical properties. A chemical may also exist in an 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 and stably produces the desired crystalline form in polymorphically pure form and does not change the crystalline form (e.g., interconvert to different crystalline forms) during the associated manufacturing steps and / or during storage.

[0007] The novel crystalline form according to the present invention is a hemisuccinate, i.e., a salt form in which there are two molecules of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine in the crystal lattice for each molecule of succinic acid.

[0008] Many 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 not suitable for pharmaceutical development because they exist as anhydrous, monohydrates and dihydrates in several forms that interconvert on drying or lose water at relatively low temperatures.

[0009] One crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate monohydrate was identified (hereinafter referred to as Form F).

[0010] Form F is a channel hydrate, and in general channel hydrates / solvates are not very stable because the solvent molecules can easily move in and out of the channels, causing the collapse of the crystal lattice. In the case of Form F, the water molecules are located in the same molecular plane as the succinic acid molecules, stabilizing the hydrate and making Form F particularly useful for use in solid pharmaceutical products such as tablets. Furthermore, Form F can be dried under moderate drying conditions such as a vacuum oven at 60°C without collapsing the crystal lattice (see Figure 8). Form F was also found to be suitable for large-scale drying.

[0011] Additionally, the crystal habit and particle size distribution were very similar between batches of Form F, and the particle size distribution data is encouraging in relation to drug product processability.

[0012] Experiments have demonstrated that Form F allows for refinement without amorphization.

[0013] Additionally, Form F is a hemisuccinate salt which allows for a higher drug loading, which is highly beneficial for high doses and for keeping the tablet as small as possible to maximize patient compliance. Summary of the Invention

[0014] 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 hemisuccinate monohydrate characterized by one or more XRPD reflections at (°2θ) of approximately 8.6, 11.9 and / or 15.8 (±0.2 degrees) 2θ.

[0015] The present invention also relates to a pharmaceutical composition comprising said crystalline form and a pharma- ceutically acceptable carrier.

[0016] In one embodiment, the invention relates to said compound or pharmaceutical composition for the treatment of a disease selected from atopic dermatitis, pruritus, pruritus and various forms of urticaria, including chronic idiopathic urticaria subtype.

[0017] The technical problem underlying the present invention is to avoid the shortcomings 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 formation ability at different humidities and during crystallization processes, filtration properties, solubility, thermodynamic properties, stability issues (e.g. due to moisture absorption), density and deformation (e.g. interconversion to other polymorphic forms or hydrate / anhydrate).

[0018] definition The term "rt" or "room temperature" as used herein 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, for example, European Pharmacopoeia 7.5, 1.2 (2012)].

[0019] 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.

[0020] The hydrate form is determined by 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 hemisuccinate molecules.

[0021] The term "monohydrate" refers to 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 hemisuccinate.

[0022] As used herein, the term "non-hygroscopic" refers to a drug substance that exhibits less than 0.2% weight gain between about 0% and 80% relative humidity.

[0023] In the context of the present invention, the term "XRPD reflection peak" refers to a specific 2θ position in an XRPD pattern where the signal to noise (calculated according to European Pharmacopoeia article 2.2.46) is greater than 3 / 1. "Absence of peaks" 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., a peak with no detectable XRPD peaks above the background signal.

[0024] In an XRPD pattern, the main features of the diffraction line profile are the 2θ position, the peak height, the peak area and the shape (e.g., peak width or asymmetry, characterized by analytical functions, empirical expressions). The 2θ position is the most important factor, since, for example, the intensity is affected by the sample preparation and the width of the peak is affected by the particle size. In addition to the diffraction peaks, X-ray diffraction experiments generate a more or less uniform background of overlapping peaks in the XRPD pattern. Besides the sample preparation, factors such as, for example, the sample holder, diffuse scattering from the air and the device, detector noise, other instrument parameters such as general radiation from the X-ray tube also affect the background. The peak-to-background ratio can be increased by minimizing the background and / or choosing a long exposure time.

[0025] Abbreviation DSC: Differential injection calorimeter DVS: Dynamic Vapor Sorption 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 description of the drawings]

[0026] [Figure 1] XRPD pattern for Form F (3-60° 2θ) [Diagram 2] XRPD pattern for Form F (3-30° 2θ) [Diagram 3] DSC and TGA curves for Form F [Figure 4] ORTREP diagram showing the absolute crystal structure of Form F. Hydrogen atoms have been removed for clarity. [Diagram 5] 13C CP / MAS NMR spectrum of Form F. The sum of the integrals for the aliphatic carbons is 5.18, which matches well with four carbons from the side chain of the molecule and one carbon from the CH2 of one of the succinic acid molecules, confirming that it is the hemisuccinate salt. [Figure 6] The TGA of Form F was run at a constant temperature of 60° C. for 24 hours. [Figure 7] XRPD time series of Form F (0-8 hours) [Figure 8] XRPD of Form F was stored in vacuum at 60° C. for various periods of time. Rapid XRPD (9 min) and general XRPD (1 h) were recorded at each time point. [Figure 9] XRPD of Form F produced as a powder (top diffraction pattern), a tablet produced at a pressure of 5.5 (middle diffraction pattern) and a tablet produced at a pressure of 7.0 (bottom diffraction pattern). [Figure 10] A) a-axis, B) b-axis, C) c-axis, and D) single crystal structure of form F shown along the molecular plane. Carbon atoms are shown in grey, nitrogen atoms in blue, oxygen atoms in red, and bromine atoms in orange. Along the b-axis the base ring systems are seen stacked in opposite directions, and along the molecular plane the succinic acid and water lie in the plane between the base molecules. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Table 1 below shows the SXRD of Form F. Single crystal X-ray analysis [Table 1]

[0028] In one embodiment, the present invention relates to a crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate.

[0029] In a further embodiment, the present invention relates to a crystalline compound as defined above, wherein the XRPD reflections include one or more XRPD reflections at about (°2θ) 8.6, 11.9, 15.8 and / or 25.8 (±0.2 degrees).

[0030] In a further embodiment, the present invention relates to a crystalline compound as defined above, comprising one or more XRPD reflections at about (°2θ) 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and / or 21.7 (±0.2 degrees).

[0031] In a further embodiment, the present invention relates to a crystalline compound as defined above, wherein the XRPD reflections include one or more XRPD reflections at about 8.6, 11.9 and 15.8 (±0.2 degrees).

[0032] In a further embodiment, the present invention relates to a crystalline compound as defined above, wherein the XRPD reflections comprise XRPD reflections at about (°2θ) 8.6, 11.9, 15.8 and 25.8 (±0.2 degrees).

[0033] In a further embodiment, the present invention relates to a crystalline compound as defined above, wherein the XRPD reflections comprise XRPD reflections at about (°2θ) 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and 21.7 (±0.2 degrees).

[0034] In a further embodiment, the present invention relates to a crystalline compound as defined above, having an XRPD pattern essentially similar to the XRPD pattern of FIG.

[0035] In a further embodiment, the present invention relates to a crystalline compound as defined above having an XRPD pattern according to the XRPD pattern of FIG.

[0036] In a further embodiment, the present invention provides a solid having peaks at one or more of 180, 60.0, 50.3 and / or 34.2 ppm ± 0.2 ppm. 13 It relates to a crystalline compound as defined above, characterized by its C CP / MAS NMR spectrum.

[0037] In a further embodiment, the present invention provides a solid having peaks at one or more of 180, 146.7, 140.5, 138.1, 130.1, 118.2, 60.0, 56.8, 50.3 and / or 34.2 ppm ± 0.2 ppm. 13 It relates to a crystalline compound as defined above, characterized by its C CP / MAS NMR spectrum.

[0038] In a further embodiment, the present invention relates to the 13 C CP / MAS NMR spectrum essentially similar 13 The present invention relates to a crystalline compound as defined above, characterized in that it has a C CP / MAS NMR spectrum:

[0039] In a further embodiment, the present invention relates to the 13 According to C CP / MAS NMR spectrum 13 It relates to a crystalline compound as defined above having a C CP / MAS NMR spectrum.

[0040] In a further embodiment, the present invention relates to a method for the preparation of a zeolite, as defined above, further characterized by one or more XRPD reflections at about (°2θ) 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and 21.7 (±0.2 degrees). 13 It concerns a crystalline compound having a C CP / MAS NMR spectrum.

[0041] In a further embodiment, the present invention relates to such crystalline compounds having a DSC curve comprising an endothermic event having an onset at about 138.4±2° C.

[0042] In a further embodiment of the present invention, Form F is characterized in having single crystal parameters substantially the same as those provided in Table 1.

[0043] In a more particularly preferred embodiment of the present invention, Form F has a structure obtained by single crystal X-ray crystallography (SXRC) as shown in FIG.

[0044] In a further embodiment, the present invention relates to said crystalline compound, wherein the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate to succinic acid is in the range of 2:1.2 to 2:0.8, preferably about 2:1.

[0045] In a further embodiment, the present invention relates to said crystalline compound, wherein the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate to water is in the range of 1:0.8 to 1:1.2, preferably about 2:1.

[0046] Method for producing Form F The crystalline forms of the present invention can be prepared by crystallizing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine in the form of the free base from a suitable solvent such as lower alcohols (e.g., methanol, ethanol, propanol and mixtures thereof), acetone, acetonitrile, lower alkyl acetates (e.g., ethyl acetate and propyl acetate), tetrahydrofuran and mixtures of these solvents with various amounts of water and / or liquid hydrocarbons (e.g., hexane and heptane) at room temperature or by cooling to a temperature below room temperature, for example, 0° C. or below, preferably −18° C.

[0047] In one specific embodiment, the solvent is 1-propanol and the crystallization is carried out at room temperature or above room temperature or at a low temperature, such as -18°C.

[0048] The crystalline forms of the present invention are formed by heating the free base in a suitable solvent in the presence of the requisite amount of succinic acid, adding water, and then cooling the reaction mixture.

[0049] The amount of succinic acid is preferably 0.5 to 0.6, more preferably 0.55 equivalents relative to 1 equivalent of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0050] The 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine is suspended in the solvent, suitably by heating the reaction mixture to 40° C., and once most of the 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine has dissolved, a small amount of water is added. The amount of water to the amount of solvent is suitably in the range of 1:15 to 1:25, suitably in the range of 1:20.

[0051] The crystalline form F of the present invention is advantageous over other salt forms because milder reaction conditions, i.e., about 0.5 equivalents of the weak acid succinic acid, are used compared to salt forms prepared from much larger amounts of strong acids, for example, to prepare the sulfate salt of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0052] Due to the mild reaction conditions, there is virtually no decomposition of the 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine molecule during the final salt formation, resulting in a significantly lower impurity burden and a purer product, mainly due to reduced decomposition.

[0053] A further aspect of the present invention relates to a pharmaceutical composition comprising a crystalline compound of the present invention and at least one pharma- ceutically acceptable excipient. The pharmaceutical composition may be in an oral dosage form, preferably a tablet and / or a capsule.

[0054] Furthermore, the present invention relates to the use of the crystalline compounds of the present invention for the preparation of a solid pharmaceutical formulation.

[0055] In another embodiment, the present invention relates to a solid pharmaceutical composition comprising an effective amount of the crystalline compound of the present invention and a pharma- ceutically 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 the treatment of any of the diseases or disorders described in U.S. Pat. No. 9,586,959, including diseases and disorders such as atopic dermatitis (AD), itch, pruritus, and any of the various types of urticaria.

[0056] The pharmaceutical composition of the present invention comprising the crystalline compound of the present invention may further comprise one or more pharma- ceutically acceptable excipients. Such excipients are preferably selected from the group consisting of diluents, sweeteners, buffers, lubricants, flow agents, flavoring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners. Other excipients known in the pharmaceutical composition field may also be used. The pharmaceutical composition may also comprise a combination of two or more excipients in one of the above groups.

[0057] Suitable binders that can be used in the pharmaceutical compositions of the invention comprising the crystalline compounds of the invention 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, starch, Further included are starches such as 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. poloxamers and poloxamines, copovidone.

[0058] Suitable diluents that can be used in the pharmaceutical compositions of the present invention containing the crystalline compounds of the present 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 excipients, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, starch, modified starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) (commercially available as Microcelac®), and cavitation-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2) (commercially available as Prosolv®).

[0059] Suitable lubricants that can be used in the pharmaceutical compositions of the present invention, including the crystalline compounds of the present invention, further include, for example, talc, colloidal silicon dioxide, starch, and magnesium stearate.

[0060] 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, starches, ion exchange resins such as Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose compositions 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.

[0061] Suitable lubricants that can be used in the pharmaceutical compositions of the present invention containing the 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.

[0062] Some formulations, e.g. tablets, may contain components that have XRPD reflection peaks in the same position or region as the crystalline compound of the present invention, or that have broad peaks. These may mask some of the XRPD patterns or peaks of the crystalline compound of the present invention when XRPD experiments are performed on a formulation containing the crystalline compound of the present invention, as opposed to a pure crystalline salt alone. That is, not all of the XRPD reflection peaks of the crystalline compound of the present invention are always visible when XRPD experiments are performed on a formulation of the crystalline compound of the present invention.

[0063] Thus, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with a pharma- ceutically acceptable vehicle, excipient or pharma- ceutically acceptable carrier(s), wherein said pharma- ceutically acceptable vehicle, excipient or pharma- ceutically acceptable carrier(s) comprises one or more components that exhibit XRPD reflection peaks, including one or more XRPD reflection peaks that overlap or obscure one or more XRPD reflection peaks of the crystalline compound of the present invention.

[0064] The same problems can occur with solid-state NMR, for example, strong signals from cellulose components are expected in the spectral region 60-110 ppm, and peaks from stearates are observed in the spectral region 15-40 ppm along with a carbonyl peak around 172 ppm.

[0065] Thus, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with a pharma- ceutically acceptable vehicle, excipient or pharma- ceutically acceptable carrier(s), wherein said pharma- ceutically acceptable vehicle, excipient or pharma- ceutically acceptable carrier(s) is / are capable of carrying one or more of the crystalline compounds of the present invention. 13 May contain one or more peaks that overlap and are hidden by C CP / MAS NMR peaks 13 It contains one or more components characterized by a C CP / MAS NMR spectrum.

[0066] The XRPD pattern obtained from 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 salt thereof can be compared to the XRPD pattern of Form F obtained from Example 1 and shown in Figure 1 to check for 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. For purposes of this comparison, the XRPD pattern shown in Figure 1 can be considered as the XRPD pattern of a 100% pure crystalline compound of Form F of the present invention.

[0067] Description of the test methods used to characterize the polymorphic forms disclosed herein XRPD: XRPD patterns were collected on a PANalytical X'pert Empyrean diffractometer operating at 45 kV and 40 mA using incident CuKα radiation. XRPD patterns were collected over the 2θ range of 3-60 degrees with a step size of 0.013°, a counting time of 198.645 s, and a transmission geometry. 25 repeats were collected. A parabolic beam CuW / Si (hybrid MPD) monochromator with a 10 mm fixed mask, fixed anti-scatter slits 1 / 8° and fixed divergence slits 1 / 16° were placed in the incident beam path to focus the CuKα X-rays through the sample onto the detector. A long anti-scatter extension was placed in the diffracted beam path to minimize background generated from air. Also, 0.02 rad Soller slits were placed in both the incident and diffracted beam paths to minimize broadening due to axial divergence.

[0068] Intensities measured by XRPD can vary considerably between samples of the same crystal structure due to sample orientation (orientation effects). Intensities measured by XRPD are also subject to experimental error. Measured peak intensities vary depending on a variety of experimental factors such as the instrument used, the test conditions used, sample size, the crystallinity (degree of structural order) of the material, and sample preparation.

[0069] For better particle statistics, the sample was placed on a 3 μm thick foil and rotated once at a rate of 16 s The diffraction patterns were collected using a PIXel RTMS detector with an active length of 3.347°, located 240 mm from the sample.

[0070] SS-NMR 13 C and 1 Solid-state NMR studies were performed using a Bruker Avance III HD 600 NMR instrument operating at Larmor frequencies of 150.9 and 600.13 MHz for H, respectively. 13 C cross-polarization (CP) magic angle spinning (MAS) NMR spectra were recorded. Experiments were performed using a dual-tuned CP / MAS probe fitted with a 4 mm (outer diameter, od) spinner. All samples were packed in a 4 mm (od) zirconia spinner. CP / MAS NMR spectra were recorded using variable amplitude cross-polarization and high power proton decoupling (TPPM) during acquisition. Operating conditions were as follows: temperature: 294 K; contact time: 6 ms; recycle delay: 16 s, 128 scans; spin speed 14.1 kHz. Chemical shifts were referenced to an external sample of α-glycine (carbonyl carbon chemical shift assigned to 176.5 ppm relative to the signal of tetramethylsilane).

[0071] TGA 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 the measurements. The sample temperature was ramped from 25°C to 500°C at 10°C / min. Nitrogen was used as the purge gas at a flow rate of 50 mL / min.

[0072] DSC Differential injection calorimeter (DSC) DSC: heating rate 10° C. / min under nitrogen atmosphere. For the measurements, about 1-2 mg of sample was placed in an open aluminum pan. Instrument Q20 from TA Instruments.

[0073] DVS: Equipment: DVS theory Method: Approximately 5 mg of material was added to an Al pan and exposed to stepwise RH changes during two consecutive cycles according to 20-30-40-50-60-70-80-70-60-50-40-30-20-10-0-10-20-30-40-50-60-70-80-90-80-70-60-50-40-30-20-10-0% RH using open loop mode. Experiments were performed using a gas flow rate of 200 mL / min and 25°C. The dm / dt criterion applied was 0.001 wt% / min for a 5 min window and the maximum allowed time was 150 min for all steps except for the 0% RH step, for which there was no criterion but which was set at 6 h.

[0074] Single crystal X-ray diffraction Data were collected using a SuperNova, dual diffractometer equipped with an Atlas CCD area detector (temperature: 120(2)K; CuKa radiation λ=1.5418Å; data collection method: ω-scan). Details can be found in the table above. Programs used to interpret the structure: CrysAlisPro, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET), ShelXL (Sheldrick, 2008): used for structure refinement and Olex2 (Dolomanov et al., 2009): used for ORTEP structure generation.

[0075] The error ranges given in this application for spectroscopic properties, including those set forth in the claims, may be more or less dependent on factors well known to those skilled in the art of spectroscopy and may vary due to sample formulation, e.g., particle size distribution, or, if a crystalline form is part of the formulation, the composition of the formulation as well as instrumental variations and other factors.

[0076] In the following the invention will be explained in more detail by means of illustrative, non-limiting examples. EXAMPLES

[0077] Example 1: Preparation of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate monohydrate 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine (1.0 eq.) and succinic acid (0.55 eq.) were mixed. 1-propanol (40 mL / g) was added. The reaction mixture was heated to 40° C. and stirred under an inert atmosphere. Water (2 mL / g) was added and the reaction mixture was stirred at 40° C. for 30 minutes and then cooled to 20° C. over 60 minutes. The resulting mixture was stirred at 20° C. for 18 hours.

[0078] The reaction mixture was filtered, and the filter cake was washed with 1-propanol (5 mL / g) and then dried under vacuum at 50° C. The isolated crystalline compound 1 The presence of hemisuccinate was confirmed by H NMR ( 1 H NMR (600 MHz): 9.95 ppm (s, 1H), 8.89 ppm (d, J=2.3 Hz, 1H), 8.58 ppm (d, J = 2.3 Hz, 1H), 4.78-5.01 ppm (m, 1H), 4.31-4.55 ppm (m, 2H), 3.94-4.10 ppm (m, 1H), 3.76 ppm (tt, J=4.9, 7.2 Hz, 1H), 2.33 ppm (s, 3H), 2.39 ppm (s, 2H, succinate). The molar ratio of 1.0:0.5 was confirmed by the fact that the integral for the succinate is only the relative amount of the two hydrogens.

[0079] The XRPD of the crystalline compound is shown in FIG.

Claims

1. A crystalline compound of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate monohydrate, characterized by one or more XRPD reflections at 2θ (±0.2°) of 8.6, 11.9 and / or 15.8°.

2. The crystalline compound according to claim 1, characterized by one or more XRPD reflections at 2θ (±0.2°) of 8.6, 11.9, 15.8 and / or 25.8°.

3. The crystalline compound according to claim 1, characterized by one or more XRPD reflections at 2θ (±0.2°) of 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and / or 21.7°.

4. The crystalline compound according to claim 1, characterized by one or more XRPD reflections at 2θ (±0.2°) of 8.6, 11.9 and 15.8°.

5. The crystalline compound according to claim 1, characterized by one or more XRPD reflections at 2θ (±0.2°) of 8.6, 11.9, 15.8 and 25.8°.

6. The crystalline compound according to claim 1, characterized by one or more XRPD reflections at 2θ (±0.2°) of 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and 21.7°.

7. The crystalline compound according to claim 1, having an XRPD pattern essentially similar to the XRPD pattern of Figure 1.

8. The crystalline compound according to claim 1, having an XRPD pattern according to the XRPD pattern of Figure 1.

9. A solid having a peak at one or more of 180, 60.0, 50.3 and / or 34.2 ppm (±0.2 ppm). 13 The crystalline compound according to claim 1, characterized by a 13C CP / MAS NMR spectrum.

10. A solid having a peak at one or more of 180, 146.7, 140.5, 138.1, 130.1, 118.2, 60.0, 56.8, 50.3 and / or 34.2 ppm (±0.2 ppm) 13 The crystalline compound according to claim 1, characterized by a C CP / MAS NMR spectrum

11. Of FIG. 5 13 A crystalline compound according to claim 9, characterized by having a 13 C CP / MAS NMR spectrum that is essentially similar to the 13 C CP / MAS NMR spectrum. 13 C CP / MAS NMR spectrum.

12. According to the 13 C CP / MAS NMR spectrum of 13 The crystalline compound according to claim 9, characterized by having a C CP / MAS NMR spectrum.

13. The crystalline compound according to claim 9, further characterized by one or more XRPD reflections at 2θ (±0.2°) of 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and 21.7°.

14. The crystalline compound according to claim 1, characterized by having the single crystal X-ray crystallographic (SXRC) parameters shown in Table 1.

15. The crystalline compound according to claim 1, having a DSC curve comprising an endothermic event having an onset value at about 138.4 ± 2 °C.

16. The crystalline compound according to claim 1, characterized in that the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine to succinic acid is in the range of 2:1.2 to 2:0.8, preferably about 2:

1.

17. The crystalline compound according to claim 1, characterized in that the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate to water is in the range of 1:0.8 to 1:1.2, preferably about 1:

1.

18. A pharmaceutical composition comprising the crystalline compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising the crystalline compound according to any one of claims 1 to 17 for the treatment of a disease selected from atopic dermatitis, itching, pruritus and various forms of urticaria.

20. The pharmaceutical composition according to claim 19, characterized in that the urticaria form includes the chronic idiopathic urticaria subtype.

21. The pharmaceutical composition according to claim 20, characterized in that the chronic idiopathic urticaria subtype includes cholinergic urticaria.

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