Crystalline form of imidazo [1,2-a] pyridine compound and method for preparing same

Abstract

The present invention relates to a crystalline form of an imidazo[1,2-a]pyridine compound, and more specifically to a monohydrate crystalline form, crystalline form A, and crystalline form B serving as an active pharmaceutical ingredient of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and as an intermediate of a final salt addition compound, and a method for preparing same. The monohydrate crystalline form, crystalline form A, and crystalline form B of the compound of chemical formula I according to the present invention have excellent stability under high-humidity or high-temperature conditions, and thus can be usefully applied to the formulation of pharmaceuticals.

Description

Crystalline form of imidazo[1,2-A]pyridine compound and method for preparing the same

[0001] The present invention relates to a crystalline form of an imidazo[1,2-a]pyridine compound and a method for preparing the same, and more specifically, to a monohydrate crystalline form, crystalline form A, crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone and a method for preparing the same. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone is a compound that exhibits gastric acid secretion inhibitory activity and can also be used as an intermediate of a final active pharmaceutical ingredient in the form of an acid addition salt for use as a pharmaceutical product.

[0002] Gastrointestinal inflammatory diseases or acid-related diseases such as peptic ulcers, gastric and duodenal ulcers, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD) are the most common digestive diseases, affecting the majority of the world's population, including Korea.

[0003] In order to solve the problems of conventional proton pump inhibitors (PPIs), recently H + / K + - ATPase's K + There is increasing interest in and need for Potassium Competitive Acid Blocker (P-CAB, acid pump antagonist) drugs, which have a mechanism of action that inhibits acid secretion by reversibly binding to a binding site and suppressing potassium-competitive competition. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) are expected to be very effective in improving nocturnal symptoms, which are a problem with irreversible proton pump inhibitors, as well as providing rapid efficacy through their mechanism and being easy to take regardless of whether it is before or after a meal.

[0004] In this regard, Korean registered patent No. 10-1777971 discloses azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone as an imidazo[1,2-a]pyridine derivative, which is a P-CAB drug, and a method for manufacturing the same, and Korean registered patent No. 10-2496869 discloses azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate salt and a method for manufacturing the same.

[0005] To ensure the safety of finished pharmaceutical products, the stability of active pharmaceutical ingredients (APIs) is critical; furthermore, to synthesize high-purity APIs, it is necessary to synthesize the final API from intermediate compounds that possess both high purity and stability. To this end, regulatory authorities require that when managing finished pharmaceutical products, they identify and control factors that may affect the product—such as the purity, impurities, and stability of each raw material—starting from the initial materials used for API synthesis, in addition to the API itself, which serves as the active ingredient.

[0006] Recently, global atmospheric temperatures have been rising due to global warming, and climatic conditions are shifting toward extremes, such as dryness in some regions or high humidity caused by heavy rainfall. To ensure the safety of pharmaceuticals, it is crucial that active pharmaceutical ingredients (APIs) remain unaffected by these extreme weather conditions.

[0007] Therefore, it is necessary to ensure high stability that is not affected by extreme weather conditions for azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone, which is an active active drug and used as an intermediate for the final salt addition compound. The development of compounds with improved purity and stability of such active drugs not only expands the formulation range of finished pharmaceutical products but also provides an opportunity to manufacture and store pharmaceutical compositions more easily.

[0008] Accordingly, the inventors of the present invention made diligent research efforts to discover a form that possesses stability even under extreme climatic conditions, as a compound intended to be used as an active active pharmaceutical ingredient and as an intermediate for final salt addition compounds. As a result, the most stable crystalline form of the imidazo[1,2-a]pyridine compound was identified under respective humidity and harsh thermodynamic conditions, thereby completing the present invention.

[0009] [Prior Art Literature]

[0010] [Patent Literature]

[0011] (Patent Document 0001) Republic of Korea Registered Patent Publication No. 10-1777971

[0012] (Patent Document 0002) Republic of Korea Registered Patent Publication No. 10-2496869

[0013] One objective of the present invention is to provide a crystalline form of ‘azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone’ of the following chemical formula I with improved stability.

[0014] [Chemical Formula I]

[0015]

[0016] Another object of the present invention is to provide a crystalline monohydrate form, crystalline form A, or crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I.

[0017] Another object of the present invention is to provide an acid addition salt of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone or a method for preparing the crystalline form thereof, characterized by using the crystalline monohydrate form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I as an intermediate.

[0018] Another object of the present invention is to provide an acid addition salt of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone or a method for preparing the same, characterized by using crystalline form A of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I as an intermediate.

[0019] Another object of the present invention is to provide an acid addition salt of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone or a method for preparing the same, characterized by using crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I as an intermediate.

[0020] Another objective of the present invention is to provide an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or a crystalline form thereof, characterized by being produced by the above-described manufacturing method.

[0021] Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or its crystalline form prepared by the above-described method, together with a pharmaceutically acceptable carrier.

[0022] Another objective of the present invention is to provide a method for producing crystalline form A, characterized by converting the solvate crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I into crystalline form A under high temperature conditions.

[0023] Another objective of the present invention is to provide a use for the crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone to be used in the manufacture of a drug for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0024] Another objective of the present invention is to provide a method for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastroduodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), comprising administering a therapeutically effective amount of the crystalline form of azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone to a subject in need thereof.

[0025] Accordingly, the inventors conducted a thorough study on the new crystal forms and confirmed surprising results that the crystal form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone monohydrate, crystal form A, and crystal form B each have excellent stability under high humidity or high temperature conditions, excellent stability when stored under extreme climatic conditions, strong crystallinity, and can be easily used as an intermediate for an addition salt form compound or in the preparation of a pharmaceutical composition containing it as an active ingredient, thereby completing the present invention.

[0026] The present invention provides a crystalline monohydrate form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I.

[0027] [Chemical Formula I]

[0028]

[0029] In addition, the present invention provides crystalline form A of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I.

[0030] In addition, the present invention provides crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone of the above formula I.

[0031] In addition, the present invention provides an acid addition salt of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone or a method for preparing the same, characterized by using the crystalline monohydrate form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I as an intermediate.

[0032] In addition, the present invention provides an acid addition salt of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone or a method for preparing the same, characterized by using crystalline form A of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I as an intermediate.

[0033] In addition, the present invention provides an acid addition salt of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone or a method for preparing the same, characterized by using crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I as an intermediate.

[0034] In addition, the present invention provides an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or a crystalline form thereof, characterized by being produced by the above-described manufacturing method.

[0035] In addition, the present invention provides a pharmaceutical composition comprising, as an active ingredient, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or its crystalline form prepared by the above-described manufacturing method, together with a pharmaceutically acceptable carrier.

[0036] In addition, the present invention provides a method for producing crystalline form A, characterized by converting the methanol solvate, ethanol solvate, or isopropanol solvate crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I into crystalline form A under high temperature conditions of 50°C to 100°C.

[0037] In addition, the present invention provides a use for the crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone to be used in the manufacture of a drug for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0038] In addition, the present invention provides a method for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastroduodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), comprising administering a therapeutically effective amount of the crystalline form of azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone to a subject who requires it.

[0039] Korean Patent No. 10-2496869, regarding a synthesis method for a citrate of a compound of Formula I and its crystalline form, employs a process of converting a compound of Formula I into an isopropanol solvate crystalline form and adding a citrate. According to the present invention, when a compound of Formula I is converted into the monohydrate crystalline form, crystalline form A, or crystalline form B of the present invention instead of the isopropanol solvate crystalline form, a more stable compound under harsh conditions can be obtained.

[0040] The crystalline form of the compound of Formula I according to the present invention has the advantage of being easily manufactured with a simple process and being obtained with high purity and a high yield of 90% or more.

[0041] Furthermore, the monohydrate crystalline form, crystalline form A, or crystalline form B of the compound of Formula I according to the present invention has excellent stability under high humidity or high temperature conditions, so it can be usefully utilized in the formulation of active pharmaceutical ingredients and final finished pharmaceutical products regardless of climate conditions.

[0042] In particular, the monohydrate crystalline form of the compound of Formula I according to the present invention is most stable under high humidity conditions, and crystalline forms A and B have excellent thermodynamic stability under high temperature conditions.

[0043] Figure 1 shows an X-ray powder diffraction (XRD) analysis of the crystalline form of the monohydrate of the compound of Formula I prepared according to Example 1 of the present invention.

[0044] Figure 2 shows the thermogravimetric analysis (TGA) of the crystalline form of the monohydrate of the compound of Formula I prepared according to Example 1 of the present invention.

[0045] Figure 3 shows a differential scanning calorimetry (DSC) analysis of the crystalline form of the monohydrate of the compound of Formula I prepared according to Example 1 of the present invention.

[0046] Figure 4 shows an X-ray powder diffraction (XRD) analysis of crystalline form A of the compound of Formula I prepared according to Example 2 of the present invention.

[0047] Figure 5 shows the thermogravimetric analysis (TGA) of crystalline form A of the compound of Formula I prepared according to Example 2 of the present invention.

[0048] Figure 6 shows a differential scanning calorimetry (DSC) analysis of crystalline form A of the compound of Formula I prepared according to Example 2 of the present invention.

[0049] Figure 7 shows the X-ray powder diffraction (XRD) analysis of the crystalline form B of the compound of Formula I prepared according to Example 3 of the present invention.

[0050] Figure 8 shows the thermogravimetric analysis (TGA) of the crystalline form B of the compound of Formula I prepared according to Example 3 of the present invention.

[0051] Figure 9 shows a differential scanning calorimetry (DSC) analysis of crystalline form B of the compound of Formula I prepared according to Example 3 of the present invention.

[0052] Figure 10 is an X-ray powder diffraction (XRD) analysis of the monohydrate crystalline form of the compound of Formula I measured while storing it in a chamber for one week under high humidity conditions of 80% relative humidity at 60°C in Experimental Example 3 of the present invention, where Figure 10a shows the initial result, 10b shows the result on day 1, 10c shows the result on day 4, and 10d shows the result on day 7.

[0053] Figure 11 shows the results of evaluating thermodynamic stability under high temperature conditions of 60°C in Experimental Example 4 of the present invention, where Figure 11a shows the crystalline form A of the compound of Formula I, 11b shows the methanol solvate, 11c shows the ethanol solvate, 11d shows the isopropanol solvate, and 11e shows the crystalline form B.

[0054] As used in this specification, the singular form may include the plural form unless the context clearly indicates otherwise.

[0055] In this specification, when a part is described as “comprising” a certain component, it means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0056] In addition, all numbers and expressions indicating the amounts of components, reaction conditions, etc. described in this specification should be understood as being modified by the term “about” in all cases unless otherwise specified.

[0057] In the present invention, the term “about” means having a value that falls within the allowable standard error of the average as considered by a person skilled in the art. Often, the term “about” means ± 15%, specifically ± 10%, more specifically ± 5% of the value or range being modified. For example, “about 10 wt%” means 10 wt% ± 1.5 wt%, specifically 10 wt% ± 1 wt%, more specifically 10 wt% ± 0.5 wt%.

[0058] In the present invention, 'azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone' of Formula I represents a free base state.

[0059]

[0060] According to one aspect of the present invention, a crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following formula I is provided.

[0061] [Chemical Formula I]

[0062]

[0063] The crystalline form of the compound of Formula I of the present invention may specifically be a monohydrate crystalline form, crystalline form A, or crystalline form B. The crystalline form of the present invention may be a crystalline solid that does not contain a molar ratio of solvent molecules substantially fixed within the crystal lattice, i.e., a crystalline solid that is not a solvate. The crystalline form A or crystalline form B may be an anhydrous crystalline form.

[0064]

[0065] 1. Crystalline form

[0066] The present invention provides a crystalline monohydrate form of the compound of the above chemical formula I.

[0067] The crystalline monohydrate form of the compound of Formula I of the present invention may include three or more diffraction peaks selected from the group consisting of 2θ values ​​of the X-ray powder diffraction pattern of 24.607°(±0.2°), 16.978°(±0.2°), 12.254°(±0.2°), 9.773°(±0.2°), 8.739°(±0.2°), 11.113°(±0.2°), and 13.458°(±0.2°).

[0068] The monohydrate crystal form of the compound of Formula I of the present invention may further include at least one diffraction peak selected from the group consisting of 2θ values ​​of the X-ray powder diffraction pattern of 22.989°(±0.2°), 22.365°(±0.2°), 17.785°(±0.2°), 25.528°(±0.2°), and 13.972°(±0.2°).

[0069] The crystalline monohydrate form of the compound of Formula I of the present invention may have a peak position of the X-ray powder diffraction pattern that substantially matches the peak position of FIG. 1.

[0070] The monohydrate crystalline form of the compound of Formula I of the present invention may exhibit a weight loss of about 4.4% at around 86°C in thermogravimetric analysis (TGA) and decompose from about 282°C onwards, and the thermogravimetric analysis record may substantially match FIG. 2.

[0071] The crystalline monohydrate form of the compound of Formula I of the present invention may have a differential scanning calorimetry (DSC) endothermic peak at 196.21°C (±0.5°C) when the heating rate is 10°C / min.

[0072] The crystalline monohydrate form of the compound of Formula I of the present invention may have a differential scanning calorimetry (DSC) endothermic peak that substantially matches that shown in FIG. 3.

[0073] The crystalline monohydrate form of the compound of Formula I of the present invention is characterized by having excellent stability under high humidity conditions of 60% to 90% relative humidity.

[0074] In addition, the monohydrate crystalline form of the compound of Formula I of the present invention is characterized by excellent stability under high temperature conditions of 50°C to 100°C and high humidity conditions of 60% to 90% relative humidity, and specifically, it was confirmed to be a crystalline form with no hygroscopicity under harsh conditions (temperature 60°C, humidity 80%).

[0075] The crystalline monohydrate form of the compound of Formula I of the present invention can be used as an intermediate for the preparation of an acid addition salt of the compound of Formula I or a crystalline form thereof, and is particularly advantageous for preparation and storage under high humidity conditions.

[0076] The acid addition salt of the compound of Formula I above or its crystalline form may be the citrate or crystalline form of the compound of Formula I.

[0077]

[0078] Determinant A

[0079] The present invention provides crystalline form A of the compound of the above chemical formula I.

[0080] The above crystalline form A may be anhydrous crystalline form.

[0081] Crystalline form A of the compound of Formula I of the present invention may include three or more diffraction peaks selected from the group consisting of 2θ values ​​of the X-ray powder diffraction pattern of 7.319°(±0.2°), 9.219°(±0.2°), 13.777°(±0.2°), 18.541°(±0.2°), 26.062°(±0.2°), 20.434°(±0.2°), 22.255°(±0.2°), 11.649°(±0.2°), and 14.693°(±0.2°).

[0082] Crystalline form A of the compound of Formula I of the present invention may further include at least one diffraction peak selected from the group consisting of 2θ values ​​of the X-ray powder diffraction pattern of 12.353°(±0.2°), 27.519°(±0.2°), 26.751°(±0.2°), 23.443°(±0.2°), 12.757°(±0.2°), and 15.507°(±0.2°).

[0083] Crystalline form A of the compound of Formula I of the present invention may have a peak position of the X-ray powder diffraction pattern that substantially matches the peak position of FIG. 4.

[0084] Crystalline form A of the compound of Formula I of the present invention may decompose from about 272°C onwards in thermogravimetric analysis (TGA), and the thermogravimetric record may substantially match FIG. 5.

[0085] Crystalline form A of the compound of Formula I of the present invention may have a differential scanning calorimetry (DSC) endothermic peak at 195.95°C (±0.5°C) when the heating rate is 10°C / min.

[0086] Crystalline form A of the compound of Formula I of the present invention may have a differential scanning calorimetry (DSC) endothermic peak that substantially matches that shown in FIG. 6.

[0087] The crystalline form A of the compound of Formula I of the present invention is characterized by excellent stability under high temperature conditions of 50°C to 100°C. Specifically, when the methanol solvate, ethanol solvate, or isopropanol solvate crystalline form is dried under harsh conditions (temperature 60°C), it is confirmed that the crystalline form A of the present invention is a crystalline form with excellent thermodynamic stability.

[0088] According to another aspect of the present invention, a method for producing crystalline form A is provided, characterized by converting the methanol solvate, ethanol solvate, or isopropanol solvate crystalline form of the compound of Formula I into crystalline form A under high temperature conditions of 50°C to 100°C.

[0089] The crystalline form A of the compound of Formula I of the present invention can be used as an intermediate for the preparation of an acid addition salt of the compound of Formula I or its crystalline form, and is particularly advantageous for preparation and storage under high temperature conditions.

[0090] The acid addition salt of the compound of Formula I above or its crystalline form may be the citrate or crystalline form of the compound of Formula I.

[0091]

[0092] Crystalline form B

[0093] The present invention provides crystalline form B of the compound of the above chemical formula I.

[0094] The above crystalline form B may be anhydrous crystalline form.

[0095] Crystalline form B of the compound of Formula I of the present invention may include three or more diffraction peaks selected from the group consisting of 2θ values ​​of the X-ray powder diffraction pattern of 10.539°(±0.2°), 13.727°(±0.2°), 7.071°(±0.2°), 25.776°(±0.2°), 15.022°(±0.2°), 22.273°(±0.2°), 28.266°(±0.2°), 20.515°(±0.2°), and 19.334°(±0.2°).

[0096] Crystalline form B of the compound of Formula I of the present invention may further include at least one diffraction peak selected from the group consisting of 2θ values ​​of the X-ray powder diffraction pattern of 21.146°(±0.2°), 24.931°(±0.2°), 24.123°(±0.2°), and 19.787°(±0.2°).

[0097] Crystalline form B of the compound of Formula I of the present invention may have a peak position of the X-ray powder diffraction pattern that substantially matches the peak position of FIG. 7.

[0098] Crystalline form B of the compound of Formula I of the present invention may decompose from about 273°C onwards in thermogravimetric analysis (TGA), and the thermogravimetric record may substantially match FIG. 8.

[0099] Crystalline form B of the compound of Formula I of the present invention may have a differential scanning calorimetry (DSC) endothermic peak at 196.59°C (±0.5°C) when the heating rate is 10°C / min.

[0100] Crystalline form B of the compound of Formula I of the present invention may have a differential scanning calorimetry (DSC) endothermic peak that substantially matches that shown in FIG. 9.

[0101] Crystalline form B of the compound of Formula I of the present invention is characterized by excellent stability under high temperature conditions of 50°C to 100°C, and specifically, it was confirmed to be a thermodynamically stable crystal form as it does not convert to another crystal form when dried under harsh conditions (temperature 60°C).

[0102] The crystalline form B of the compound of Formula I of the present invention can be used as an intermediate for the preparation of an acid addition salt of the compound of Formula I or its crystalline form, and is particularly advantageous for preparation and storage under high temperature conditions.

[0103] The acid addition salt of the compound of Formula I above or its crystalline form may be the citrate or crystalline form of the compound of Formula I.

[0104]

[0105] The crystalline form of a pharmaceutical ingredient can be characterized by one or more of various methods, including melting point, XRD, DSC, solid-state nuclear magnetic resonance spectroscopy, infrared spectroscopy, Raman spectroscopy, and the presence of hydrates. In particular, 2theta (2θ), which indicates the diffraction angle in XRD, or the d-value, which indicates the interplanar spacing, serve as decisive means for characterizing the crystalline form. According to guidelines and regulations on good manufacturing practices for drugs published by drug regulatory authorities in each country, the uniformity of pharmaceutical ingredients is one of the requirements for drug approval. According to drug manufacturing regulations, it is not only necessary for the uniformity of pharmaceutical ingredients to meet standard criteria, but it is also crucial to ensure that this uniformity is maintained consistently across every batch of pharmaceutical ingredient production. These requirements are demanded of drug manufacturers by the regulations of drug regulatory authorities in each country. Accordingly, the crystalline form of the compound of Formula I according to the present invention, as defined above by XRD, DSC, and melting point, will always be confirmed to be uniform within the acceptable margin of error in this field, regardless of the manufacturing batch, drying time, storage period, storage method, and measurement method.

[0106]

[0107] According to another aspect of the present invention, the monohydrate crystalline form, crystalline form A, and crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of Formula I may be intermediates for use in preparing an acid addition salt of a compound of Formula I or a crystalline form thereof, specifically, may be intermediates for use in preparing a citrate or a crystalline form of a citrate.

[0108]

[0109] According to another aspect of the present invention, a pharmaceutical composition is provided comprising, together with a pharmaceutically acceptable carrier, the crystalline monohydrate form, crystalline form A, or crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the above formula I as an active ingredient.

[0110] The pharmaceutical composition according to the present invention may further comprise one or more pharmaceutically acceptable carriers, one or more excipients and / or diluents.

[0111] Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids, e.g., ethanol, glycerol, water, etc. The amount of carrier in the therapeutic composition may be in the range of about 1% to about 99% by weight based on the total weight of the therapeutic composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and diluents include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, wetting agents, extenders, antioxidants, lubricants, flavoring agents, thickeners, coloring agents, surfactants, emulsifiers, suspending agents, etc. Examples of such excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, and it is obvious to a person skilled in the art that any other pharmaceutically acceptable carriers, excipients, and diluents may be used.

[0112] The pharmaceutical composition of the present invention contains azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone in a therapeutically effective amount.

[0113] The pharmaceutical composition of the present invention can treat or prevent diseases selected from the group consisting of peptic ulcers, gastric and duodenal ulcers, nonsteroidal anti-inflammatory drugs (NSAID)-induced ulcers, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0114]

[0115] According to another aspect of the present invention, a method is provided for preparing an acid addition salt of a compound of Formula I or the crystalline form thereof by using the crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of Formula I as an intermediate.

[0116]

[0117] According to another aspect of the present invention, an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or a crystalline form thereof is provided, characterized by being produced by the above-described manufacturing method.

[0118] The acid addition salt of the compound of Formula I or its crystalline form prepared by the above manufacturing method has excellent purity and stability, which is advantageous for formulation.

[0119] The acid addition salt of the compound of Formula I above or its crystalline form may be the citrate or crystalline form of the compound of Formula I.

[0120] According to another aspect of the present invention, a pharmaceutical composition is provided comprising, as an active ingredient, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or its crystalline form prepared by the above-described manufacturing method, together with a pharmaceutically acceptable carrier.

[0121] The pharmaceutical composition of the present invention contains an acid addition salt of a compound of Formula I or a crystalline form thereof in a therapeutically effective amount.

[0122] The acid addition salt of the compound of Formula I above or its crystalline form may be the citrate or crystalline form of the compound of Formula I.

[0123] The pharmaceutical composition of the present invention can treat or prevent diseases selected from the group consisting of peptic ulcers, gastric and duodenal ulcers, nonsteroidal anti-inflammatory drugs (NSAID)-induced ulcers, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0124]

[0125] According to another aspect of the present invention, the crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone is used in the manufacture of a drug for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

[0126]

[0127] According to another aspect of the present invention, a method for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastroduodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD) is provided, comprising administering a therapeutically effective amount of the crystalline form of azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone to a subject in need thereof.

[0128] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the present invention pertains. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0129] In addition, the experimental process specified in this specification is identical to the experimental process ordinarily performed in the art unless specifically described otherwise.

[0130] The present invention will be described in detail below.

[0131]

[0132] <Measurement Method>

[0133] The following measurement method is commonly applied to each of the embodiments according to the present invention.

[0134] - NMR analysis

[0135] Nuclear magnetic resonance (NMR) analysis was performed using a Bruker 400.

[0136] - Thermogravimetric Analysis (TGA)

[0137] Thermogravimetric analysis was performed using a TGA 8000 (PerkinElmer) at 30°C to 800°C by weighing 0.5 mg to 2 mg of sample into a ceramic crucible and measuring at 5°C / min.

[0138] - Thermal Analysis (DSC)

[0139] Differential scanning calorimetry (DSC) was performed using a DSC 8000 (PerkinElmer). Samples were evaluated using a linear heating ramp of 10°C / min in the range of 30°C to 300°C.

[0140] - X-ray powder diffraction (XRD)

[0141] X-ray powder diffraction patterns were obtained using a solid-state detector with a D8 Focus (Bruker ASX) in a step size of 0.02° over a diffraction angle (2θ) range of 4° to 40°.

[0142] - HPLC Purity Analysis

[0143] Purity analysis was performed on the obtained samples using the Agilent 1260 series.

[0144]

[0145] Example 1: Preparation of the crystalline monohydrate form of the compound of Formula I

[0146] 95.00 mL of dichloromethane and 9.50 g of 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid were added to a reactor and cooled to 0–5°C. 1.35 g of hydroxybenzotriazole hydrate, 4.13 g of azetidine hydrochloride, 4.46 g of triethylamine, and 8.45 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added while maintaining the temperature at 0–5°C. The temperature was raised to 38–42°C (reflux temperature) and stirred for 2 hours. Once the reaction was complete, the temperature was cooled to 20–25°C, and a 5% aqueous sodium bicarbonate solution (2.50 g sodium bicarbonate + 47.50 mL of purified water) was added and stirred for 10 minutes. After stirring, a 20% aqueous sodium chloride solution (11.88 g sodium chloride + 47.50 mL purified water) was added to the organic layer collected by layer separation, and the mixture was stirred for 10 minutes. After stirring, 9.50 g anhydrous magnesium sulfate was added to the organic layer collected by layer separation, stirred for 20 minutes, and then filtered. After washing with 28.50 mL of dichloromethane, the organic layer was concentrated under reduced pressure to approximately 38 mL while maintaining the temperature below 30°C. 65.70 mL of methanol was added and stirred, and the mixture was concentrated under reduced pressure to approximately 21 mL; then, 65.70 mL of methanol was added to the concentrate, and the mixture was concentrated again by azeotropically to 21 mL. The solution, which was completely dissolved by heating to 65°C, was cooled to 55°C, and 187.6 mL of water was added dropwise over 1 hour. After adding dropwise, the mixture was stirred for 1 hour at 10°C intervals from 50°C to 0°C, and after filtration, vacuum dried at 20-25°C to obtain 8.88g (94.7%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone monohydrate.

[0147]

[0148] Analysis 1: XRD, TGA, and DSC measurements of the crystalline monohydrate form

[0149] Figure 1 shows the results of measuring the X-ray powder diffraction of the monohydrate crystalline form of the compound of Formula I according to the present invention. The XRD pattern of the monohydrate crystalline form according to the present invention includes diffraction peaks with 2θ values ​​(unit: °) of 24.607°, 16.978°, 12.254°, 9.773°, 8.739°, 11.113°, and 13.458°. Additionally, it further includes at least one diffraction peak selected from the group consisting of 22.989°, 22.365°, 17.785°, 25.528°, and 13.972°.

[0150] Thermogravimetric analysis (TGA) of the monohydrate crystalline form of the compound of Formula I according to the present invention was performed using a TGA 8000 (PerkinElmer). Samples were measured at a rate of 5°C / min in the range of 30°C to 800°C. The results are shown in Figure 2, where a weight loss of 4.373% was observed at around 86°C, and decomposition was confirmed starting from approximately 282°C.

[0151] Differential scanning calorimetry (DSC) of the crystalline monohydrate form of the compound of Formula I according to the present invention was performed using a DSC 8000 (PerkinElmer). The samples were evaluated using a linear heating ramp of 10°C / min in the range of 30°C to 300°C. The results are shown in Fig. 3, and the endothermic peak of the DSC appeared at 196.21°C.

[0152]

[0153] Example 2: Preparation of Crystalline Form A of Compound of Formula I

[0154] 95.00 mL of dichloromethane and 9.50 g of 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid were added to a reactor and cooled to 0–5°C. 1.35 g of hydroxybenzotriazole hydrate, 4.13 g of azetidine hydrochloride, 4.46 g of triethylamine, and 8.45 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added while maintaining the temperature at 0–5°C. The temperature was raised to 38–42°C (reflux temperature) and stirred for 2 hours. Once the reaction was complete, the temperature was cooled to 20–25°C, and a 5% aqueous sodium bicarbonate solution (2.50 g sodium bicarbonate + 47.50 mL of purified water) was added and stirred for 10 minutes. After stirring, a 20% aqueous sodium chloride solution (11.88 g sodium chloride + 47.50 mL purified water) was added to the organic layer collected by layer separation, stirred for 10 minutes, and then 9.50 g anhydrous magnesium sulfate was added to the organic layer collected by layer separation and stirred for 20 minutes, followed by filtration. After washing with 28.50 mL of dichloromethane, the organic layer was concentrated under reduced pressure while maintaining the temperature below 30°C, and vacuum dried at 20–25°C to obtain 6.41 g (98.0%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone type A.

[0155]

[0156] Analysis 2: XRD, TGA, and DSC measurements of Crystalline Form A

[0157] Figure 4 shows the results of measuring the X-ray powder diffraction of the crystalline form A of the compound of Formula I according to the present invention. The XRD pattern of the crystalline form A according to the present invention includes diffraction peaks with 2θ values ​​(unit: °) of 7.319°, 9.219°, 13.777°, 18.541°, 26.062°, 20.434°, 22.255°, 11.649°, and 14.693°. Additionally, it further includes at least one diffraction peak selected from the group consisting of 12.353°, 27.519°, 26.751°, 23.443°, 12.757°, and 15.507°.

[0158] Thermogravimetric analysis (TGA) of the crystalline form A of the compound of Formula I according to the present invention was performed using a TGA 8000 (PerkinElmer). Samples were measured at a rate of 5°C / min in the range of 30°C to 800°C. The results are shown in Fig. 5, and it was confirmed that decomposition occurs from approximately 272°C onwards.

[0159] Differential scanning calorimetry (DSC) of the crystalline form A of the compound of Formula I according to the present invention was performed using a DSC 8000 (PerkinElmer). Samples were evaluated using a linear heating ramp of 10°C / min in the range of 30°C to 300°C. The results are shown in Fig. 6, and the endothermic peak of the DSC appeared at 195.95°C.

[0160]

[0161] Example 3: Preparation of Crystalline Form B of Compound of Formula I

[0162] 95.00 mL of dichloromethane and 9.50 g of 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid were added to a reactor and cooled to 0–5°C. 1.35 g of hydroxybenzotriazole hydrate, 4.13 g of azetidine hydrochloride, 4.46 g of triethylamine, and 8.45 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added while maintaining the temperature at 0–5°C. The temperature was raised to 38–42°C (reflux temperature) and stirred for 2 hours. Once the reaction was complete, the temperature was cooled to 20–25°C, and a 5% aqueous sodium bicarbonate solution (2.50 g sodium bicarbonate + 47.50 mL of purified water) was added and stirred for 10 minutes. After stirring, a 20% aqueous sodium chloride solution (11.88 g sodium chloride + 47.50 mL purified water) was added to the organic layer collected by layer separation, and after stirring for 10 minutes, 9.50 g anhydrous magnesium sulfate was added to the organic layer collected by layer separation, stirred for 20 minutes, and then filtered. After washing with 28.50 mL of dichloromethane, the organic layer was maintained at 30°C or below, and 47.50 mL of methanol was added to the concentrate concentrated under reduced pressure to approximately 38 mL, and the solution was concentrated again by azeotropy to 38 mL. A solution completely dissolved by heating to 65℃ was cooled to 50–55℃, 46.9 mL of water was added, the solution was cooled to 20–25℃ and stirred for 2 hours, filtered, and vacuum dried at 20–25℃ to obtain 9.65 g (96.5%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone type B.

[0163]

[0164] Analysis 3: XRD, TGA, and DSC measurements of Crystalline Form B

[0165] Figure 7 shows the results of measuring the X-ray powder diffraction of the B-type crystalline form of the compound of Formula I according to the present invention. The XRD pattern of the B-type crystalline form according to the present invention includes diffraction peaks with 2θ values ​​(unit: °) of 10.539°, 13.727°, 7.071°, 25.776°, 15.022°, 22.273°, 28.266°, 20.515°, and 19.334°. Additionally, it further includes at least one diffraction peak selected from the group consisting of 21.146°, 24.931°, 24.123°, and 19.787°.

[0166] Thermogravimetric analysis (TGA) of the crystalline form B of the compound of Formula I according to the present invention was performed using a TGA 8000 (PerkinElmer). Samples were measured at a rate of 5°C / min in the range of 30°C to 800°C. The results are shown in Fig. 8, and it was confirmed that decomposition occurs from approximately 273°C onwards.

[0167] Differential scanning calorimetry (DSC) of the crystalline form B of the compound of Formula I according to the present invention was performed using a DSC 8000 (PerkinElmer). Samples were evaluated using a linear heating ramp of 10°C / min in the range of 30°C to 300°C. The results are shown in Fig. 9, and the endothermic peak of the DSC appeared at 196.59°C.

[0168]

[0169] Example 4: Preparation of the crystalline form of the methanol (MeOH) solvate of the compound of Formula I

[0170] 95.00 mL of dichloromethane and 9.50 g of 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid were added to a reactor and cooled to 0–5°C. 1.35 g of hydroxybenzotriazole hydrate, 4.13 g of azetidine hydrochloride, 4.46 g of triethylamine, and 8.45 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added while maintaining the temperature at 0–5°C. The temperature was raised to 38–42°C (reflux temperature) and stirred for 2 hours. Once the reaction was complete, the temperature was cooled to 20–25°C, and a 5% sodium bicarbonate aqueous solution (2.50 g sodium bicarbonate + 47.50 mL purified water) was added and stirred for 10 minutes. After layer separation, a 20% sodium chloride aqueous solution (11.88 g sodium chloride + 47.50 mL purified water) was added to the collected organic layer and stirred for 10 minutes. Then, 9.50 g anhydrous magnesium sulfate was added to the collected organic layer and stirred for 20 minutes, after which the mixture was filtered. After washing with 28.50 mL of dichloromethane, the organic layer was concentrated under reduced pressure to approximately 38 mL while maintaining the temperature below 30°C. 65.70 mL of methanol was added and stirred, and after concentrating under reduced pressure to about 21 mL, 65.70 mL of methanol was added to the concentrate and concentrated again to 21 mL using an azeotropic method. 50 mL of methanol was added and stirred at 0–5°C for 1 hour, then filtered and vacuum dried at 20–25°C to obtain 8.63 g (92.0%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone methanol solvate.

[0171]

[0172] Example 5: Preparation of the crystalline form of the ethanol (EtOH) solvate of the compound of Formula I

[0173] 95.00 mL of dichloromethane and 9.50 g of 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid were added to a reactor and cooled to 0–5°C. 1.35 g of hydroxybenzotriazole hydrate, 4.13 g of azetidine hydrochloride, 4.46 g of triethylamine, and 8.45 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added while maintaining the temperature at 0–5°C. The temperature was raised to 38–42°C (reflux temperature) and stirred for 2 hours. Once the reaction was complete, the temperature was cooled to 20–25°C, and a 5% sodium bicarbonate aqueous solution (2.50 g sodium bicarbonate + 47.50 mL purified water) was added and stirred for 10 minutes. After layer separation, a 20% sodium chloride aqueous solution (11.88 g sodium chloride + 47.50 mL purified water) was added to the collected organic layer and stirred for 10 minutes. Then, 9.50 g anhydrous magnesium sulfate was added to the collected organic layer and stirred for 20 minutes, after which the mixture was filtered. After washing with 28.50 mL of dichloromethane, the organic layer was concentrated under reduced pressure to approximately 38 mL while maintaining the temperature below 30°C, and 65.70 mL of ethanol was added and stirred. The solution was concentrated under reduced pressure to approximately 21 mL, 65.70 mL of ethanol was added to the concentrate, and the solution was concentrated again by azeotropy to 21 mL. 50 mL of ethanol was added and stirred at 0–5°C for 1 hour, then filtered and vacuum dried at 20–25°C to obtain 8.25 g (88.0%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone ethanol solvate.

[0174]

[0175] Comparative Example 1: Preparation of the crystalline form of the solvate of the compound of Formula I, isopropyl alcohol (IPA).

[0176] 95.00 mL of dichloromethane and 9.50 g of 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid were added to a reactor and cooled to 0–5°C. 1.35 g of hydroxybenzotriazole hydrate, 4.13 g of azetidine hydrochloride, 4.46 g of triethylamine, and 8.45 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added while maintaining the temperature at 0–5°C. The temperature was raised to 38–42°C (reflux temperature) and stirred for 2 hours. Once the reaction was complete, the temperature was cooled to 20–25°C, and a 5% sodium bicarbonate aqueous solution (2.50 g sodium bicarbonate + 47.50 mL purified water) was added and stirred for 10 minutes. A 20% sodium chloride aqueous solution (11.88 g sodium chloride + 47.50 mL purified water) was added to the organic layer collected by layer separation and stirred for 10 minutes. Then, 9.50 g anhydrous magnesium sulfate was added to the organic layer collected by layer separation and stirred for 20 minutes, after which the mixture was filtered. After washing with 28.50 mL of dichloromethane, the organic layer was concentrated under reduced pressure to approximately 38 mL while maintaining the temperature below 30°C, and 65.70 mL of isopropyl alcohol was added and stirred. After concentrating under reduced pressure to approximately 21 mL, 65.70 mL of isopropyl alcohol was added to the concentrate, and it was concentrated again by azeotropy to 21 mL. 50 mL of isopropyl alcohol was added and stirred at 0–5°C for 1 hour, then filtered and vacuum dried at 20–25°C to obtain 8.91 g (95.0%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone isopropanol solvate.

[0177]

[0178] Experimental Example 1: Evaluation of Photostability (Purity)

[0179] For the crystalline form of the compound of Formula I according to Examples 1 to 3 and Comparative Example 1 of the present invention, each sample was placed thinly in a Petri dish and then irradiated with Visible light of 35k lux at a total irradiation amount of 1200k lux using a light stability chamber (CARON 6542-2) at 25°C and 60% humidity, and then HPLC was performed to measure purity after irradiating with UV light of 35W at a total irradiation amount of 200 watts using a light stability chamber (CARON 6542-2) at 25°C and 60% humidity.

[0180] The results of measuring the change in purity are shown in Table 1 below.

[0181]

[0182] [Table 1]

[0183]

[0184]

[0185] As a result, it was confirmed that the crystalline form according to Examples 1 to 3 of the present invention has superior photostability compared to the conventional isopropanol solvate crystalline form according to Comparative Example 1.

[0186]

[0187] Experimental Example 2: Evaluation of Humidity Stability (Moisture and Purity)

[0188] For the crystalline forms of the compounds of Formula I according to Example 1 and Comparative Example 1 of the present invention, the moisture and purity of each sample were measured after being stored in a chamber with 90% relative humidity at 25°C for one week, and the results are shown in Table 2.

[0189] [Table 2]

[0190]

[0191]

[0192] As a result, it was confirmed that the monohydrate crystalline form according to Example 1 of the present invention has superior humidity stability compared to the conventional isopropanol solvate crystalline form according to Comparative Example 1. This superior humidity stability means that when a product is manufactured using the monohydrate crystalline form of the present invention, it can be very advantageous for handling or storage in high-humidity climatic conditions.

[0193]

[0194] Experimental Example 3: Harsh Test (Evaluation of Stability under High Humidity Conditions)

[0195] For the crystalline form of the monohydrate of the compound of Formula I prepared in Example 1 above, the moisture and purity of each sample were measured after being stored in a chamber for one week under harsh conditions of 60°C and 80% relative humidity, and the results are shown in Table 3.

[0196] [Table 3]

[0197]

[0198]

[0199] As a result, it was confirmed that the monohydrate crystalline form of the compound of Formula I according to the present invention has excellent moisture retention stability even under high humidity conditions (Figs. 10a to 10d). This excellent moisture retention stability means that when using the monohydrate crystalline form of the present invention to produce a product under high humidity conditions, it can be very advantageous for handling or storage.

[0200]

[0201] Experimental Example 4: Evaluation of Thermodynamic Stability

[0202] As a result of drying the methanol solvate (Fig. 11b), ethanol solvate (Fig. 11c), or isopropanol solvate (Fig. 11d) of the compound of Formula I prepared in Examples 4, 5 and Comparative Example 1 at a high temperature of 60°C, it was confirmed that the compound of Formula I was converted into crystalline form A (Fig. 11a).

[0203] On the other hand, it was confirmed that in the case of crystalline type B, it does not convert to crystalline type A even when dried under high temperature conditions, but maintains crystalline type B (Fig. 11e).

[0204] These results indicate that crystalline forms A and B are the most thermodynamically stable under high-temperature conditions. This excellent thermodynamic stability implies that the crystalline forms A and B of the present invention can be highly advantageous for handling and storage when commercializing products under high-temperature conditions.

[0205]

[0206] Experimental Example 5: Evaluation of Temperature Stability (Purity)

[0207] The purity of the crystalline form of the compound of Formula I according to Examples 1 to 3 of the present invention was measured after being left at 60°C for one week. The purity measurement was performed using HPLC.

[0208] The results of the purity measurement are shown in Table 4 below.

[0209] [Table 4]

[0210]

[0211]

[0212] As a result, it was confirmed that the monohydrate crystalline form and crystalline forms A and B of the compound of Formula I according to the present invention have excellent temperature stability. This excellent temperature stability means that it can be very advantageous for the handling or storage of the compound.

[0213]

[0214] Experimental Example 6: Evaluation of acid addition salt of compound of Formula I or its crystalline form (purity, stability)

[0215] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate was prepared using the crystalline form of the compound of Formula I prepared in Examples 1 to 3 above and the isopropanol solvate of the compound of Formula I, and the purity and stability of the prepared citrate were evaluated.

[0216] Preparation of the citrate of the compound of Chemical Formula I

[0217] Approximately 10 g of each of the crystalline forms obtained in Examples 1 to 3 and Comparative Example 1 was taken and stirred with approximately 167 g of acetone at 20°C to 25°C for 10 minutes. Subsequently, a solution of citric acid (approximately 5 g) dissolved in acetone (approximately 33 g) was slowly added dropwise over 60 minutes or more and stirred at the same temperature for 1 hour. Then, the temperature was raised to 50°C to 55°C and stirred for an additional hour. The temperature was cooled to 20°C to 25°C and stirred for an additional hour. The resulting solid was filtered and washed with acetone, and then vacuum dried at 40°C to prepare azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate salt.

[0218] Evaluation method

[0219] The specific evaluation method was performed in the same manner as in Experimental Examples 1 to 5 above, and the stability evaluation conditions are as follows:

[0220] - Temperature condition: 60℃ for 7 days

[0221] - Humidity conditions: 60℃ RH 80% 7 days

[0222] - UV conditions: 200 watt

[0223] - Vis condition: 1200k lux

[0224] The results of purity and stability measurements are shown in Table 5 below.

[0225]

[0226] [Table 5]

[0227]

[0228]

[0229] As a result, it was confirmed that the light, temperature, and humidity stability of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate or its crystalline form, prepared using the crystalline form, crystalline form A, and crystalline form B of the monohydrate of the compound of Formula I of the present invention, is equivalent to or better than that of the citrate or its crystalline form prepared with the conventional isopropanol solvate.

[0230]

[0231] In conclusion, it was confirmed that while the crystalline forms of the existing compound of Formula I, including the isopropanol solvate, methanol solvate, and ethanol solvate, change under high temperature or high humidity conditions, among the free base crystalline forms of the compound of Formula I of the present invention, the monohydrate crystalline form is the most stable under high humidity conditions, particularly high temperature and high humidity conditions, and crystalline forms A and B are the most stable under high temperature conditions, particularly high temperature and dry conditions. Therefore, it was confirmed that when synthesizing the citrate of the compound of Formula I of the present invention, depending on the temperature or humidity conditions by country, region, and season, converting the existing isopropanol solvate into the free base monohydrate crystalline form or free base crystalline forms A and B allows for longer storage in a more stable state, and enables the synthesis of the citrate compound of Formula I, which is the final active pharmaceutical ingredient, with higher purity.

[0232] This means that depending on temperature or humidity conditions, the most stable crystalline form of the compound of chemical formula I can be selected to produce acid addition salt compounds (raw materials) and finished pharmaceutical products with higher purity.

[0233]

[0234] Although the present invention has been described above with reference to preferred embodiments, those skilled in the art will understand that various modifications and changes can be made to the invention without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

1. Crystalline monohydrate form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I: [Chemical Formula I] .

2. The monohydrate crystalline form according to claim 1, characterized in that the crystalline form comprises three or more diffraction peaks selected from the group consisting of 2θ values ​​of the powder X-ray diffraction pattern of 24.607° (±0.2°), 16.978° (±0.2°), 12.254° (±0.2°), 9.773° (±0.2°), 8.739° (±0.2°), 11.113° (±0.2°), and 13.458° (±0.2°).

3. The monohydrate crystalline form according to claim 2, further comprising at least one diffraction peak selected from the group consisting of 2θ values ​​of the powder X-ray diffraction pattern of 22.989°(±0.2°), 22.365°(±0.2°), 17.785°(±0.2°), 25.528°(±0.2°), and 13.972°(±0.2°).

4. A monohydrate crystalline form according to claim 1, characterized by having a differential scanning calorimetry (DSC) endothermic peak at 196.21℃ (±0.5℃) when the heating rate is 10℃ / min.

5. The crystalline form of claim 1, characterized in that the crystalline form has excellent stability under high humidity conditions of 60% to 90% relative humidity.

6. The monohydrate crystalline form according to claim 1, characterized in that the crystalline form has excellent stability under high temperature conditions of 50°C to 100°C and high humidity conditions of 60% to 90% relative humidity.

7. The crystalline form of claim 1, characterized in that the crystalline form is an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone acid addition salt or an intermediate for use in preparing the crystalline form thereof.

8. Crystalline form A of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I: [Chemical Formula I] .

9. In claim 8, the crystalline form is characterized by comprising three or more diffraction peaks selected from the group consisting of 2θ values ​​of the powder X-ray diffraction pattern, 7.319°(±0.2°), 9.219°(±0.2°), 13.777°(±0.2°), 18.541°(±0.2°), 26.062°(±0.2°), 20.434°(±0.2°), 22.255°(±0.2°), 11.649°(±0.2°), and 14.693°(±0.2°).

10. The crystalline form A according to claim 9, further comprising at least one diffraction peak selected from the group consisting of 2θ values ​​of the powder X-ray diffraction pattern of 12.353°(±0.2°), 27.519°(±0.2°), 26.751°(±0.2°), 23.443°(±0.2°), 12.757°(±0.2°), and 15.507°(±0.2°).

11. Crystalline form A, characterized in that, in claim 8, it has a differential scanning calorimetry (DSC) endothermic peak at 195.95℃ (±0.5℃) when the heating rate is 10℃ / min.

12. In claim 8, the crystalline form A is characterized by having excellent stability under high temperature conditions of 50℃ to 100℃.

13. Crystalline form A according to claim 8, characterized in that the crystalline form is an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone acid addition salt or an intermediate for use in preparing the crystalline form thereof.

14. Crystalline form B of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I: [Chemical Formula I] .

15. In claim 14, the crystalline form is characterized by comprising three or more diffraction peaks selected from the group consisting of 2θ values ​​of the powder X-ray diffraction pattern of 10.539°(±0.2°), 13.727°(±0.2°), 7.071°(±0.2°), 25.776°(±0.2°), 15.022°(±0.2°), 22.273°(±0.2°), 28.266°(±0.2°), 20.515°(±0.2°), and 19.334°(±0.2°).

16. The crystalline form B according to claim 15, further comprising at least one diffraction peak selected from the group consisting of 2θ values ​​of the powder X-ray diffraction pattern of 21.146°(±0.2°), 24.931°(±0.2°), 24.123°(±0.2°), and 19.787°(±0.2°).

17. Crystalline form B according to claim 14, characterized by having a differential scanning calorimetry (DSC) endothermic peak at 196.59℃ (±0.5℃) when the heating rate is 10℃ / min.

18. Crystalline form B according to claim 14, wherein the crystalline form is characterized by having excellent stability under high temperature conditions of 50°C to 100°C.

19. Crystalline form B according to claim 14, wherein the crystalline form is azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone acid addition salt or an intermediate for use in preparing the crystalline form thereof.

20. A method for preparing an azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone acid addition salt or a crystalline form thereof, comprising using the crystalline form of any one of claims 1 to 19 as an intermediate.

21. A method according to claim 20, characterized in that the acid addition salt is a citrate.

22. A method for preparing crystalline form A comprising converting a methanol solvate, ethanol solvate, or isopropanol solvate crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone of the following chemical formula I into crystalline form A under high temperature conditions of 50°C to 100°C: [Chemical Formula I] .

23. A crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate or citrate prepared by the method of claim 20 or 21.

24. A pharmaceutical composition for the prevention or treatment of a disease 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 reflux disease (NERD), comprising as an active ingredient the crystalline form of claim 23 together with a pharmaceutically acceptable carrier.

25. Use of the crystalline form of paragraph 23 for the manufacture of a drug for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastroduodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD).

26. A method for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastroduodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), comprising administering a therapeutically effective amount of the crystalline form of claim 23 to a subject in need thereof.

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