Novel salts of imidazo[1,2-a]pyridine compounds, their crystal forms, and production methods

Abstract

In the novel salt, crystal form, and production method of the imidazo[1,2-a]pyridine compound of the present invention, the novel salt of the imidazo[1,2-a]pyridine compound is azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

Description

Technical Field

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

Background Art

[0002] Inflammatory diseases of the digestive tract, such as peptic ulcer, gastric and duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), and non-erosive gastroesophageal reflux disease (NERD), or gastric acid-related diseases are the most common digestive diseases suffered by most of the world's population, including in Korea.

[0003] In order to solve the problems of conventional proton pump inhibitors (PPIs), in recent years, among proton pump inhibitors (PPIs), the interest and need for Potassium Competitive Acid Blocker (P-CAB, acid pump antagonist), which reversibly binds to the K + / K + -ATPase K + binding site and has an action mechanism of suppressing acid secretion through potassium-competitive inhibition, have been increasing. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) are expected to have a rapid onset of effect due to their action mechanism, can be taken regardless of whether it is before or after a meal, and are very effective in improving the nighttime effect, which was a weakness of irreversible proton pump inhibitors.

[0004] On the other hand, in order to be considered as a candidate substance for development as a drug, a compound must have not only desirable biological properties but also physical properties that enable its use in the production of a pharmaceutical composition. Furthermore, it is desirable for these compounds to have a solid phase so that they can be easily produced and stably formulated.

[0005] Therefore, the inventors of the present invention have made intensive research efforts to explore a form that has stability in various aspects and is industrially applicable for the pharmaceutical use of imidazo[1,2-a]pyridine compounds. As a result, they have found a novel salt that exhibits a remarkable and unpredictable effect, and thus completed the present invention.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] One object of the present invention is to provide a novel salt of an imidazo[1,2-a]pyridine compound.

[0008] Another object of the present invention is to provide a crystal form of a novel salt of an imidazo[1,2-a]pyridine compound.

[0009] Yet another object of the present invention is to provide a method for producing a novel salt of an imidazo[1,2-a]pyridine compound.

Means for Solving the Problems

[0010] Novel salt of imidazo[1,2-a]pyridine compound

[0011] (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.

[0012] Hereinafter, in this specification, those simply referred to as "citrate of Chemical Formula I" or "citrate" both mean "azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate".

[0013] 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.

[0014] [Chemical Formula I] [Chemical Structure]

[0015] (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 in 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 may be 1:0.5 to 1:1.

[0016] (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.

[0017] [Chemical Formula II] [Chemical Structure]

[0018] In the above Formula II, n represents 0.3 to 1.3.

[0019] In one embodiment, n in the formula II may be from 0.5 to 1.

[0020] (4) In any of (1) to (3) above, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be an anhydride.

[0021] (5) In any of (1) to (4) above, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be in crystalline form or amorphous form.

[0022] (6) In any of (1) to (5) above, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be in anhydrous crystalline form.

[0023] (7) In any of (1) to (6) above, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be crystalline form A which shows a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 5.46°, 7.14°, 10.61°, 11.82°, 18.27°, and 25.77°.

[0024] (8) In (7) above, the powder X-ray diffraction pattern of crystalline form A may further include at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values of 10.93°, 13.11°, 14.15°, 15.84°, 16.35°, 19.79°, and 24.21°.

[0025] (9) In the above (7) or (8), when the heating rate is 10 °C / min, crystalline form A may have differential scanning calorimetry (DSC) endothermic peaks at 88.69 °C, 135.61 °C, and 154.84 °C (±0.5 °C).

[0026] (10) In any of the above (1) to (6), azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be crystalline form B showing a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 7.03°, 7.69°, 9.47°, 13.21°, 14.86°, and 21.13°.

[0027] (11) In the above (10), when the heating rate is 10 °C / min, crystalline form B may have a differential scanning calorimetry (DSC) endothermic peak at 144.57 °C (±0.5 °C).

[0028] (12) In any of the above (1) to (6), azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate may be crystalline form C1 showing a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 7.35°, 15.31°, 17.42°, and 22.26°.

[0029] (13) In the above (12), the powder X-ray diffraction pattern of crystalline form C1 may further include at least one or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 10.23°, 12.90°, 14.68°, 15.97°, 18.21°, 21.22°, and 26.00°.

[0030] (14) In the above (12) or (13), when the heating rate is 10 °C / min, crystalline form C1 may have a differential scanning calorimetry (DSC) endothermic peak at 168.93 °C (±0.5 °C).

[0031] (15) In any of (1) to (6) above, the citrate of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be crystalline form C2 showing a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 5.63°, 8.90°, 9.51°, and 13.01°.

[0032] (16) In (15) above, the powder X-ray diffraction pattern of crystalline form C2 may further include at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values of 12.31°, 14.34°, 14.80°, 18.38°, 18.75°, and 19.62°.

[0033] (17) In (15) or (16) above, crystalline form C2 may have a differential scanning calorimetry (DSC) endothermic peak at 161.48 °C (±0.5 °C) when the heating rate is 10 °C / min.

[0034] (18) In any of (1) to (5) above, the amorphous form of the citrate of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may have a differential scanning calorimetry (DSC) endothermic peak at 161.42 °C (±0.5 °C) when the heating rate is 10 °C / min.

[0035] (19) In any of (1) to (11) above, the crystalline forms A and B of the citrate according to the present invention may each have a molar ratio of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to citric acid of 1:0.5.

[0036] (20) In any of the above (1) to (6) and (12) to (17), 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 in the citrate crystal forms C1 and C2 according to the present invention may be 1:1.

[0037] 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 exhibits unexpectedly excellent bioavailability, and thus is used as an active ingredient of a pharmaceutical composition, and can also exhibit very excellent effects in the prevention or treatment of inflammatory diseases of the digestive tract or gastric acid-related diseases.

[0038] In addition, 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 be easily produced by a simple process, and has the advantages of being obtained in a high purity and a high yield of 90% or more.

[0039] Furthermore, 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 generate various crystal forms due to minute differences such as reaction temperature and reaction rate even under similar solvent conditions, and these crystal forms are excellent in light stability, heat / moisture stability, long-term storage stability, etc., and can be effectively utilized in the formulation of pharmaceuticals.

[0040] The pharmaceutical composition of the present invention contains azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate in a therapeutically effective amount.

[0041] The pharmaceutical composition of the present invention can treat or prevent diseases selected from the group consisting of peptic ulcer, gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive gastroesophageal reflux disease (NERD).

[0042] Process for producing a novel salt of an imidazo[1,2-a]pyridine compound

[0043] (21) The process for producing azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention includes a step of reacting azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with citric acid to produce the citrate salt.

[0044] (22) In the step of producing the citrate salt according to (21) above, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid may be reacted under at least one solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP), and purified water.

[0045] (23) In (21) or (22) above, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be synthesized according to the following Reaction Scheme 1.

[0046] [Reaction Scheme 1] [Chemical formula]

[0047] (24) In the reaction formula 1 according to the above (23), 8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid may be obtained according to the description in Korean Registered Patent Publication No. 10-1777971, and the specific steps of the reaction formula 1 may also be carried out according to the disclosed content therein.

[0048] (25) In any of the above (21)-(24), azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone in the step of producing the citrate salt may be a non-solvate, a solvate, or a mixture thereof.

[0049] (26) In any of the above (23)-(25), azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained according to the reaction formula 1 may be crystallized in an alcohol solvent having 1 to 3 carbon atoms and vacuum dried, and the obtained solvate, non-solvate, or a mixture thereof may 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 may be obtained by vacuum drying at about 20 °C or higher to about 35 °C or lower. The non-solvate of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be obtained by vacuum drying at about 45 °C or higher and about 60 °C or lower. The mixture of the solvate and the non-solvate may be obtained by vacuum drying at higher than about 35 °C and lower than about 45 °C.

[0050] (27) In any of the above (21) to (26), in the step of producing the citrate, a citrate may be produced in which azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are included in a molar ratio of about 1:0.3 to about 1:1.3. For example, in the step of producing the citrate, a citrate may be produced 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.

[0051] (28) In any of the above (21) to (27), the step of producing the citrate may be carried out by mixing a solvate, non-solvate, or a mixture thereof of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid so that they have a weight ratio of about 1:1.3 to about 1:0.3.

[0052] (29) In any of the above (21) to (28), the step of producing the citrate may include the step of mixing a solvate, non-solvate, or a mixture thereof of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3- dimethylimidazo[1,2-a]pyridin-6-yl}methanone, and a first solution containing a first solvent, and a second solution containing citric acid and a second solvent.

[0053] (30) In the above (29), the second solution may be added after first stirring the first solution in a reactor, or the first solution may be added after first stirring the second solution in a reactor.

[0054] (31) In the above (29) or (30), the first solvent and the second solvent may each independently contain at least one solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF, NMP, and purified water.

[0055] (32) In any of the above (29) to (31), the first solvent may be a single solvent of purified water, or a mixed solvent containing at least one organic solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF, and NMP together with purified water. Here, the second solvent may be a single solvent of purified water, or a mixed solvent containing at least one organic solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF, and NMP together with purified water. Under the first and second solvent conditions, the citrate according to the present invention may be in crystal form A.

[0056] (33) In any of the above (29) to (31), the first solvent is an organic solvent, and the second solvent may be a single solvent of purified water or a mixed solvent containing one or more organic solvents together with purified water. Under the first and second solvent conditions, the citrate according to the present invention may be in crystal form A.

[0057] (34) In any of the above (29) to (31), the first solvent is an organic solvent, the second solvent is an organic solvent, and the first and second solvents may be the same as each other. Under the condition that the first and second solvents are organic solvents and are alcohols having 1 to 3 carbon atoms, the citrate according to the present invention may be in crystal form B.

[0058] (35) In any of the above (29) to (31), the first solvent may be acetone, or may be a mixed solvent of acetone and one or more organic solvents other than acetone, and the second solvent may be acetone. Under the first and second solvent conditions, the citrate according to the present invention may be in crystal form C1 or crystal form C2.

[0059] (36) In any of the above (21) to (33), in the step of producing 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 about 10 °C to about 30 °C, desirably at about 20 °C to about 25 °C, and the subsequent stirring step may also be continued at the same temperature. Under the temperature conditions, the citrate according to the present invention may be in crystal form A.

[0060] (37) In any of the above (21) to (31) and (34), in the step of producing the citrate, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are reacted at about 10 °C to about 30 °C, desirably at about 20 °C to about 25 °C, and then cooled and stirred at about 0 °C to about 10 °C, desirably at about 0 °C to about 5 °C. Under the process conditions, the citrate according to the present invention may be in crystal form B.

[0061] (38) In any of the above (21) to (31) and (35), in the step of producing the citrate, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are reacted at about 45 °C to about 60 °C, desirably at about 50 °C to about 55 °C, and then cooled and stirred at about 10 °C to about 30 °C, desirably at about 20 °C to about 25 °C. Under the process conditions, the citrate according to the present invention may be in crystal form C1.

[0062] (39) In any of the above (21)-(31) and (35), in the step of producing 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 about 10°C to about 30°C, preferably about 20°C to about 25°C, and then cooled and stirred at about 0°C to about 10°C, preferably about 0°C to about 5°C. Here, the time for adding citric acid to azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone at about 10°C to about 30°C may be carried out in a short time within 15 minutes, preferably within 10 minutes. Under the above process conditions, the citrate may be crystalline C1.

[0063] (40) In any of the above (21)-(31) and (35), in the step of producing 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 about 10°C to about 30°C, preferably about 20°C to about 25°C, 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. Here, the time for adding citric acid to azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be at least 30 minutes or more, preferably 60 minutes or more. Under the above process conditions, the citrate according to the present invention may be crystalline form C2.

[0064] (41) In any of the above (21) to (40), the step of producing the citrate may include the steps of filtering, washing, and drying the solid produced 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. The steps of filtering and washing may each be carried out by a method commonly used in the production of salts. The drying step may be carried out at about 35°C to about 50°C, preferably about 35°C to about 45°C, and may be carried out by vacuum drying or nitrogen drying.

Advantages of the Invention

[0065] In the novel salt of the imidazo[1,2-a]pyridine compound of the present invention, its crystal form, and the production method, the citrate of the imidazo[1,2-a]pyridine compound of the present invention exhibits unexpectedly excellent bioavailability, and thus can be used as an active ingredient of a pharmaceutical composition, and can also exhibit very excellent effects in the prevention or treatment of inflammatory diseases of the digestive tract or gastric acid-related diseases.

[0066] In addition, 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 be easily produced in a simple process, and has the advantages of being obtained in high purity and in a high yield of 90% or more.

[0067] Furthermore, 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 produce various crystal forms due to fine differences such as reaction temperature and reaction rate even under similar solvent conditions, and these crystal forms are excellent in light stability, heat / moisture stability, long-term storage stability, etc., and can be effectively utilized in the formulation of pharmaceuticals.

Brief Description of the Drawings

[0068]

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Mode for Carrying Out the Invention

[0069] Hereinafter, unless otherwise defined, all terms used in this specification, including technical or scientific terms, shall have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention pertains. Terms defined as in commonly used dictionaries shall be interpreted to have a meaning consistent with the meaning in the context of the relevant technology, and shall not be interpreted in an ideal or overly formal sense unless clearly defined in the present application.

[0070] <Measurement Method> The following measurement methods are commonly applied to each of the examples according to the present invention.

[0071] 1. X-ray Powder Diffraction (XPRD) The X-ray powder diffraction pattern was obtained using D8 Focus (Bruker ASX) with a solid-state detector over a range of diffraction angles (2θ) from 2° to 40° with a step size of 0.02°.

[0072] 2. Thermal Analysis (DSC) Differential Scanning Calorimetry (DSC) was performed using DSC8000 (PerkinElmer). The samples were evaluated using a linear heating ramp of 10 °C / min in the range of 30 °C to 300 °C.

[0073] 3. Thermogravimetric Analysis (TGA) Thermogravimetric analysis was performed using TGA8000 (PerkinElmer). Samples of 0.5 mg to 2 mg were weighed into a ceramic crucible and measured at 30 °C to 900 °C under the condition of 5 °C / min.

[0074] 4. NMR Analysis Nuclear magnetic resonance (NMR) analysis was performed using a Varian Mercury 400.

[0075] 5. Measurement / Analysis of Moisture Content For the obtained samples, the moisture content was measured using an 870KF Titrino Plus (Metrohm) Karl Fischer moisture meter.

[0076] Production Example 1: Synthesis of Compound I 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 method for producing the compound of Example 6 in Korean Patent Registration Publication No. 10-1777971. 1 H NMR (400 MHz, CDCl3); δ 7.63 (d, J = 1.2 Hz, 1H), 7.13 (dd, J = 8.4, 6.8 Hz, 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 = 4.4 Hz, 2H), 3.75 - 3.69 (m, 1H), 2.43 - 2.34 (m, 13H)

[0077] Production Example 2: Production of Solvate of Compound I The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained in Production Example 1 was crystallized with an alcohol solvent (isopropyl alcohol, IPA) and 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]pyridin-6-yl}methanone.

[0078] Example 1(1): Production of Citrate Salt of Compound I - Crystal Form A 10 g of the solvate of Compound I obtained in Production Example 2 and 211 g of purified water or a mixed solvent of purified water (dichloromethane, DMF, NMP, or acetone) were added to a reactor and stirred at 20°C to 25°C for 10 minutes. Subsequently, a solution prepared by dissolving 4.9 g of citric acid in 42.3 g of purified water was added at about 20°C to 25°C, and it was confirmed that a solid was formed. Subsequently, after stirring at the same temperature for 2 hours, the formed solid was filtered, washed with 25.4 g of purified water, and dried under vacuum or under nitrogen at about 40°C to produce 9.70 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0079] Example 1(2): Preparation of Compound I Citrate - Crystal Form A A solution prepared by dissolving 9.8 g of citric acid, 16.9 g of purified water, or a mixed solvent of purified water (acetone, DMF, or NMP) was added to a reactor and stirred at 20°C to 25°C for 10 minutes. Then, at the same temperature, a solution prepared by dissolving 20 g of the solvate of Compound I obtained in Production Example 2 in 90 g of dichloromethane was added, and it was confirmed that a solid was formed. Subsequently, after stirring at the same temperature for 2 hours, the formed solid was filtered, washed with 50.0 g of purified water, and then dried under vacuum or under nitrogen at about 40°C to produce 19.4 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0080] Analysis 1 - XRD, DSC, and TGA Measurement Results of Crystal Form A Referring to FIG. 1 and Table 1 below, the 2θ values (unit: °) of the XRD pattern of Crystal Form A according to the present invention can be confirmed. Specifically, the XRD pattern of Crystal Form A according to the present invention includes diffraction peaks with 2θ values of 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°. Referring to FIG. 2, for Crystal Form A, endothermic peaks in the DSC appear at 88.69°C, 135.61°C, and 154.84°C. Referring to FIG. 3, as a result of measurement by TGA, it is confirmed that the crystalline form A decomposes in three stages. Specifically, the decomposition occurs at about 56.98°C to 72.37°C in the first stage, about 161.59°C to 196.61°C in the second stage, and about 301.27°C to 350.19°C in the third stage, and the maximum inflection points of decomposition are confirmed at about 67.85°C, 179.58°C, and 330.88°C, respectively. On the other hand, from the moisture content, it can be confirmed that the crystalline form A is an anhydride. Also, it was confirmed that in the crystalline form A according to the present invention, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are bonded at a molar ratio of about 1:0.5.

[0081] [Table 1] [Table 1]

[0082] Example 2: Production of Compound I Citrate - Crystalline Form B 166.2 g of IPA and 10 g of the solvate of Compound I obtained in Production Example 2 were added to a reactor and stirred for 10 minutes. Subsequently, a solution prepared by dissolving 4.9 g of citric acid in 33.2 g of IPA was added at 20°C to 25°C, and it was confirmed that a solid was formed. Subsequently, the mixture was stirred at the same temperature for 1 hour, cooled to 0°C to 5°C, and stirred for another 1 hour. The obtained solid was filtered, washed with 19.9 g of IPA, and 9.63 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate was obtained.

[0083] Analysis 2 - XRD, DSC, and TGA Measurement Results of Crystalline Form B Referring to FIG. 4 and Table 2 below, the 2θ values (unit: °) of the XRD pattern of the crystalline form B according to the present invention can be confirmed. Specifically, the XRD pattern of the crystalline form B according to the present invention includes diffraction peaks with 2θ values of 7.03°, 7.69°, 9.47°, 13.21°, 14.86°, and 21.13°. Referring to Figure 5, for crystalline form B, an endothermic peak in DSC appears at 144.57 °C. Referring to Figure 6, as a result of TGA analysis, it is confirmed that the decomposition of crystalline form B occurs in two stages. Specifically, the decomposition of crystalline form B occurs at about 163.24 °C to 196.32 °C in the first stage and at about 305.85 °C to 342.24 °C in the second stage, and the maximum inflection points of decomposition are confirmed at about 180.52 °C and 331.48 °C, respectively. On the other hand, from the moisture content, it can be confirmed that crystalline form B is an anhydride. Furthermore, it was confirmed that in crystalline form B according to the present invention, 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.

[0084] [Table 2]

Table 2

[0085] Example 3(1): Preparation of Compound I Citrate - Crystalline Form C1 After adding 167.2 g of acetone and 10 g of the solvate of Compound I obtained in Production Example 2 to the reactor, the mixture was heated to 50 °C to 55 °C and stirred for 10 minutes. Then, to a solution prepared by dissolving 4.9 g of citric acid in 33.4 g of acetone was added, and the mixture was stirred at the same temperature for 1 hour, cooled to 20 °C to 25 °C, and further stirred for 1 hour. The resulting solid was filtered, washed with 20.1 g of acetone, and then vacuum dried at about 40 °C to obtain 11.75 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0086] Example 3(2) to Example 3(4): Preparation of Compound I Citrate - Crystalline Form C1 The production process of the citrate of Compound I described in Example 3(1) was substantially the same, except that, as the solvent added to the reactor together with the solvate, the solvents shown in Table 3 below were used as a mixed solvent together with acetone, to obtain the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to Examples 3(2) to 3(4) of the present invention, respectively.

[0087] [Table 3] [Table 3]

[0088] Example 3(5): Production of Compound I Citrate - Crystal Form C1 167.2 g of acetone or 32.1 g of dichloromethane and 10 g of the solvate of Compound I obtained in Production Example 2 were added to a reactor, and the mixture was stirred at 10°C to 30°C for 10 minutes. Then, a solution prepared by dissolving 4.9 g of citric acid in 33.4 g of acetone was added within 10 minutes, and the mixture was stirred at the same temperature for 1 hour. Subsequently, the mixture was cooled to 0°C to 5°C and further stirred for 1 hour. The resulting solid was filtered, washed with 20.1 g of acetone, and then dried under vacuum at about 40°C to obtain 11.74 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0089] Analysis 3 - XRD, DSC, and TGA Measurement Results of Crystal Form C1 Referring to Figure 7 and Table 4 below, the 2θ values (unit: °) of the XRD pattern of Crystal Form C1 of the present invention can be confirmed. Specifically, the XRD pattern of Crystal Form C1 according to the present invention includes diffraction peaks at 2θ values of 7.35°, 10.23°, 12.90°, 14.68°, 15.31°, 15.97°, 17.42°, 18.21°, 21.22°, 22.26°, and 26.00°. Referring to Figure 8, Crystal Form C1 shows an endothermic peak in DSC at 168.93°C. Referring to Fig. 9, as a result of TGA analysis, it is confirmed that the crystalline form C1 decomposes in two stages. Specifically, the crystalline form C1 decomposes at about 172.76 °C to 192.20 °C in the first stage and at about 297.93 °C to 337.46 °C in the second stage, and the maximum inflection points of decomposition are confirmed at 178.36 °C and 324.77 °C, respectively. On the other hand, from the moisture content, it can be confirmed that the crystalline form C1 is an anhydride. In addition, it was confirmed that the crystalline form C1 according to the present invention is formed by the combination of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in a molar ratio of about 1:1.

[0090] [Table 4]

Table 4

[0091] Example 4(1): Production of Compound I Citrate - Crystalline Form C2 167.2 g of acetone and 10 g of the solvate of Compound I obtained in Production Example 2 were added to a reactor, and then stirred at 20 °C to 25 °C for 10 minutes. Then, a solution prepared by dissolving 4.9 g of citric acid in 33.4 g of acetone was slowly added dropwise over 60 minutes or more, and stirred at the same temperature for 1 hour. Subsequently, after raising the temperature to 50 °C to 55 °C, stirring was continued for another 1 hour. After cooling to 20 °C to 25 °C and further stirring for 1 hour, the resulting solid was filtered, washed with 20.1 g of acetone, and then vacuum dried at 40 °C to obtain 11.76 g of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0092] Examples 4(2) to 4(4): Production of Compound I Citrate - Crystalline Form C2 The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to Examples 4(2) to 4(4) of the present invention was obtained in substantially the same process as the manufacturing process of the citrate described in Example 4(1), except that, as the solvent added together with the solvate to the reactor, the solvents shown in Table 5 below were used as a mixed solvent together with acetone.

[0093] [Table 5] [Table 5]

[0094] XRD, DSC and TGA measurement results of Analytical 4 - Crystal Form C2 Referring to FIG. 10 and Table 6 below, the 2θ values (unit: °) of the XRD pattern of Crystal Form C2 of the present invention can be confirmed. Specifically, the XRD pattern of Crystal Form C2 according to the present invention includes diffraction peaks where 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°. Referring to FIG. 11, the endothermic peak of the DSC of Crystal Form C2 appears at 161.48°C. Referring to FIG. 12, as a result of the TGA analysis, it is confirmed that the decomposition of Crystal Form C2 occurs in two stages. Specifically, the decomposition of Crystal Form C2 occurs at about 166.37°C to 191.88°C in the first stage and at about 282.15°C to 311.08°C in the second stage, and the maximum inflection points of the decomposition are confirmed at 173.44°C and 304.81°C, respectively. In addition, it was confirmed that in Crystal Form C2 according to the present invention, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are bonded at a molar ratio of about 1:1.

[0095] [Table 6] [Table 6]

[0096] Example 5(1): Preparation of Compound I Citrate - Amorphous To the 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 the mixture was stirred at 20 °C to 25 °C for 20 minutes to dissolve. Then, the solid formed by concentration was 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.

[0097] Example 5(2) and 5(3): Preparation of Compound I Citrate - Amorphous Except for using the alcohol solvents shown in Table 7 below instead of methanol, in substantially the same process as the production process of Compound I citrate described in Example 5(1), amorphous azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to Example 5(2) and Example 5(3) of the present invention were obtained respectively.

[0098] [Table 7] [Table 7]

[0099] Analysis 5 - Measurement Results of DSC and TGA of Amorphous Referring to Figure 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 according to Examples 5(1) to 5(3) of the present invention is amorphous. Referring to Figure 14, for the amorphous form of Compound I of the present invention, an endothermic peak in DSC appears at 161.42 °C. Referring to Fig. 15, as a result of TGA analysis, it is confirmed that the amorphous form of the present invention decomposes in three stages. Specifically, the amorphous form decomposes at about 79.55°C to 118.51°C in the first stage, about 165.24°C to 190.12°C in the second stage, and finally about 289.01°C to 333.88°C in the third stage. The maximum inflection points of decomposition are confirmed to be 105.71°C, 175.22°C, and 315.61°C, respectively. On the other hand, from the moisture content, it can be confirmed that the amorphous form is also an anhydride.

[0100] Experimental Example 1: Evaluation of Bioavailability The bioavailability of 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 was evaluated with azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained according to Production Example 1 as a comparative example. The specific pharmacokinetic test and its evaluation method are as follows.

[0101] <Drug Administration and Blood Sampling> Fasted male beagle dogs were orally administered with a 10 mg / kg dose of 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 was collected from the jugular vein each time, centrifuged to separate plasma, and frozen and stored in an ultra-low temperature freezer until analysis.

[0102] <Plasma Pretreatment> Plasma pretreatment was performed by the protein precipitation method. 300 μl of acetonitrile containing an internal standard substance (200 ng / ml carbamazepine) was added to 100 μl of a plasma sample and mixed. After sufficient mixing, it was centrifuged at 12,000 rpm for 10 minutes, and then the upper layer liquid was transferred to an analysis vial and injected into LC-MS / MS to analyze the blood concentration of the compound.

[0103] <LC-MS / MS Analysis Conditions>

Table 8

[0104] <Pharmacokinetic evaluation> Time to reach the maximum plasma concentration (T max ), maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC0- t , AUC 0-inf ) parameters were determined using PK Solution. The results are shown in Table 8 below.

[0105] [Table 8] [Table 9]

[0106] Referring to Table 8 above, azetidin-1-yl {8-[(2,6-dimethyl benzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention reached the maximum plasma concentration in a significantly shorter time than the compound I (free base) of the comparative example, and it was confirmed that C max increased significantly more than 11 times compared to the comparative example, and it was also confirmed that the AUC was significantly improved by more than 5 times compared to the comparative example. That is, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention exhibits excellent bioavailability beyond the normally predictable level.

[0107] Accordingly, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention exhibits extremely excellent bioavailability that the inventor could not predict, and is used as an active ingredient of a pharmaceutical composition, and is expected to exhibit extremely excellent effects in the prevention or treatment of inflammatory diseases of the digestive tract or gastric acid-related diseases.

[0108] Experimental Example 2: Evaluation of photostability For the 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, after the sample was thinly spread in a Petri dish and placed, Visible with a light intensity of 35 k lux was irradiated under the conditions of 25 °C and 60% humidity using a photostability chamber (CARON6542-2) so that the total irradiation dose became 1200 k lux. After the sample was thinly spread in a Petri dish and placed, UV with a light intensity of 35 W was irradiated under the conditions of 25 °C and 60% humidity using a photostability chamber (CARON6542-2) so that the total irradiation dose became 200 watt, and then the presence or absence of discoloration was visually observed. The results are shown in Table 9 below. As the property of the solid, the conformity determination is made only when it maintains a white to slightly yellowish white powder form.

[0109] [Table 9] [Table 10]

[0110] Referring to Table 9, 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 remains slightly colored or slightly white and conforms to the property standard even when irradiated with ultraviolet rays and visible light. Thus, it can be seen 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 has excellent photostability.

[0111] Experimental Example 3: Evaluation of Short-Term Storage Stability (Heat / Moisture) The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone according to Example 4(1) of the present invention The purity of citrate was measured, and after leaving it standing at 60 °C for 4 days, the purity was measured again. The purity was measured by HPLC. Also, for 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, after leaving it standing under conditions of 75 to 90% humidity (RH) for 2 days, the purity was measured. The results are shown in Table 10 below.

[0112] [Table 10] [Table 11]

[0113] Referring to Table 10, it can be confirmed that the purity of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention does not substantially change even when left standing under high temperature or high humidity conditions. Therefore, it can be seen that azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention has stability against heat and moisture, respectively.

[0114] Experimental Example 4: Evaluation of long-term storage stability Immediately after the production of 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 visually confirmed, the water content, purity, and XRD were measured respectively, and then after primary sealing in a polyethylene bag and then secondary sealing in an aluminum bag, and storing under conditions of 25 ± 2 °C and 60 ± 5% RH, the properties after 12 months, 24 months, and 36 months were visually confirmed, and the water content, purity, and XRD were measured. The results are shown in Table 11 and Figure 16 below.

[0115] [Table 11] [Table 12]

[0116] Referring to Table 11, it can be confirmed that azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention is stably retained even after 36 months of production.

[0117] Also, referring to FIG. 16 which is the XRD analysis result after 36 months, there is no substantial change in the XRD pattern immediately after the production of the citrate of the present invention shown in FIG. 10. Specifically, it can be confirmed that each diffraction peak is not shifted and is retained as it is. That is, it can be confirmed that the citrate according to the present invention is very excellent in long-term storage stability.

[0118] Experimental Example 5: Evaluation of Thermal and Moisture Stability (Accelerated Conditions) Immediately after the production of 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 visually confirmed, the water content, purity and XRD were measured respectively, then it was first sealed in a polyethylene bag and then second sealed in an aluminum bag, and after storage under accelerated conditions of 40 ± 2°C and 75 ± 5% RH, the properties after 1 month and 6 months were visually confirmed, and the water content, purity and XRD were measured. The results are shown in Table 12 below.

[0119] [Table 12] [Table 13]

[0120] Referring to Table 12, it can be confirmed that azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to the present invention is stably retained even when six months have passed after being manufactured under accelerated conditions.

[0121] As described above with reference to the preferred embodiments of the present invention, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention described in the following claims.

Claims

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

2. The 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. The 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 an anhydride.

4. The 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 in crystalline form.

5. The 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 in anhydrous crystalline form.

6. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to Claim 1, which is crystalline form A containing three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 5.46°, 7.14°, 10.61°, 11.82°, 18.27° and 25.77° in the powder X-ray diffraction pattern.

7. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to Claim 6, which is crystalline form A further containing at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values of 10.93°, 13.11°, 14.15°, 15.84°, 16.35°, 19.79° and 24.21° in the powder X-ray diffraction pattern.

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

9. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methane citrate according to claim 1, which is crystalline form B containing three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 7.03°, 7.69°, 9.47°, 13.21°, 14.86°, and 21.13° in the powder X-ray diffraction pattern.

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

11. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methane citrate according to claim 1, which is crystalline form C1 containing three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 7.35°, 15.31°, 17.42°, and 22.26° in the powder X-ray diffraction pattern.

12. The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methane citrate according to claim 11, which is crystalline form C1 further containing at least one or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values of 10.23°, 12.90°, 14.68°, 15.97°, 18.21°, 21.22°, and 26.00° in the powder X-ray diffraction pattern.

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

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

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

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, which has an endothermic peak in differential scanning calorimetry (DSC) at 161.48 °C (±0.5 °C) when the heating rate is 10 °C / min.

17. The 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 producing azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate, comprising the step of reacting azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid under at least one solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP) and purified water.

19. In the step, azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone for reaction with citric acid is a solvate, the method for producing azetidin-1-yl { 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 18.

20. In the step, a citrate is produced 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, the method for producing azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to claim 18.

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

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