Novel salt of imidazo [1, 2-a] pyridine compound, crystal form and preparation method thereof

Abstract

In the novel salt of the imidazo [1, 2-a] pyridine compound, the crystal form thereof and the preparation method of the novel salt of the imidazo [1, 2-a] pyridine compound, the novel salt of the imidazo [1, 2-a] pyridine compound is azetidine-1-yl {8-[(2, 6-dimethyl benzyl) amino]-2, 3-dimethyl imidazo [1, 2-a] pyridine-6-yl} ketone citrate.

Description

Technical Field

[0001] The present invention relates to a novel salt of an imidazo[1,2-a]pyridine compound, a crystal form thereof and a preparation method thereof. Background of the Invention

[0003] Gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), etc. are the most common digestive system diseases in most of the world's population, including Korea.

[0004] In order to solve the problems of traditional proton pump inhibitors (PPIs), there has been an increasing interest and demand for PPIs, potassium-competitive acid blockers (P-CABs, acid pump antagonists), which have the ability to reversibly bind to H + / K + -K of ATPase + The mechanism of binding sites to inhibit acid secretion by potassium competitive inhibition between proton pump inhibitors. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) are expected to have rapid efficacy in mechanism, be easy to take effect regardless of when they are taken before or after meals, and be very effective in improving nighttime symptoms, which is a problem with irreversible proton pump inhibitors.

[0005] At the same time, the compound is not only required to have good biological properties, but also to have sufficient physical properties to be used for preparing pharmaceutical compositions, so that it can be considered as a candidate material for developing drugs. In addition, this compound is preferably in a solid phase for ease of preparation and stable formulation.

[0006] Therefore, the present inventors conducted intensive research to find a form that is stable in all aspects and can be industrialized in order to use imidazo[1,2-a]pyridine compounds for pharmaceutical purposes. As a result, they identified a new salt that exhibited unexpected significant effects, thereby completing the present invention.

[0007] Related technical references

[0008] Patent Documents

[0009] Korean registered patent publication number No.10-1777971 Summary of the invention

[0010] Technical issues

[0011] One object of the present invention is to provide novel salts of imidazo[1,2-a]pyridine compounds.

[0012] Another object of the present invention is to provide a crystalline form of a novel salt of an imidazo[1,2-a]pyridine compound.

[0013] Another object of the present invention is to provide a method for preparing a novel salt of an imidazo[1,2-a]pyridine compound.

[0014] Technical Solution

[0015] Novel salts of imidazo[1,2-a]pyridine compounds

[0016] (1) The novel salt of the imidazo[1,2-a]pyridine compound according to the present invention is azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0017] Hereinafter, the term "citrate of Formula I" or "citrate salt" simply used herein refers to "azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate".

[0018] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is represented by the following Chemical Formula I:

[0019] [Chemical Formula I]

[0020]

[0021] (2) In the above (1), in the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the citrate, the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid may be 1:0.3 to 1:1.3. For example, the molar ratio is 1:0.5 to 1:1.

[0022] (3) In the above (1) or (2), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention can be represented by the following chemical formula II:

[0023] [Chemical Formula II]

[0024]

[0025] In the above Chemical Formula II, n represents 0.3 to 1.3.

[0026] In one embodiment, n of the above Chemical Formula II may be 0.5 to 1.

[0027] (4) In any one of the above (1) to (3), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be anhydrous.

[0028] (5) In any of the above (1) to (4), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be crystalline or amorphous.

[0029] (6) In any one of the above (1) to (5), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be anhydrous crystalline.

[0030] (7) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate can be form A, whose powder X-ray diffraction pattern contains at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 5.46°, 7.14°, 10.61°, 11.82°, 18.27° and 25.77°.

[0031] (8) In the above (7), the powder X-ray diffraction pattern of Form A may also include at least one diffraction peak, wherein the 2θ (±0.2°) value is selected from 10.93°, 13.11°, 14.15°, 15.84°, 16.35°, 19.79° and 24.21°.

[0032] (9) In the above (7) or (8), when the heating rate is 10°C / min, the differential scanning calorimetry (DSC) endothermic peaks of Form A may be 88.69°, 135.61° and 154.84° (±0.5°C).

[0033] (10) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate can be a crystalline form B, whose powder X-ray diffraction pattern includes at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 7.03°, 7.69°, 9.47°, 13.21°, 14.86° and 21.13°.

[0034] (11) In the above (10), when the heating rate is 10°C / min, the differential scanning calorimetry (DSC) endothermic peak of Form B may be 144.57°C (±0.5°C).

[0035] (12) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate can be a crystalline form C1, whose powder X-ray diffraction pattern includes at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 7.35°, 15.31°, 17.42° and 22.26°.

[0036] (13) In the above (12), the powder X-ray diffraction pattern of Form C1 may also include at least one diffraction peak, wherein the 2θ (±0.2°) value is selected from 10.23°, 12.90°, 14.68°, 15.97°, 18.21°, 21.22° and 26.00°.

[0037] (14) In the above (12) or (13), when the heating rate is 10°C / min, the differential scanning calorimetry (DSC) endothermic peak of Form C1 may be 168.93°C (±0.5°C).

[0038] (15) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate can be a crystalline form C2, whose powder X-ray diffraction pattern includes at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 5.63°, 8.90°, 9.51° and 13.01°.

[0039] (16) In the above (15), the powder X-ray diffraction pattern of Form C2 may also include at least one diffraction peak, wherein the 2θ (±0.2°) value is selected from 12.31°, 14.34°, 14.80°, 18.38°, 18.75° and 19.62°.

[0040] (17) In the above (15) or (16), when the heating rate is 10°C / min, the differential scanning calorimetry (DSC) endothermic peak of Form C2 can be 161.48° (±0.5°C).

[0041] (18) In any one of the above (1) to (5), at a heating rate of 10°C / min, the amorphous differential scanning calorimetry (DSC) endothermic peak of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate can be 161.42°C (±0.5°C).

[0042] (19) In any one of the above (1) to (11), in each of the crystalline forms A and B of the citrate of the present invention, the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid can be 1:0.5.

[0043] (20) In any of the above (1) to (6) and (12) to (17), in each of the citrate crystalline forms C1 and C2 of the present invention, the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid can be 1:1.

[0044] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention can exhibit unexpectedly excellent bioavailability, and can therefore be used as an active ingredient of a pharmaceutical composition to exhibit excellent effects in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0045] Furthermore, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention has the advantages of being easily prepared by a simple process and being obtained in high purity with a high yield of 90% or more.

[0046] In addition, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention can be used to formulate pharmaceutical products because even under similar solvent conditions, different crystal forms can be produced due to slight differences in reaction temperature, reaction rate, etc., and these crystal forms have excellent light stability, heat / humidity stability, long-term storage stability, etc.

[0047] The pharmaceutical composition of the present invention comprises a therapeutically effective amount of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0048] The pharmaceutical composition of the present invention can treat or prevent diseases selected from the following: peptic ulcer, gastric / duodenal ulcer, ulcer caused by nonsteroidal anti-inflammatory drugs (NSAIDs), Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD).

[0049] Preparation method of novel salt of imidazo[1,2-a]pyridine compound

[0050] (21) A method for preparing the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention, comprising reacting azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with citric acid to prepare a citrate.

[0051] (22) In the preparation of the citrate salt in the above (21), azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be reacted with citric acid in the presence of at least one solvent selected from an alcohol having 1 to 3 carbon atoms, acetone, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP) and purified water.

[0052] (23) In the above (21) or (22), azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be synthesized according to the following reaction formula 1:

[0053] [Reaction 1]

[0054]

[0055] (24) In the above reaction formula (23), 8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid can be obtained according to the method described in Korean Patent Publication No. 10-1777971, and the specific process of the above reaction formula (1) can also be carried out according to the contents disclosed therein.

[0056] (25) In any one of the above (21) to (24), in the preparation of the citrate, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be a non-solvate, a solvate or a mixture thereof.

[0057] (26) In any one of the above (23) to (25), the solvate, non-solvate or a mixture thereof obtained by crystallizing the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained according to the above reaction formula 1 in an alcohol solvent having 1 to 3 carbon atoms and then vacuum drying can be reacted with citric acid. The solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be obtained by vacuum drying at a temperature of about 20° C. or more to about 35° C. or less. A non-solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be obtained by vacuum drying at a temperature of about 45° C. or higher and about 60° C. or lower. A mixture of the solvate and the non-solvate can be obtained by vacuum drying at a temperature of higher than about 35° C. and lower than about 45° C.

[0058] (27) In any one of the above (21) to (26), in the preparation of the citrate, a citrate in which the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid is about 1:0.3 to about 1:1.3 can be prepared. For example, in the preparation of the citrate, a citrate in which the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid is about 1:1 or about 1:0.5 can be prepared.

[0059] (28) In any one of the above (21) to (27), in the preparation of the citrate salt, a solvate, a non-solvate or a mixture thereof obtained from azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be mixed with citric acid in a weight ratio of about 1:1.3 to about 1:0.3.

[0060] (29) In any one of the above (21) to (28), the preparation of the citrate salt may include mixing a first solution and a second solution, wherein the first solution comprises a solvate, a non-solvate or a mixture thereof obtained from azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone and a first solvent, and the second solution comprises citric acid and a second solvent.

[0061] (30) In the above (29), the first solution may be first stirred in the reactor and then the second solution may be added, or the second solution may be first stirred in the reactor and then the first solution may be added.

[0062] (31) In the above (29) or (30), the first solvent and the second solvent may each independently include at least one solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF, NMP and purified water.

[0063] (32) In any one of the above (29) to (31), the first solvent may be a single solvent of purified water, or a mixed solvent of at least one organic solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF and NMP and purified water. In this case, the second solvent may be a single solvent of purified water, or a mixed solvent of at least one organic solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF and NMP and purified water. Under the conditions of the first and second solvents, the citrate of the present invention may be Form A.

[0064] (33) In any one of the above (29) to (31), the first solvent may be an organic solvent, and the second solvent may be a single solvent of purified water, or a mixed solvent comprising at least one organic solvent and purified water. Under the conditions of the first solvent and the second solvent, the citrate salt of the present invention may be Form A.

[0065] (34) In any one of the above (29) to (31), the first solvent may be an organic solvent, the second solvent may be an organic solvent, and the first solvent and the second solvent may be the same. Under the condition that the first solvent and the second solvent are alcohols having 1 to 3 carbon atoms as organic solvents, the citrate of the present invention may be Form B.

[0066] (35) In any one of the above (29) to (31), the first solvent may be acetone or a mixed solvent in which at least one organic solvent other than acetone is mixed with acetone, and the second solvent may be acetone. Under the conditions of the first solvent and the second solvent, the citrate salt of the present invention may be the crystalline form C1 or the crystalline form C2.

[0067] (36) In any one of the above (21) to (33), in the preparation of the citrate, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid can be reacted at a temperature of about 10°C to about 30°C, preferably about 20°C to about 25°C, and the subsequent stirring process can be continuously carried out at the same temperature. Under this temperature condition, the citrate of the present invention can be a crystalline form A.

[0068] (37) In any one of the above (21) to (31) and (34), in the preparation of the citrate, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid may be reacted at a temperature of about 10°C to about 30°C, preferably about 20°C to about 25°C, and then cooled and stirred at a temperature of about 0°C to about 10°C, preferably about 0°C to about 5°C. Under these process conditions, the citrate of the present invention may be a crystalline form B.

[0069] (38) In any one of the above (21) to (31) and (35), in the preparation of the citrate, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid may be reacted at a temperature of about 45° C. to about 60° C., preferably about 50° C. to about 55° C., and then cooled and stirred at a temperature of about 10° C. to about 30° C., preferably about 20° C. to about 25° C. Under these process conditions, the citrate of the present invention may be a crystalline form C1.

[0070] (39) In any one of the above (21) to (31) and (35), in the preparation of the citrate, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid can be reacted at a temperature of about 10°C to about 30°C, preferably about 20°C to about 25°C, and then cooled and stirred at a temperature of about 0°C to about 10°C, preferably about 0°C to about 5°C. The reaction can be carried out at about 10°C to about 30°C in a short time, wherein the time required for introducing citric acid into azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is set to 15 minutes, preferably 10 minutes. Under these process conditions, the citrate of the crystalline form C1 can be obtained.

[0071] (40) In any one of the above (21) to (31) and (35), in the preparation of the citrate, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be reacted with citric acid at a temperature of about 10°C to about 30°C, preferably about 20°C to about 25°C, and then heated and stirred at about 45°C to about 60°C, preferably about 50°C to about 55°C, and then cooled and stirred at about 10°C to about 30°C, preferably about 20°C to about 25°C. The time required for introducing citric acid into azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be set to at least 30 minutes, preferably at least 60 minutes. Under these process conditions, the citrate of the present invention can be a crystalline form C2.

[0072] (41) In any one of the above (21) to (40), the preparation of the citrate salt may include: filtering the solid generated by the reaction of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with citric acid, i.e., the citrate salt; washing; and drying. The filtering and washing may each be performed by a method implemented in conventional salt preparation. The drying may be performed at a temperature of about 35°C to about 50°C, preferably about 35°C to about 45°C, and may be performed in a vacuum drying or nitrogen drying manner.

[0073] Beneficial effects

[0074] In the novel salt of the imidazo[1,2-a]pyridine compound of the present invention, its crystal form and preparation method thereof, the citrate salt of the imidazo[1,2-a]pyridine compound of the present invention can exhibit unexpectedly excellent bioavailability, and can therefore be used as an active ingredient of a pharmaceutical composition to exhibit excellent effects in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0075] In addition, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention has the advantages of being easily prepared by a simple process and obtaining high purity in a high yield of 90% or more.

[0076] In addition, the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention can be used to formulate pharmaceutical products because even under similar solvent conditions, different crystal forms can be generated due to slight differences in reaction temperature, reaction rate, etc., and these crystal forms have excellent light stability, heat / moisture stability, long-term storage stability, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 , Figure 2 and Figure 3 They are respectively the XRD, DSC and TGA analysis result diagrams of the citrate crystal form A according to the present invention.

[0078] Figure 4 , Figure 5 and Figure 6 They are respectively the XRD, DSC and TGA analysis result diagrams of the citrate crystal form B according to the present invention.

[0079] Figure 7 , Figure 8 and Fig. 9 They are respectively the XRD, DSC and TGA analysis result diagrams of the citrate crystal form C1 according to the present invention.

[0080] Fig.10 , Fig.11 and Fig.12 They are respectively the XRD, DSC and TGA analysis result diagrams of the citrate salt crystal form C2 according to the present invention.

[0081] Fig.13 , Fig.14 and Fig.15 They are respectively XRD, DSC and TGA analysis result diagrams of the amorphous citrate of the present invention.

[0082] Fig.163 is a graph showing the XRD analysis result of the citrate salt of the present invention after storage for 36 months. DETAILED DESCRIPTION

[0083] Hereinafter, all terms used herein, including technical terms or scientific terms, unless otherwise defined, have the same meaning as those generally understood by ordinary technicians in the field to which the present invention belongs. Unless explicitly defined in this application, these terms (such as those defined in general dictionaries) should be interpreted as having the same meaning as the contextual meaning in the relevant field, and should not be interpreted as having an ideal or overly formal meaning.

[0084] <Measurement method>

[0085] The following measuring methods are commonly applicable to each embodiment according to the present invention.

[0086] 1. X-ray powder diffraction (XPRD)

[0087] X-ray powder diffraction patterns were obtained by solid phase detector using D8 Focus (Bruker ASX) in the diffraction angle (2θ) range of 2° to 40° with a step size of 0.02°.

[0088] 2. Thermal analysis (DSC)

[0089] Differential Scanning Calorimetry (DSC) was performed using a DSC 8000 (PerkinElmer). The samples were evaluated over the range of 30°C to 300°C using a linear heating ramp of 10°C / min.

[0090] 3. Thermogravimetric analysis (TGA)

[0091] Thermogravimetric analysis was performed using TGA 8000 (PerkinElmer) at 30° C. to 900° C., wherein 0.5 mg to 2 mg of a sample was weighed into a ceramic crucible and then measured at 5° C. / min.

[0092] 4. NMR analysis

[0093] Nuclear magnetic resonance (NMR) analysis was performed using a Varian Mercury 400.

[0094] 5. Moisture content measurement / analysis

[0095] The moisture content of the resulting samples was measured using a 870KF Titrino Plus (Metrohm) Karl-Fischer moisture meter. Preparation Example 1: Synthesis of Compound I

[0096] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was synthesized in the same manner as the preparation method of the compound of Example 6 in Korean Registered Patent Publication No. 10-1777971.

[0097] 1 H NMR (400MHz, CDCl3); δ7.63(d,J=1.2Hz,1H),7.13(dd,J=8.4,6.8Hz,1H),7.06-7.04(m,2H),6.42(d,J=1.2 Hz,1H),4.86-4.84(m,1H),4.41-4.28(m,4H),4.37(d,J=4.4Hz,2H),3.75-3.69(m,1H),2.43-2.34(m,13H)

[0098] Preparation Example 2: Preparation of the Solvate of Compound I

[0099] The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone obtained in Preparation Example 1 was crystallized in an alcohol solvent (isopropanol, IPA), and then vacuum dried at about 30°C to 35°C to obtain a solvate of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone.

[0100] Example 1 (1): Preparation of Compound I Citrate Salt - Form A

[0101] 10 g of the solvate of Compound I obtained in the above-mentioned Preparation Example 2 and 211 g of purified water or a mixed solvent with purified water (dichloromethane, DMF, NMP, or acetone) were added to the reactor, and then stirred at 20° C. to 25° C. for 10 minutes. Subsequently, a solution obtained by dissolving 42.3 g of purified water in 4.9 g of citric acid was added at about 20° C. to 25° C. to confirm that a solid was generated, and then stirring was continued at the same temperature for 2 hours, after which the obtained solid was filtered, washed with 25.4 g of purified water, and then vacuum dried at about 40° C. or dried under nitrogen, thereby preparing 9.70 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0102] Example 1(2): Preparation of Compound I Citrate Salt - Form A

[0103] A solution obtained by dissolving 16.9 g of purified water or a mixed solvent of purified water (acetone, DMF, or NMP) in 9.8 g of citric acid was added to the reactor, and then stirred at 20° C. to 25° C. for 10 minutes. Subsequently, a solution prepared by dissolving 90 g of dichloromethane in 20 g of the solvate of Compound I obtained in the above-mentioned Preparation Example 2 was added at the same temperature to confirm that a solid was generated, and then stirring was continued at the same temperature for 2 hours, after which the obtained solid was filtered, washed with 50.0 g of purified water, and vacuum dried or nitrogen dried at about 40° C., thereby obtaining 19.4 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0104] Analysis 1- XRD, DSC and TGA measurement results of Form A

[0105] See also Figure 1 And the following Table 1, the 2θ value (unit: °) of the XRD pattern of the crystalline form A according to the present invention can be determined. Specifically, the XRD pattern of the crystalline form A according to the present invention includes diffraction peaks, wherein the 2θ values ​​are 5.46°, 7.14°, 10.61°, 10.93°, 11.82°, 13.11°, 14.15°, 15.84°, 16.35°, 18.27°, 19.79°, 24.21°, and 25.77°.

[0106] See also Figure 2 , Form A shows DSC endothermic peaks at 88.69°C, 135.61°C and 154.84°C.

[0107] See also Figure 3 , TGA measurement results confirmed that Form A decomposed in three steps. Specifically, it was found that the decomposition occurred in the first step of about 56.98°C to 72.37°C, the second step of about 161.59°C to 196.61°C, and the third step of about 301.27°C to 350.19°C, and the maximum inflection points of the decomposition were confirmed to be at about 67.85°C, 179.58°C, and 330.88°C, respectively.

[0108] At the same time, it can be confirmed by the water content that Form A is anhydrous.

[0109] In addition, it was confirmed that the crystalline form A of the present invention is a crystalline form in which azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are combined at a molar ratio of about 1:0.5.

[0110] [Table 1]

[0111]

[0112] Example 2: Preparation of Compound I Citrate Salt-Form B

[0113] 166.2 g of IPA and 10 g of the solvate of compound I obtained in the above-mentioned Preparation Example 2 were added to the reactor, and then stirred for 10 minutes. Subsequently, a solution of 33.2 g of IPA dissolved in 4.9 g of citric acid was added at 20° C. to 25° C. to confirm that solids were generated, and then stirred at the same temperature for 1 hour, cooled to 0° C. to 5° C., and stirred for another hour. The resulting solid was filtered and washed with 19.9 g of IPA to obtain 9.63 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0114] Analysis of XRD, DSC and TGA measurement results of Form 2-B

[0115] See also Figure 4 And the following Table 2, the 2θ value (unit: °) of the XRD pattern of the crystalline form B according to the present invention can be determined. Specifically, the XRD pattern of the crystalline form B according to the present invention includes diffraction peaks, wherein the 2θ values ​​are 7.03°, 7.69°, 9.47°, 13.21°, 14.86°, and 21.13°.

[0116] See also Figure 5 , Form B shows a DSC endothermic peak at 144.57°C.

[0117] See also Figure 6 , TGA analysis results confirmed that Form B decomposed in two steps. Specifically, it was found that the decomposition occurred in the first step from about 163.24°C to 196.32°C and the second step from about 305.85°C to 342.24°C, and the maximum inflection points of the decomposition were confirmed to be about 180.52°C and 331.48°C, respectively.

[0118] At the same time, it can be confirmed by the water content that Form B is anhydrous.

[0119] In addition, it was confirmed that the crystal form B of the present invention is a crystal form in which azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are combined at a molar ratio of about 1:0.5.

[0120] [Table 2]

[0121]

[0122] Example 3(1): Preparation of Compound I Citrate Salt - Form C1

[0123] 167.2 g of acetone and 10 g of the solvate of compound I obtained in the above-mentioned Preparation Example 2 were added to the reactor, and then heated to 50° C. to 55° C. and stirred for 10 minutes. Subsequently, a solution of 33.4 g of acetone dissolved in 4.9 g of citric acid was added and stirred at the same temperature for 1 hour, then cooled to 20° C. to 25° C. and stirred for another 1 hour. The resulting solid was filtered, washed with 20.1 g of acetone, and then dried in vacuo at about 40° C. to obtain 11.75 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}ketone citrate.

[0124] Examples 3(2) to 3(4): Preparation of Compound I Citrate Salt - Form C1

[0125] The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate salts of Examples 3(2) to 3(4) of the present invention were obtained respectively, and their preparation methods were basically the same as the preparation method of the citrate salt of Compound I described in Example 3(1), except that the solvents shown in Table 3 below were used as mixed solvents together with acetone as solvents and added to the reactor together with the solvate.

[0126] [Table 3]

[0127]

[0128] Example 3(5): Preparation of Compound I Citrate Salt - Form C1

[0129] 167.2 g of acetone or 32.1 g of dichloromethane and 10 g of the solvate of compound I obtained in the above-mentioned preparation example 2 were added to the reactor, and then stirred at 10°C to 30°C for 10 minutes. Then, a solution of 33.4 g of acetone dissolved in 4.9 g of citric acid was added within 10 minutes and stirred at the same temperature for 1 hour. The resulting mixture was then cooled to 0°C to 5°C and continued to stir for 1 hour. The solid obtained was filtered and washed with 20.1 g of acetone, and then vacuum dried at about 40°C to obtain 11.74 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}ketone citrate.

[0130] Analysis 3- XRD, DSC and TGA measurement results of Form C1

[0131] See also Figure 7The 2θ values ​​(unit: °) of the XRD pattern of the crystal form C1 according to the present invention can be confirmed as shown in Table 4 below. Specifically, the XRD pattern of the crystal form C1 according to the present invention includes diffraction peaks, wherein the 2θ values ​​are 7.35°, 10.23°, 12.90°, 14.68°, 15.31°, 15.97°, 17.42°, 18.21°, 21.22°, 22.26°, and 26.00°.

[0132] See also Figure 8 , Form C1 shows a DSC endothermic peak at 168.93°C.

[0133] See also Fig. 9 The TGA analysis results confirmed that the crystal form C1 decomposed in two steps. Specifically, it was found that the decomposition occurred in the first step from about 172.76°C to 192.20°C and the second step from about 297.93°C to 337.46°C, and the maximum inflection points of the decomposition were confirmed to be at 178.36°C and 324.77°C, respectively.

[0134] At the same time, it can be confirmed by the water content that Form C1 is anhydrous.

[0135] Furthermore, it was confirmed that the crystalline form C1 of the present invention is a crystalline form in which azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are combined in a molar ratio of about 1:1.

[0136] [Table 4]

[0137]

[0138]

[0139] Example 4(1): Preparation of Compound I Citrate Salt - Form C2

[0140] 167.2 g of acetone and 10 g of the solvate of compound I obtained in the above-mentioned preparation example 2 were added to the reactor, and then stirred at 20°C to 25°C for 10 minutes. Then, a solution of 33.4 g of acetone dissolved in 4.9 g of citric acid was slowly added dropwise over 60 minutes or more, and stirred at the same temperature for 1 hour. The resulting mixture was then heated to 50°C to 55°C and stirred for another hour. The resulting mixture was cooled to 20°C to 25°C and continued to stir for 1 hour, after which the resulting solid was filtered and washed with 20.1 g of acetone, and then vacuum dried at 40°C to obtain 11.76 g of azetidine-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}ketone citrate.

[0141] Examples 4(2) to 4(4): Preparation of Compound I Citrate Salt - Form C2

[0142] The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate salts of Examples 4(2) to 4(4) of the present invention were obtained respectively, and the preparation method thereof was basically the same as the preparation method of the citrate salt described in Example 4(1), except that the solvent shown in Table 5 below was used as a mixed solvent together with acetone as a solvent and added to the reactor together with the solvate.

[0143] [Table 5]

[0144]

[0145] Analysis of XRD, DSC and TGA measurement results of 4-Crystal C2

[0146] See also Fig.10 The 2θ values ​​(unit: °) of the XRD pattern of the crystalline form C2 of the present invention can be confirmed as shown in Table 6 below. Specifically, the XRD pattern of the crystalline form C2 of the present invention includes diffraction peaks, wherein the 2θ values ​​are 5.63°, 8.90°, 9.51°, 12.31°, 13.01°, 14.34°, 14.80°, 18.38°, 18.75°, and 19.62°.

[0147] See also Fig.11 , Form C2 shows a DSC endothermic peak at 161.48°C.

[0148] See also Fig.12 The TGA analysis results confirmed that the crystal form C2 decomposed in two steps. Specifically, it was found that the decomposition occurred in the first step from about 166.37°C to 191.88°C and the second step from about 282.15°C to 311.08°C, and the maximum inflection points of the decomposition were confirmed to be at 173.44°C and 304.81°C, respectively.

[0149] In addition, it is also confirmed that the crystalline form C2 according to the present invention is a crystalline form in which azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are combined in a molar ratio of about 1:1.

[0150] [Table 6]

[0151]

[0152]

[0153] Example 5(1): Preparation of Compound I Citrate Salt-Amorphous Form

[0154] In a reactor, 237.6 g of methanol was added to 10 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate prepared according to Example 3(1), and then stirred at 20° C. to 25° C. for 20 minutes to be dissolved. The solid obtained by concentration was then vacuum dried at about 40° C. to obtain 9.8 g of amorphous azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0155] Examples 5(2) and 5(3): Preparation of Compound I Citrate Salt - Amorphous

[0156] The amorphous form of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate of Examples 5(2) and 5(3) of the present invention was obtained respectively. The preparation method thereof was basically the same as the preparation method of the citrate of Compound I described in Example 5(1), except that an alcohol solvent as shown in Table 7 below was used instead of methanol.

[0157] [Table 7]

[0158]

[0159] Analysis 5 - DSC and TGA Measurement Results of Amorphous

[0160] See also Fig.13 It can be confirmed that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of Examples 5(1) to 5(3) of the present invention is amorphous.

[0161] See also Fig.14 The amorphous form of the compound I of the present invention shows a DSC endothermic peak at 161.42°C.

[0162] See also Fig.15 The TGA analysis results confirmed that the amorphous material of the present invention decomposed in three steps. Specifically, it was found that the decomposition occurred in the first step of about 79.55°C to 118.51°C, the second step of about 165.24°C to 190.12°C, and the final third step of about 289.01°C to 333.88°C, and the maximum inflection points of the decomposition were confirmed to be 105.71°C, 175.22°C, and 315.61°C, respectively.

[0163] At the same time, the water content can confirm that the amorphous substance is also anhydrous.

[0164] Experimental Example 1: Bioavailability Evaluation

[0165] The bioavailability of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate prepared in Example 4(1) of the present invention was evaluated, and azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained according to Preparation Example 1 was used as a comparative example. The specific pharmacokinetic experiments and evaluation methods are described below.

[0166] <Administration and Blood Collection>

[0167] Male beagle dogs on an empty stomach were orally administered 10 mg / kg capsules, and blood was collected at 0.08, 0.25, 0.5, 1, 3, 5, 8, and 24 hours after administration. 3 ml of blood collected via the jugular vein was centrifuged to separate plasma, which was then stored frozen in a cryogenic refrigerator for analysis.

[0168] <Plasma Pretreatment>

[0169] Protein precipitation was used for plasma pretreatment. 300 μl of acetonitrile containing an internal standard (200 ng / ml carbamazepine) was added to 100 μl of plasma sample and mixed. After thorough mixing, the resulting mixture was centrifuged at 12,000 rpm for 10 minutes, and then the supernatant was transferred to a detection vial and injected into LC-MS / MS to analyze the blood concentration of the compound.

[0170] <LC-MS / MS Analysis Conditions>

[0171]

[0172] <Pharmacokinetic Evaluation>

[0173] The maximum plasma concentration time (T max ), maximum plasma concentration (C max ), and area under the plasma concentration-time curve (AUC 0-t , AUC 0-inf ) parameters were measured using PK solutions, and the results are shown in Table 8 below.

[0174] [Table 8]

[0175]

[0176] Referring to Table 8 above, it can be confirmed that azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention reaches the maximum plasma concentration in a significantly shorter time compared to Compound I (free base) of the comparative example, Cmax The bioavailability of the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention is significantly improved to 11 times or more than that of the compound of the comparative example, and it can be confirmed that the AUC is also significantly improved by 5 times or more compared with the compound of the comparative example. In other words, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of the present invention exhibits significantly excellent bioavailability, which is significantly beyond the conventionally predictable level.

[0177] Therefore, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention can exhibit very excellent bioavailability that the inventors had not expected, and can therefore be used as an active ingredient of a pharmaceutical composition, thereby showing very excellent effects in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0178] Experimental Example 2: Photostability evaluation

[0179] For the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate of Example 4(1) of the present invention, the sample was spread thinly in a culture dish and then irradiated with visible light at a light intensity of 35k lux to a total irradiation of 1200k lux using a light stability test box (CARON 6542-2) at 25°C and 60% humidity. The sample was spread thinly in a culture dish and irradiated with ultraviolet light at a light intensity of 35W to a total irradiation of 200 watts in a light stability test box (CARON 6542-2) at 25°C and 60% humidity, and the color change was observed with the naked eye. The results are shown in Table 9 below. It is judged to be applicable only when the white to light yellowish off-white powder form maintains solid properties.

[0180] [Table 9]

[0181]

[0182] Referring to Table 9, it can be confirmed that the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate according to the present invention can still maintain the standard suitable properties of off-white or slightly off-white even under ultraviolet and visible light irradiation. It can be seen that the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate according to the present invention has excellent photostability.

[0183] Experimental Example 3: Short-term storage stability evaluation (heat / humidity)

[0184] The purity of the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}ketone citrate of Example 4(1) of the present invention was determined, and then the purity was determined after being placed at 60°C for 4 days. The purity determination was performed by HPLC. In addition, for the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}ketone citrate of Example 4(1) of the present invention, the purity was determined after being placed under conditions of 75 to 90% humidity (RH) for 2 days. The results are shown in Table 10 below.

[0185] [Table 10]

[0186]

[0187] Referring to Table 10, it can be confirmed that the purity of the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate according to the present invention is substantially unchanged even when placed under high temperature conditions or high humidity conditions. It can be seen that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate according to the present invention is stable to heat and humidity, respectively. Experimental Example 4: Evaluation of long-term storage stability

[0188] After preparing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to Example 4(1) of the present invention, the properties were immediately confirmed by naked eyes, and the moisture content, purity and XRD were measured respectively. Subsequently, it was first sealed in a polyethylene bag, then sealed in an aluminum bag for a second time, and then stored at 25±2°C and 60±5% RH for 12, 24 and 36 months, and the properties were confirmed by naked eyes and the moisture content, purity and XRD were measured. The results are shown in Tables 11 and 11 below. Fig.16 shown.

[0189] [Table 11]

[0190]

[0191] Referring to Table 11, it can be confirmed that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention can remain stable even at a time point of 36 months after preparation.

[0192] Also, see Fig.16 , which is the XRD analysis result after 36 months, it can be confirmed that the XRD spectrum remains unchanged, specifically Fig.10 The diffraction peaks of the citrate of the present invention shown in FIG. 1 are not shifted when compared with the diffraction peaks immediately after preparation. In other words, it can be confirmed that the citrate of the present invention has very excellent long-term storage stability.

[0193] Experimental Example 5: Evaluation of thermal stability and stability (accelerated conditions)

[0194] After preparing azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate according to Example 4 (1) of the present invention, the properties were immediately confirmed by naked eye, and the moisture content, purity and XRD were measured respectively. Subsequently, it was first sealed in a polyethylene bag, then sealed in an aluminum bag for a second time, and then stored under accelerated conditions of 40±2°C and 75±5% RH for 1 month and 6 months, and the properties were confirmed by naked eye, and the moisture content, purity and XRD were measured. The results are shown in Table 12 below.

[0195] [Table 12]

[0196]

[0197] Referring to Table 12, it can be confirmed that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention can remain stable under accelerated conditions even at a time point of six months after preparation.

[0198] The invention has been described with reference to the preferred exemplary embodiments herein, but it will be appreciated by those skilled in the art that various changes and modifications may be made thereto without departing from the spirit and scope of the invention, as set forth in the scope of the following patent claims.

Claims

1. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

2. Azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the molar ratio of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid is 1:0.3 to 1:1.

3.

3. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the citrate is anhydrous.

4. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the citrate is crystalline.

5. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the citrate is anhydrous and crystalline.

6. Azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate is Form A, which includes at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 5.46°, 7.14°, 10.61°, 11.82°, 18.27° and 25.77°.

7. Azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 6, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate is Form A, which further comprises at least one diffraction peak, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 10.93°, 13.11°, 14.15°, 15.84°, 16.35°, 19.79° and 24.21°.

8. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 6, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate has differential scanning calorimetry (DSC) endothermic peaks at 88.69° C., 135.61° C. and 154.84° C. (±0.5° C.) at a heating rate of 10° C. / min.

9. Azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate is a crystalline form B comprising at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 7.03°, 7.69°, 9.47°, 13.21°, 14.86° and 21.13°.

10. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 9, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate has a differential scanning calorimetry (DSC) endothermic peak at 144.57° C. (±0.5° C.) at a heating rate of 10° C. / min.

11. Azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate is a crystalline form C1, which includes at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 7.35°, 15.31°, 17.42° and 22.26°.

12. Azetidin-1-yl {8-[(2,6-dimethylbenzyl)amina]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 11, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate is a crystalline form C1, which further comprises at least one diffraction peak, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 10.23°, 12.90°, 14.68°, 15.97°, 18.21°, 21.22° and 26.00°.

13. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 11, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate has a differential scanning calorimetry (DSC) endothermic peak at 168.93°C (±0.5°C) at a heating rate of 10°C / min.

14. Azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate is a crystalline form C2, which includes at least three diffraction peaks, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 5.63°, 8.90°, 9.51° and 13.01°.

15. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 14, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amina]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate is a crystalline form C2, which further comprises at least one diffraction peak, wherein the 2θ (±0.2°) value of the powder X-ray diffraction pattern is selected from 12.31°, 14.34°, 14.80°, 18.38°, 18.75° and 19.62°.

16. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 14, wherein the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate has a differential scanning calorimetry (DSC) endothermic peak at 161.48°C (±0.5°C) at a heating rate of 10°C / min.

17. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 1, wherein the citrate is amorphous.

18. A method for preparing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate, the method comprising: Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is reacted with citric acid in the presence of at least one solvent selected from an alcohol having 1 to 3 carbon atoms, acetone, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP) and purified water.

19. The method according to claim 18, wherein the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone reacted with citric acid in the step is a solvate.

20. The method according to claim 18, wherein in the step, a citrate salt is prepared in which the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid is 1:0.3 to 1:1.

3.

21. The method of claim 18, wherein the step comprises mixing a first solution comprising azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent and a second solution comprising citric acid and a second solvent, wherein the first solvent is a single solvent of acetone or a mixed solvent comprising acetone and at least one selected from an alcohol having 1 to 3 carbon atoms, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF) and N-methylpyrrolidone (NMP), and The second solvent is acetone.

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