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

Abstract

Novel crystalline forms of 1-(8-pyridino[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine hemisuccinate and pharmaceutical compositions comprising the thereof are also disclosed. The use of the novel polymorph for treating diseases such as atopic dermatitis (AD), pruritus, pruritus, and various forms of urticaria, such as the subtype of chronic idiopathic urticaria, is also revealed.

Description

[Technical Field]

[0001] This invention relates to a novel crystalline form of 1-(8-pyridano[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine hemisuccinate, pharmaceutical compositions comprising the novel crystalline form of 1-(8-pyridano[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine hemisuccinate, 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 subtypes of chronic idiopathic urticaria, such as cholinergic urticaria. A method for preparing the crystalline form of the invention is also provided herein. [Previous Technology]

[0002] U.S. Patent No. 9,586,959 relates particularly to the compound 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising the thereof. This patent discloses the preparation of various salts of the compound 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine.

[0003] 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine exhibits strong histamine 4 receptor inhibition and demonstrates inhibitory effects against histamine-induced infiltration of inflammatory cells (such as mast cells and eosinophils). Therefore, the compound possesses strong anti-inflammatory and antipruritic effects and is thus suitable for treating a range of diseases, such as those disclosed in U.S. Patent No. 9,586,959, including Alzheimer's disease (AD).

[0004] Different crystalline solid forms of compounds may have different physical properties, such as chemical stability, physical stability, hygroscopicity, melting point, solubility, dissolution rate, morphology and bioavailability, making them more or less suitable as active ingredients in pharmaceutical products.

[0005] Furthermore, a chemical entity can exist in several different crystalline solid forms, including different polymorphic forms sharing the same overall chemical formula (e.g., anhydrous forms), and different solvates of the same chemical entity that do not share the same overall chemical formula (e.g., hemihydrates, monohydrates, and dihydrates). These crystalline solid forms have different crystal structures and different physical properties. Different crystalline solid forms can be distinguished from each other by, for example, melting point, XRPD plots, spectroscopic features (e.g., FT-IR, Raman, and SS-NMR), and other physical and chemical properties. A chemical entity can also exist in an amorphous form.

[0006] Therefore, the selected actual crystalline form plays an important role in the research and development and manufacturing of active pharmaceutical ingredients. If a single crystal form is required, it is important that the crystallization process stably and reliably produces the desired crystalline form in a polymorphic pure form, and that the crystalline form does not change (e.g., transform into different crystalline forms) during the relevant manufacturing process and / or during storage.

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

[0008] Several different salts of 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine have been identified. Some salts exist as anhydrous, monohydrate, and dihydrate, each in several polymorphic forms, which interconvert upon drying or loss of water at relatively low temperatures, and are therefore unsuitable for pharmaceutical development.

[0009] A crystalline form of 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine hemisuccinate monohydrate has been identified (hereinafter referred to as form F).

[0010] Form F is a channel hydrate, and generally channel hydrates / solvents are not extremely stable because solvent molecules can easily move in and out of the channel, causing lattice collapse. In the case of form F, water molecules are positioned in the same molecular plane as succinic acid molecules, stabilizing the hydrate and making form F particularly suitable for solid pharmaceutical products, such as tablets. Furthermore, form F can be dried under moderately dry conditions, such as in a vacuum oven at 60°C (see Figure 8) without lattice collapse. Additionally, form F has been found to be suitable for large-scale drying.

[0011] Furthermore, the crystal inertia and particle size distribution are very similar between batches of form F, and the particle size distribution data regarding the processability of the drug is promising.

[0012] Experiments have shown that form F is resistant to micronization without undergoing amorphization.

[0013] Furthermore, form F is a hemisuccinate, which will allow for a higher drug loading. This can be extremely beneficial at high doses, and for optimal patient compliance, the tablet size should be kept as small as possible. [Summary of the Invention]

[0014] This invention relates to crystalline 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine hemisuccinate monohydrate, characterized by one or more XRPD reflections at approximately (°2θ) 8.6, 11.9 and / or 15.8 (±0.2°).

[0015] This invention also relates to a pharmaceutical composition comprising the crystalline form mentioned above and a pharmaceutically acceptable carrier.

[0016] In one embodiment, the present invention relates to a compound or pharmaceutical composition as described above for the treatment of diseases selected from atopic dermatitis, pruritus, pruritus and various forms of urticaria, including subtypes of chronic idiopathic urticaria.

Implementation Method

[0018] The potential technical problem of 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-methylacetidine-3-amine, such as the ability to form crystals, filtration characteristics, solubility, thermodynamic properties, stability problems (e.g. due to water absorption), density, and transformation under different humidity levels and during the crystallization process (e.g., mutual transformation into other polymorphic forms or hydrates / anhydrouses).

[0019] As defined herein, the term “rt” or “room temperature” indicates that the applied temperature is not critical and need not be maintained at an exact temperature value. Generally, “rt” or “room temperature” should be understood to mean a temperature of about 15°C to about 25°C [see, for example, the European Pharmacopoeia 7.5, 1.2 (2012)].

[0020] As used herein, the term "solvent" describes a crystalline compound in which solvent molecules are 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.

[0021] The type of hydrate depends on the molar ratio of the water molecule to the 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine hemisuccinate molecule.

[0022] The term "monohydrate" means that each mole of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine hemisuccinate contains 0.8 to 1.2 moles of water.

[0023] As the term “non-hygroscopic” is used herein, the increase in the mass of the active pharmaceutical ingredient is less than 0.2 wt% in the range of about 0% to 80% relative humidity.

[0024] In the context of this invention, the term "XRPD reflection peak" refers to a specific 2Θ position in an XRPD plot where the signal-to-noise ratio (calculated according to section 2.2.46 of the European Pharmacopoeia) is greater than 3 / 1. "No peak" is defined herein as a peak with an intensity of at most 1% of the highest peak in the XRPD of a sample of the compound of the invention, such as 0.5% or 0.2%, i.e., no detectable XRPD peaks above the background signal.

[0025] In an XRPD plot, the main characteristics of the diffraction profile are the 2Θ position, peak height, peak area, and shape (characterized by, for example, peak width or asymmetry, analytical function, and empirical representation). The 2Θ position is the most important factor because, for example, intensity will be affected by sample preparation, and peak width will be affected by particle size. In addition to diffraction peaks, X-ray diffraction experiments also produce an almost uniform background in the XRPD plot, on which the diffraction peaks are superimposed. Other factors besides sample preparation also contribute to the background, such as the sample holder, diffuse scattering from air and equipment, other instrument parameters (such as detector noise), and general radiation from the X-ray tube. The peak-to-background ratio can be increased by minimizing the background and / or by selecting an extended exposure time.

[0026] Abbreviations: DSC: Differential Scanning Calorimetry; DVS: Dynamic Vapor Adsorption; TGA: Pyrolysis Gravimetric Analysis; XRPD: X-ray Powder Diffraction; 13C CP / MAS NMR: 13C Cross-Polarized Magic Angle Rotating Nuclear Magnetic Resonance; SXRD: Single Crystal X-ray Diffraction.

[0027] Table 1 below shows the SXRD single-crystal X-ray analysis of form F. LEO152020G, Form F Crystal data Chemical formula 2(C 12 H 12 BrN7)·C4H6O4·2(H2O) M r 822.47 Crystal system, space group Triclinic crystal system, P1 Temperature (K) 120 a,b,c(Å) 7.8767 (2), 9.8582 (3), 11.7062 (3) a, b, g (°) 110.731 (2), 106.260 (2), 98.961 (2) V(Å 3 ) 782.55 (4) Z 1 Radiation type CuKa m (mm -1 ) 3.88 Data collection diffractometer SuperNova, dual light source, Cu at zero, Atlas diffractometer Absorption correction Multiscan CrysAlis PRO, Agilent Technologies, version 1.171.36.28 (released February 1, 2013, CrysAlis171.NET) (compiled February 1, 2013, 16:14:44) uses empirical absorption correction of spherical harmonic functions, implemented in the SCALE3 ABSPACK scaling algorithm. Measured, independent and observed [I³ 2u(I)] reflectance 11730, 5706, 5692 R int 0.021 (sin q / l) max (Å -1 ) 0.623 optimization R[F 2 > 2s(F 2 )],wR(F 2 ),S 0.048, 0.177, 1.69 Reflection number 5706 Number of parameters 211 Limited number 3 (D / s) max 1.663 Dρ max , Dρ min (e Å -3 ) 1.01, -0.77 Table 1. Crystal parameters derived from single-crystal structure determination

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

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

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

[0031] In another embodiment, the present invention relates to a crystalline compound as defined above, wherein the XRPD reflection comprises one or more XRPD reflections at approximately 8.6, 11.9 and 15.8 (±0.2°).

[0032] In another embodiment, the present invention relates to a crystalline compound as defined above, wherein the XRPD reflection is included at approximately (°2θ) 8.6, 11.9, 15.8 and 25.8 (±0.2°).

[0033] In another embodiment, the present invention relates to a crystalline compound as defined above, wherein the XRPD reflection is included at approximately (°2θ) 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and 21.7 (±0.2°).

[0034] In another embodiment, the present invention relates to a crystalline compound as defined above, wherein the crystalline compound has an XRPD plot substantially similar to the XRPD plot in FIG1.

[0035] In another embodiment, the present invention relates to a crystalline compound as defined above, wherein the crystalline compound has an XRPD diagram according to the XRPD diagram in FIG1.

[0036] In another embodiment, the present invention relates to a crystalline compound as defined above, wherein the crystalline compound is characterized by a solid-state 13C CP / MAS NMR spectrum with peaks at one or more of 180, 60.0, 50.3 and / or 34.2 ppm ± 0.2 ppm.

[0037] In another embodiment, the present invention relates to a crystalline compound as defined above, wherein the crystalline compound is characterized by a solid-state 13C CP / MAS NMR spectrum with 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.

[0038] In another embodiment, the present invention relates to a crystalline compound as defined above, characterized by having a 13C CP / MAS NMR spectrum substantially similar to the 13C CP / MAS NMR spectrum in Figure 5.

[0039] In another embodiment, the present invention relates to a crystalline compound as defined above, characterized by having a 13C CP / MAS NMR spectrum according to the 13C CP / MAS NMR spectrum in Figure 5.

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

[0041] In another embodiment, the present invention relates to a crystalline compound as described above, having a DSC curve that includes an endothermic event with an initial value of about 138.4 ± 2 °C.

[0042] In another embodiment of the present invention, form F is characterized by having single crystal parameters that are substantially the same as those provided in Table 1.

[0043] In one more particularly preferred embodiment of the present invention, form F has the structure obtained by single-crystal X-ray crystallography (SXRC) as shown in FIG4.

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

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

[0046] Method for preparing form F The crystalline form of the present invention can be prepared from 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine in the form of a free base by crystallization at rt, or cooled to a temperature below rt, such as below 0°C, preferably -18°C.

[0047] In one particular embodiment, the solvent is 1-propanol, and crystallization is carried out at rt or higher or lower temperatures (such as -18°C).

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

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

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

[0051] The crystalline form F of the present invention has advantages over other salt forms because it uses milder reaction conditions, that is, compared with salt forms prepared by a larger amount of stronger acid, such as the sulfate used to prepare, for example, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine, about 0.5 equivalents of the weak acid succinic acid.

[0052] Due to the mild reaction conditions, there is essentially no degradation of the 1-(8-bromopyridino[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine molecule during the final salt formation, and a higher purity product is produced mainly due to the reduced degradation and a significantly lower impurity burden.

[0053] 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 in the form of tablets and / or capsules.

[0054] In addition, the present invention relates to the use of the crystalline compound of the present invention in the preparation of solid pharmaceutical preparations.

[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 pharmaceutically acceptable carrier, and a method thereof. Furthermore, the present invention relates to the pharmaceutical compositions and / or the crystalline compounds of the present invention for the treatment of any of the diseases or conditions mentioned in U.S. Patent No. 9,586,959, including diseases and conditions such as atopic dermatitis (AD), pruritus, pruritus, and various forms of urticaria.

[0056] The pharmaceutical compositions of the present invention comprising the crystalline compounds of the present invention may further comprise one or more pharmaceutically 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 art of pharmaceutical compositions may also be used. Furthermore, the pharmaceutical composition may comprise a combination of two or more excipients also belonging to one of the groups mentioned above.

[0057] Suitable adhesives that can be used in pharmaceutical compositions of the present invention comprising the crystalline compounds of the present invention further comprise, for example, alkyl cellulose, such as methyl cellulose; hydroxyalkyl cellulose, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; hydroxyalkylalkyl cellulose, such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; carboxyl cellulose, such as carboxymethyl cellulose; alkali metal salts of carboxyl cellulose, such as sodium carboxymethyl cellulose; carboxylalkyl cellulose, such as carboxymethyl ethyl cellulose; carboxyl cellulose esters; starch, such as starch 1551; modified starch, such as sodium carboxymethyl starch. Pectin; chitin derivatives, such as polyglucosamine, heparin and heparin-like substances; polysaccharides, such as alginic acid; alkali metals and their ammonium salts; carrageenan; galactomannan; tragacanth gum; agar-agar; gum arabic; guar gum; and saffron gum; polyacrylic acid and its salts; polymethacrylic acid and its salts; methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone; copolymers of polyvinylpyrrolidone and vinyl acetate; polyepoxides, such as ethylene oxide and propylene oxide; and copolymers of ethylene oxide and propylene oxide, such as poloxamer and poloxamine; copovidone.

[0058] Suitable diluents for use in pharmaceutical compositions of the present invention containing crystalline compounds of the present invention further include, for example, calcium carbonate, dicalcium phosphate, dicalcium phosphate dihydrate, tricalcium phosphate, calcium sulfate, microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, glucose binder, dextrin, dextran excipient, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, starch, modified starch, sodium chloride, sucrose, compressible sugar, powdered sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) (which is commercially available from Microcelac®), and a co-treated spray-dried mixture of microcrystalline cellulose and colloidal silica (98:2) (which is commercially available from Prosolv®).

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

[0060] Suitable disintegrants that can be used in pharmaceutical compositions of the present invention containing crystalline compounds of the present invention further include, for example, starch, ion exchange resins (e.g., Amberlite), croscarmellose, modified cellulose gum (e.g., croscarmellose sodium), sodium glycolate starch, sodium carboxymethyl cellulose, sodium dodecyl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginate, and powdered cellulose.

[0061] Suitable lubricants for pharmaceutical compositions of the present invention that also contain 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 or broad peaks at the same positions or regions as the crystalline compounds of the present invention. Compared to pure crystalline salts alone, these components may obscure some XRPD patterns or peaks of the crystalline compounds of the present invention when XRPD experiments are performed on formulations containing the crystalline compounds of the present invention. This means that when XRPD experiments are performed on formulations of crystalline compounds, not all XRPD reflection peaks of the crystalline compounds of the present invention can always be observed.

[0063] Therefore, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein and a pharmaceutically acceptable medium, excipient or pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable medium, excipient or pharmaceutically acceptable carrier comprises one or more components exhibiting an XRPD reflection peak that overlaps with one or more XRPD reflection peaks of the crystalline compound of the present invention and hides the XRPD reflection peaks of one or more XRPD reflection peaks of the crystalline compound of the present invention.

[0064] The same problem can occur in the case of solid-state NMR, where, for example, a strong signal from the cellulose component should be expected in the spectral region of 60-110 ppm, and a peak from stearate can be seen in the spectral region of 15-40 ppm, along with a carbonyl peak of about 172 ppm.

[0065] Therefore, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein and a pharmaceutically acceptable medium, excipient or pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable medium, excipient or pharmaceutically acceptable carrier comprises one or more components, characterized in that it may include one or more 13C CP / MAS NMR spectra that overlap with and conceal the peaks of one or more 13C CP / MAS NMR peaks of the crystalline compound of the present invention.

[0066] The absence of other crystalline forms of 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine can be tested by comparing XRPD plots collected from any crystalline form of 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine or its salts with, for example, XRPD plots from form F shown in Example 1 and Figure 1. For such comparisons, the XRPD plot shown in Figure 1 can be considered as the XRPD plot of the 100% pure crystalline compound of form F of the present invention.

[0067] Description of the test method used to characterize the polycrystalline form disclosed herein: XRPD: XRPD patterns were collected using an incident Cu Kα radiation at 45 kV and 40 mA with a PANalytical X'pert Empyrean diffractometer. XRPD patterns were collected in 2θ over a range of 3 to 60° with a step size of 0.013°, a counting time of 198.645 s, and with transmission geometry. The process was repeated 25 times and summarized. In the incident beam path, a parabolic Cu W / Si (hybrid MPD) monochromator, along with a 10 mm fixed shield, a 1 / 8° fixed antiscattering slit, and a 1 / 16° fixed divergence slit, was placed to linearly focus Cu Kα X-rays through the sample and onto the detector. Long antiscattering extensions were placed in the diffracted beam path to minimize background generated by air. In addition, a Soller slit of 0.02 radians is placed on the incident beam path and the diffracted beam path to minimize axial divergence.

[0068] Due to orientation within the sample, the intensity measured in XRPD can vary significantly between samples with the same crystal structure (orientation effect). The intensity measured in XRPD will also include experimental error. The measured peak intensity will vary depending on various experimental factors, such as the equipment used, the test conditions used, the sample size, the crystallinity of the material (the degree of structural order), and sample preparation.

[0069] The sample was placed on a 3 μm thick foil that rotated once every 16 s for better particle statistics. Diffraction patterns were collected using a PIXel RTMS detector with an effective length of 3.347° and a distance of 240 mm from the sample.

[0070] SS-NMR was performed using a Bruker Avance III HD 600 NMR instrument, operating at Larmor frequencies of 150.9 MHz and 600.13 MHz for 13C and 1H, respectively, recording solid-state 13C cross-polarized (CP) magic-angle rotation (MAS) NMR spectra. Experiments were conducted using a dual-tuned CP / MAS probe fitted with a 4 mm (od) rotator. All samples were encapsulated in a 4 mm (od) zirconia rotator. Variable amplitude cross-polarization and high-power proton decoupling (TPPM) were used to record CP / MAS NMR spectra during collection. Operating conditions were: temperature: 298 K; contact time: 6 ms; recirculation delay: 16 s, 128 scans; rotation rate: 14.1 kHz. Chemical shifts were referenced to the external sample of α-glycine (carbonyl carbon chemical shift distribution was 176.5 ppm relative to the tetramethylsilane signal).

[0071] Thermogravimetric analysis (TGA) was performed using a TGA550 instrument from TA Instruments. Approximately 1 to 10 mg of sample was loaded into a ceramic dish for measurement. The sample temperature was gradually increased from 25°C to 500°C at a rate of 10°C / min. Nitrogen gas was used as the purge gas at a flow rate of 50 mL / min.

[0072] Differential Scanning Calorimetry (DSC): DSC is performed under a nitrogen atmosphere at a heating rate of 10 °C / min. Approximately 1–2 mg of sample is loaded into an open aluminum dish for measurement. An Instrument Q20 from TA Instruments is used.

[0073] DVS: Instrument: DVS Advantage

[0074] Method: Approximately 5 mg of the substance was added to an Al disk and exposed to a gradual RH change 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 an open-loop mode. Experiments were conducted at a gas flow rate of 200 ml / min and at 25°C. The applied dm / dt standard was 0.001 wt% / min over a 5-minute window, with a maximum permissible time of 150 minutes for all steps, except for steps without a standard at 0% RH but set to 6 hours.

[0075] Single-crystal X-ray diffraction was performed using a SuperNova dual-source diffractometer with an Atlas CCD region detector (temperature: 120(2) K; CuKα radiation λ=1.5418 Å; data collection method: ω scan). Other details are shown in the table above. Programs used for solving the structure: CrysAlisPro, Agilent Technologies, version 1.171.37.34 (released May 22, 2014, CrysAlis171.NET), ShelXL (Sheldrick, 2008) for optimizing the structure, and Olex2 (Dolomanov et al., 2009) for ORTEP plots.

[0076] Regarding the spectral characteristics, the given errors in this application, including those within the scope of the claims, may vary more or less depending on factors known to a person skilled in spectroscopy and may depend, for example, on sample preparation, such as particle size distribution, or, if the crystalline form is part of a formulation, on the composition of the formulation, as well as instrument fluctuations and other factors.

[0077] The invention will be described in more detail below by way of illustrative and non-limiting examples.

[0078] Example 1: Preparation of 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine hemisuccinate monohydrate. A mixture of 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacridine-3-amine (1.0 equivalent) and succinic acid (0.55 equivalent) was added. 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, followed by cooling to 20°C over a 60-minute period. The resulting mixture was stirred at 20°C for 18 hours.

[0079] The reaction mixture was filtered, and the filter cake was washed with 1-propanol (5 mL / g) and dried under vacuum at 50 °C. The presence of hemisuccinate was confirmed by 1H NMR of the isolated crystalline compound (1H 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 integral of succinate is equivalent to the relative amounts of two hydrogen atoms, which confirms a molar ratio of 1.0:0.5.

[0080] The XRPD of the crystalline compound is shown in Figure 1. [Simplified Explanation of the Diagram]

[0017] Figure 1: XRPD plot of form F (3-60° 2θ). Figure 2: XRPD plot of form F (3-30° 2θ). Figure 3: DSC and TGA curves of form F. Figure 4: ORTREP diagram of the absolute crystal structure of form F. Hydrogen atoms have been excluded for easier viewing. Figure 5: 13C CP / MAS NMR spectrum of form F. The integral of aliphatic carbons confirms that this is a hemisuccinate, as the total integral of aliphatic carbons is 5.18, which is in good agreement with the four carbons of the side chain of the molecule and the carbon from one CH2 in the succinic acid molecule. Figure 6: TGA of form F after running 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 stored in vacuum at 60°C for different durations. Records were made at various time points of rapid XRPD (9 min) and normal XRPD (1 hour). Figure 9: XRPD (top diffraction pattern) of F as a powder, XRPD (middle diffraction pattern) of an ingot prepared at 5.5°C, and XRPD (bottom diffraction pattern) of an ingot prepared at 7.0°C. Figure 10: Single crystal structure of F as shown along the A) a-axis, B) b-axis, C) c-axis, and D) molecular plane. Carbon atoms are shown in gray, nitrogen atoms in blue, oxygen atoms in red, and bromine atoms in orange. Along the b-axis, the base ring system is stacked in opposite directions, and along the molecular plane, succinic acid and water are located in the plane between the base molecules.

Claims

1. A crystalline compound of 1-(8-pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylacetidine-3-amine hemisuccinate monohydrate, characterized in that XRPD reflection is at (°2θ) = 8.6, 11.9 and 15.8 (±0.2°).

2. The crystalline compound of claim 1, wherein XRPD is reflected at (°2θ) = 8.6, 11.9, 15.8 and 25.8 (±0.2°).

3. The crystalline compound of claim 1, wherein XRPD is reflected at (°2θ) = 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and 21.7 (±0.2°).

4. The crystalline compound of claim 1, wherein the crystalline compound has an XRPD diagram according to the XRPD diagram in Figure 1.

5. The crystalline compound of claim 1, wherein the crystalline compound is characterized by a solid-state 13C CP / MAS NMR spectrum with peaks at one or more of 180, 60.0, 50.3 and / or 34.2 ppm ± 0.2 ppm.

6. The crystalline compound of claim 5, wherein the crystalline compound is characterized by a solid-state 13C CP / MAS NMR spectrum with 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.

7. The crystalline compound of claim 5, wherein the 13C CP / MAS NMR spectrum is as shown in Figure 5.

8. The crystalline compound of claim 5, wherein one or more XRPD reflections are further at (°2θ) 8.6, 9.9, 11.9, 13.3, 15.8, 16.1, 17.3 and 21.7 (±0.2°).

9. The crystalline compound of claim 1, wherein the crystalline compound is characterized by having single-crystal X-ray crystallography (SXRC) parameters as shown in the table below: .

10. The crystalline compound of claim 1, having a DSC curve including an endothermic event with an initial value of 138.4 ± 2 °C.

11. A pharmaceutical composition comprising a crystalline compound as claimed in any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11 is used to treat atopic dermatitis, pruritus, pruritus and various forms of urticaria.

13. The pharmaceutical composition of claim 12, wherein the forms of urticaria include the subtype of chronic idiopathic urticaria.

14. The pharmaceutical composition of claim 13, wherein the subtypes of chronic idiopathic urticaria include cholinergic urticaria.

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