Novel crystalline forms of tegoprazan sulfonate and pharmaceutical compositions containing the same

Abstract

This invention relates to a novel crystalline form of tegoprazan sulfonate and a method for producing the same, and more specifically, to a novel crystalline form of tegoprazan sulfonate and a method for producing the same, which exhibits significantly improved raw material stability, non-hygroscopicity and solubility, as well as pharmacological effects equivalent to or better than those of the conventional free base form of tegoprazan. The novel crystalline form of tegoprazan sulfonate according to the present invention has excellent raw material stability, non-hygroscopicity, and solubility, and can therefore be usefully used in the development of new formulations of tegoprazan.

Description

[Technical Field]

[0001] The present invention relates to a novel crystalline form of tegoprazan sulfonic acid salt and a pharmaceutical composition containing the same, as well as a method for producing the novel crystalline form of tegoprazan sulfonic acid salt and a pharmaceutical composition containing the same. More specifically, the present invention relates to a novel crystalline form of tegoprazan sulfonic acid salt that exhibits significantly improved raw material stability, non-hygroscopicity, and solubility, and that shows pharmacological effects equivalent to or better than those of the conventional tegoprazan free base form, a pharmaceutical composition containing the same, and a method for producing the same. [Background technology]

[0002] H in parietal cells present in the gastric mucosa + / K + - Through the action of the proton pump, which is an ATPase (proton pump), potassium ions (K + ) flows into the cell, protons (H + Gastric acid secretion occurs when protons (H) are secreted into the stomach. Subsequently, protons (H) secreted into the stomach + ) is a chloride ion (Cl - ) combines with other substances to form gastric acid, which can lead to gastrointestinal disorders.

[0003] Proton pump inhibitors (PPIs), after being administered orally as a prodrug, are converted to their active form through absorption and metabolic processes, and then irreversibly inhibit the proton pump. This has the disadvantage of a delayed onset of action.

[0004] Unlike proton pump inhibitors, tegoprazan, a type of benzimidazole derivative with the compound name [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide]) and the structure of chemical formula 1, competitively binds to potassium ions and releases hydrogen ions (H) into the stomach. + It suppresses gastric acid secretion by inhibiting the release of protons (see International Publication No. 2007 / 072146, etc.). For this reason, tegoprazan is called a potassium-competitive acid blocker (P-CAB) and is known to have a faster onset of action than PPI drugs.

[0005] [Chemical formula 1] JPEG2026533900000002.jpg54170

[0006] Tegoprazan, through this mechanism of action, has preventive and therapeutic effects on gastrointestinal diseases, such as gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcers, gastric and duodenal ulcers, ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, indigestion and functional indigestion, Zollinger-Ellison syndrome, non-erosive gastroesophageal reflux disease (NERD), visceral-referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, and asthma, which are caused by proton pump antagonistic activity.

[0007] Furthermore, K-CAB tablets (K-Cap tablets) or K-CAB orally disintegrating tablets (K-Cap orally disintegrating tablets), which contain tegoprazan as the active ingredient, are approved and marketed for use in the treatment of erosive reflux disease, non-erosive reflux disease, gastric ulcers, combination antibiotic therapy for Helicobacter pylori eradication in patients with peptic ulcers and / or chronic atrophic gastritis, and maintenance therapy after treatment of erosive reflux disease.

[0008] However, tegoprazan still has several issues that need to be addressed, including its low stability and the need to improve its solubility.

[0009] To address these challenges, studies have been conducted on the salt forms of tegoprazan, and pyroglutamate and malate salts are described as acid addition salts of tegoprazan in international publication patent 2018 / 056697, among others. While the pyroglutamate or malate salts of tegoprazan have relatively good water solubility and precipitation stability, they have the disadvantage of being difficult to formulate due to their amorphous form and resulting low stability.

[0010] Furthermore, International Publication No. 2007 / 072146 lists pharmaceutically acceptable salts of tegoprazan, including acetate, adipine, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, and malate. Examples of salts listed include maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinophoate, but for these salts, neither physicochemical properties nor manufacturing examples are described.

[0011] On the other hand, as a crystal form of tegoprazan, International Publication No. 2016 / 117814 describes the crystal form of tegoprazan free base and a method for producing it. While this crystal form of tegoprazan free base has advantages from a formulation standpoint, such as relatively low denaturation rate and electrostatic generation ability even under harsh light conditions, and the stability of the crystal form itself has been improved to some extent, it has the disadvantage of extremely low water solubility (0.02 mg / mL, pH 6.8) and low bioavailability.

[0012] As described above, the crystalline form of tegoprazan free base has relatively excellent stability and is relatively easy to formulate into preparations such as sustained-release formulations, but on the other hand, it has the disadvantage of low bioavailability due to low solubility, making formulation difficult. In contrast, amorphous acid addition salts and the like of tegoprazan have the advantage of relatively high solubility and excellent bioavailability, but on the other hand, due to low stability, they are inferior in storage stability, and have the disadvantage that it is difficult to control the drug release rate and blood concentration.

[0013] Accordingly, there remains a continuing demand for a form of tegoprazan that has excellent physicochemical properties, particularly excellent stability, and that exhibits excellent bioavailability due to its high solubility, that is, a demand for the raw material thereof.

[0014] Under such a technical background, the present inventors have conducted intensive studies to develop a tegoprazan raw material that is excellent in stability and non-hygroscopicity, and also has excellent solubility despite being in a crystalline form. As a result, the present inventors have found that the crystalline form of a sulfonate salt of tegoprazan has non-hygroscopicity, and is excellent in stability and solubility, thereby completing the present invention. [Prior Art Documents] [Patent Documents]

[0015] [Patent Document 1] International Publication No. 2007 / 072146 [Patent Document 2] International Publication No. 2016 / 117814 [Patent Document 3] International Publication No. 2018 / 056697 [Summary of the Invention] [Problem to be Solved by the Invention]

[0016] An object of the present invention is to provide a crystalline form of a sulfonate salt of tegoprazan, which is excellent in physical properties such as raw material stability, non-hygroscopicity and solubility, and a method for producing the same.

[0017] Furthermore, the present invention provides a pharmaceutical composition comprising the crystalline form of the sulfonate salt of tegoprazan described above, as well as a method of treating a patient in need of treatment using the crystalline form of the sulfonate salt of tegoprazan and the pharmaceutical composition comprising said crystalline form, and a method for producing a medicament for use therein. [MEANS FOR SOLVING THE PROBLEMS]

[0018] To solve the above problems, the present invention provides a crystalline form of the sulfonate salt of tegoprazan represented by Chemical Formula 2 and a production method thereof.

[0019] [Chemical Formula 2] JPEG2026533900000003.jpg54170

[0020] In the above Chemical Formula 2, n and m are each independently 1 or 2, and R may be, but is not limited to, hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl.

[0021] More preferably, the crystalline form of the sulfonate salt of tegoprazan according to the present invention may be, but is not limited to, the crystalline form of tegoprazan mesylate represented by Chemical Formula 3, the crystalline form of tegoprazan esylate represented by Chemical Formula 4, the crystalline form of tegoprazan hemiedisylate represented by Chemical Formula 5, or the crystalline form of tegoprazan besylate represented by Chemical Formula 6.

[0022] [Chemical Formula 3] JPEG2026533900000004.jpg49170

[0023] [Chemical Formula 4] JPEG2026533900000005.jpg50170

[0024] [Chemical Formula 5] JPEG2026533900000006.jpg50170

[0025] [Chemical formula 6] JPEG2026533900000007.jpg44170

[0026] In another embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of tegoprazan sulfonate, preferably a crystalline form of tegoprazan sulfonate having the structure of chemical formulas 3 to 6, and a method for producing the same. [Effects of the Invention]

[0027] The crystalline form of tegoprazan sulfonate according to the present invention is non-hygroscopic and highly stable, and also exhibits superior solubility compared to conventional crystalline forms of tegoprazan free base, thus providing the remarkable effect of being excellent in both bioavailability and stability.

[0028] Furthermore, the tegoprazan sulfonate and its crystalline form according to the present invention have the advantage of being reproducible and easy to mass-produce, from the viewpoint of the manufacturing method. [Brief explanation of the drawing]

[0029] [Figure 1] This figure shows the 1H-NMR result of the crystalline form of tegoprazan mesylate of chemical formula 3, prepared according to Example 1 of the present invention. [Figure 2] This figure shows the PXRD results for the crystalline form of tegoprazan mesylate of chemical formula 3, produced according to Example 1 of the present invention. [Figure 3] This figure shows the 1H-NMR result of the crystalline form of tegoprazan esylate of chemical formula 4, which was prepared according to Example 2 of the present invention. [Figure 4] This figure shows the PXRD results for the crystalline form of tegoprazan esylate of chemical formula 4, produced according to Example 2 of the present invention. [Figure 5] This figure shows the 1H-NMR result of the crystalline form of tegoprazanhemiedisylate of chemical formula 5, which was prepared according to Example 3 of the present invention. [Figure 6] This figure shows the PXRD results for the crystalline form of tegoprazanhemiedisylate of chemical formula 5, prepared according to Example 3 of the present invention. [Figure 7] This figure shows the 1H-NMR result of the crystalline form of tegoprazanbesylate of chemical formula 6, which was prepared according to Example 4 of the present invention. [Figure 8] This figure shows the PXRD results for the crystalline form of tegoprazan besylate of chemical formula 6, which was produced according to Example 4 of the present invention. [Figure 9] This figure shows the DSC measurement results of the crystalline form of tegoprazan mesylate of chemical formula 3, produced according to Example 1 of the present invention. [Figure 10] This figure shows the DSC measurement results of the crystalline form of tegoprazan esylate of chemical formula 4, which was produced according to Example 2 of the present invention. [Figure 11] This figure shows the DSC measurement results of the crystalline form of tegoprazanhemiedisylate of chemical formula 5, which was produced according to Example 3 of the present invention. [Figure 12] This figure shows the DSC measurement results of the crystalline form of tegoprazan besylate of chemical formula 6, which was produced according to Example 4 of the present invention. [Figure 13] This figure shows the DSC measurement results of amorphous tegoprazan mesylate of chemical formula 3, prepared according to Example 1 of the present invention. [Figure 14] This figure shows the DSC measurement results of amorphous tegoprazan ethylate of chemical formula 4, prepared according to Example 2 of the present invention. [Figure 15] This figure shows the DSC measurement results of amorphous tegoprazanhemiedisylate of chemical formula 5, prepared according to Example 3 of the present invention. [Figure 16] This figure shows the DSC measurement results of amorphous tegoprazanbesylate of chemical formula 6, prepared according to Example 4 of the present invention. [Modes for carrying out the invention]

[0030] Unless otherwise defined, all technical and scientific terms used herein have the meanings that are ordinarily understood by those skilled in the art. The nomenclature and experimental methods described below are known and commonly used in the art.

[0031] For the convenience of understanding the present invention, certain terms are defined herein. Unless otherwise defined herein, scientific and technical terms used herein have the meanings generally understood by those skilled in the art. The term "including" as used herein does not exclude other components, unless otherwise stated.

[0032] The crystalline form of tegoprazan sulfonate represented by chemical formula 2 according to the present invention has low hygroscopicity and excellent stability, and in terms of raw material storage, it has an effect equivalent to or better than conventional tegoprazan free base. Furthermore, it has the advantage of superior solubility compared to conventional tegoprazan free base and high bioavailability at the time of administration.

[0033] Therefore, the present invention relates to the crystalline form of the sulfonate of tegoprazan represented by chemical formula 2.

[0034] [Chemical formula 2] JPEG2026533900000008.jpg52170

[0035] In the above chemical formula 2, n and m are each independently 1 or 2, and R may be, but is not limited to, hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl.

[0036] More preferably, the crystalline form of the tegoprazan sulfonate represented by chemical formula 2 according to the present invention may be, but is not limited to, the crystalline form of tegoprazan mesylate represented by chemical formula 3, the crystalline form of tegoprazan esylate represented by chemical formula 4, the crystalline form of tegoprazan hemyedisylate represented by chemical formula 5, or the crystalline form of tegoprazan vesicate represented by chemical formula 6.

[0037] [Chemical formula 3] JPEG2026533900000009.jpg49170

[0038] [Chemical formula 4] JPEG2026533900000010.jpg49170

[0039] [Chemical formula 5] JPEG2026533900000011.jpg49170

[0040] [Chemical formula 6] JPEG2026533900000012.jpg43170

[0041] More preferably, the crystalline form of the tegoprazan mesylate of chemical formula 3 is characterized by having peaks in the X-ray powder diffraction pattern (PXRD) at 2θ diffraction angles of 8.8°, 9.7°, 14.5°, 15.9°, 17.5°, 19.3°, 20.6°, 21.4°, 23.4°, and 25.2° (2θ±0.2°), and preferably has the X-ray powder diffraction pattern shown in Figure 2.

[0042] The crystalline form of the tegoprazan esylate of chemical formula 4 is characterized by having peaks in the X-ray powder diffraction pattern (PXRD) at 2θ diffraction angles of 8.8°, 9.7°, 14.3°, 14.8°, 16.0°, 17.2°, 19.3°, 20.4°, 21.5°, 23.2°, 24.1°, and 25.2° (2θ±0.2°), and preferably has the X-ray powder diffraction pattern shown in Figure 4.

[0043] Furthermore, the crystalline form of tegoprazan hemiedisylate of chemical formula 5 is characterized by having peaks at 2θ diffraction angles of 4.1°, 8.4°, 12.5°, 15.4°, 16.7°, 17.7°, 19.9°, 23.0°, 23.4°, and 25.9° (2θ±0.2°) in the X-ray powder diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern shown in Figure 6.

[0044] The crystalline form of tegoprazan besylate of chemical formula 6 is characterized by having peaks in the X-ray powder diffraction pattern (PXRD) at 2θ diffraction angles of 9.2°, 10.0°, 11.2°, 12.7°, 16.4°, 17.7°, 18.3°, 21.0°, 22.8°, 24.2°, 24.5°, and 25.6° (2θ±0.2°), and preferably has the X-ray powder diffraction pattern shown in Figure 8.

[0045] Furthermore, the present invention relates to a pharmaceutical composition comprising a crystalline form of tegoprazan sulfonate represented by chemical formula 2, preferably a crystalline form of tegoprazan mesylate represented by chemical formula 3, a crystalline form of tegoprazan esylate represented by chemical formula 4, a crystalline form of tegoprazan hemyedisylate represented by chemical formula 5, or a crystalline form of tegoprazan besylate represented by chemical formula 6.

[0046] The pharmaceutical composition comprising a crystalline form of tegoprazan sulfonate represented by chemical formula 2, preferably represented by chemical formulas 3 to 6, according to the present invention may further contain one or more pharmaceutically acceptable excipients, one or more of which may be selected from the group consisting of fillers (diluents), disintegrants, binders, lubricants (smoothing agents), preservatives, antioxidants, buffers, chelating agents, solubilizers, and sweeteners.

[0047] As a non-limiting example, fillers (diluents) used in the pharmaceutical compositions according to the present invention include microcrystalline cellulose, D-mannitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, pregelatinized starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, and microcrystalline silicified cellulose. One or more substances selected from the group consisting of cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, sorbitol, starch, sucrose, talc, xylitol, maltose / maltodextrin, and maltitol may be used, but are not limited to these.

[0048] As a non-limiting example, the disintegrant included in the pharmaceutical composition according to the present invention may be one or more selected from the group consisting of croscarmellose sodium, crospovidone, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, crospovidone, docusate sodium, guar gum, hydroxypropylcellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, and pregelled starch, but is not limited to these.

[0049] As a non-limiting example, the binder used in the pharmaceutical formulation according to the present invention may be one or more selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin, liquid glucose, guar gum, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelled starch, and sucrose, but is not limited to these.

[0050] As a non-limiting example, the lubricant used in the pharmaceutical composition according to the present invention may be one or more selected from the group consisting of colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, glyceryl behenate, hydrogenated castor oil, stearic acid, glyceryl palmitostearate, glyceryl monostearate, calcium silicate, powdered cellulose, and starch, but is not limited to these.

[0051] Furthermore, the product may contain, but is not limited to, one or more additives selected from the group consisting of Pearlitol Flash, Maltitol, Sucralose, Enzyme-treated Stevia, and Peppermint Micron.

[0052] In another embodiment, the present invention provides a pharmaceutical preparation comprising a pharmaceutical composition according to the present invention. The pharmaceutical preparation may be a solid preparation such as a tablet, pill, powder, granule, or capsule, or a liquid preparation such as a suspension, liquid, emulsion, or syrup, and is preferably a solid preparation. Preferably, the pharmaceutical preparation may be in the form of pellets, granules, capsules, or tablets, and the tablet is more preferably a film-coated tablet or an orally disintegrating tablet containing a film coating layer.

[0053] The film coating layer can be formed using one or more coating bases selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide, and xanthan gum, whereby the film coating layer may comprise one or more film coating bases selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide, and xanthan gum, but is not limited thereto.

[0054] The polyvinyl alcohol and the copolymer of polyvinyl alcohol and polyethylene used as the film coating base may have a weight average molecular weight of about 2,500 to 1,000,000, preferably about 2,500 to 500,000, and the xanthan gum may have a weight average molecular weight of about 2,000,000, but are not limited thereto.

[0055] Illustratively, commercially available Opadry II TM or Opadry AMB TM (Colorcon, USA), Kollicoat IR TM (BASF, Germany) and other water-soluble film coating bases can be used, but are not limited thereto.

[0056] The content of the water-soluble film coating base may be 0.5 to 5% by weight, preferably 0.8 to 3% by weight, more preferably 1 to 2% by weight, relative to the total weight of the preparation, but is not limited thereto.

[0057] The pharmaceutical compositions and pharmaceutical preparations according to the present invention can be used to treat gastrointestinal diseases, such as gastroesophageal diseases, gastroesophageal reflux disease, peptic ulcers, gastric ulcers and duodenal ulcers, ulcers caused by nonsteroidal anti-inflammatory drugs, gastritis, Helicobacter pylori infection, indigestion and functional indigestion, Zollinger-Ellison syndrome, non-erosive gastroesophageal reflux disease, visceral-referred pain, heartburn, nausea, esophagitis, and dysphagia. Furthermore, they can also be used for the prevention and treatment of diseases caused by proton pump antagonistic activity, such as salivation, airway disorders, and asthma.

[0058] Preferably, it can be used for the treatment of erosive reflux disease, non-erosive reflux disease, gastric ulcers, antibiotic combination therapy for Helicobacter pylori eradication in patients with peptic ulcers and / or chronic atrophic gastritis, and maintenance therapy after treatment of erosive reflux disease.

[0059] Accordingly, the present invention relates to the use of a pharmaceutical composition or pharmaceutical preparation according to the present invention for the treatment of gastrointestinal diseases, and to a method for treating gastrointestinal diseases characterized by administering a pharmaceutical composition or pharmaceutical preparation according to the present invention to a patient in need of treatment.

[0060] Another embodiment of the present invention relates to a method for producing a crystalline form of the tegoprazan sulfonate of chemical formula 2, preferably chemical formulas 3 to 6, according to the present invention.

[0061] Specifically, the method for producing the crystalline form of tegoprazan sulfonate according to the present invention is: i) After adding the free base of tegoprazan of chemical formula 1 to an organic solvent, the suspension is stirred. ii) Adding a mixture of sulfonic acid and an organic solvent to the solution and stirring, iii) The procedure may include, but is not limited to, a step of cooling the solution and then stirring it to induce crystal precipitation.

[0062] In the method for producing the crystalline form of tegoprazan sulfonate according to the present invention, The organic solvent in steps i) and ii) above may be acetone, isopropanol, a mixed solution of acetone and isopropanol, or a mixed solution of acetone and methyl tert-butyl ether, but is not limited to these, with acetone or a mixed solution of acetone and isopropanol being more preferred.

[0063] More specifically, the method for producing the crystalline form of tegoprazan sulfonate according to the present invention may include the following steps. i) A step of preparing a solution by adding tegoprazan free base of chemical formula 1 to an organic solvent and then suspending and stirring it at 0-5°C or room temperature. ii) Adding a mixture of sulfonic acid and an organic solvent to the solution, dissolving it, and stirring, iii) A step of cooling the solution to a temperature of 0 to 5°C to precipitate crystals. The procedure may further include, selectively, a step of generating a secondary crystal using the seed crystal obtained in step iii).

[0064] In this invention, "room temperature" means a temperature range of 15 to 30°C, preferably 17 to 27°C, and more preferably 20 to 25°C.

[0065] In the manufacturing method of the present invention, the tegoprazan free base used may be directly produced by the method disclosed in International Publication No. 2016 / 117814, etc., or it may be purchased. Furthermore, in the manufacturing method of the present invention, it is preferable to use 10 to 30 mL of organic solvent per 1 g of tegoprazan.

[0066] In the manufacturing method of the present invention, the stirring in steps i), ii), and iii) may be carried out at a temperature of 0 to 5°C or at room temperature, but is not limited thereto.

[0067] The present invention will be described in more detail below through examples. These examples are for illustrative purposes only and it will be obvious to those ordinary skill in the art to which the present invention pertains that the scope of the present invention is not limited by these examples. [Examples]

[0068] In the following examples, 1 1H NMR measurements are performed using a Bruker UltraShield. TM A 400MHz (400Hz) frequency was used for the analysis. HPLC analysis was performed using an Agilent 1200 series, melting point measurement was performed using an SRS OptiMelt MPA100, and PXRD measurement was performed using a Bruker AXS D8 Advance X-ray diffractometer.

[0069] Example 1: Preparation of crystalline form of tegoprazan mesylate

[0070] 70 mL of acetone was added to the reaction vessel, and 10.0 g of tegoprazan free base was added, followed by stirring at 0-5°C. A mixed solution of 2.43 g of methanesulfonic acid and 30 mL of acetone was slowly added to the suspension while maintaining the temperature below 10°C. The reaction vessel was stirred at 0-5°C, and precipitation of a solid was confirmed after 30 minutes. 2 mL of methanol was added to the suspension, and the mixture was stirred at room temperature for 2 hours. The suspension was filtered under nitrogen gas, and the filtered solid was washed with 50 mL of acetone. The solid was vacuum-dried at 30°C for 2 hours to obtain 11.6 g of white crystalline form of tegoprazan mesylate of chemical formula 3.

[0071] ( 1H NMR(400MHz,DMSO-d6)δ14.76(brs,1H), 7.51-7.34(m,2H), 6.88(td,J=9.7,2.5Hz,1H), 6.75(dd,J=10.4,1.7Hz,1H), 6.07(s,1H), 4.41(d,J= 11.2Hz,1H), 4.31-4.19(m,1H), 2.99(d,J=37.8Hz,6H), 2.71(s,3H), 2.32(s,3H), 2.26(dd,J=15.3,2.2Hz,1H), 2.15(tt,J=15.8,3.8Hz,1H)).

[0072] The crystalline form of the manufactured tegoprazan mesylate is shown in Figure 1. 1 It is characterized by having H-NMR properties and an X-ray powder diffraction pattern (PXRD) with peaks at 2θ diffraction angles of 8.8°, 9.7°, 14.5°, 15.9°, 17.5°, 19.3°, 20.6°, 21.4°, 23.4°, and 25.2° (2θ±0.2°), preferably having the X-ray powder diffraction pattern shown in Figure 2.

[0073] Example 2: Preparation of crystalline form of tegoprazan ethylate

[0074] 70 mL of acetone was added to the reaction vessel, and 10.0 g of tegoprazan free base was added, followed by stirring at 0-5°C. A mixed solution of 3.98 g of 70 wt% ethanesulfonic acid and 30 mL of acetone was slowly added to the suspension while maintaining the temperature below 10°C. The reaction vessel was stirred at 0-5°C, and 2 mL of methanol was added. The reaction vessel was stirred again at room temperature for 2 hours. The suspension was filtered under nitrogen gas, and the filtered solid was washed with 50 mL of acetone. The solid was vacuum-dried at 30°C for 2 hours to obtain 12.4 g of white crystalline form of tegoprazan ethylate of chemical formula 4.

[0075] ( 1H NMR(400MHz,DMSO-d6)δ14.74(brs,1H), 7.54-7.28(m,2H), 6.88(td,J=9.6, 2.5Hz,1H), 6.75(dd,J=10.4,1.7Hz,1H), 6.07(s,1H), 4.41(d,J=11.0Hz,1H ), 4.32-4.13(m,1H), 2.99(d,J=37.4Hz,6H), 2.71(s,3H), 2.39(q,J=7.4Hz, 2H), 2.25(dd,J=15.3,2.1Hz,1H), 2.21-2.10(m,1H), 1.05(t,J=7.4Hz,3H)).

[0076] The crystalline form of the manufactured tegoprazan ethylate is shown in Figure 3. 1 It has H-NMR properties and is characterized by having peaks in the X-ray powder diffraction pattern (PXRD) at 2θ diffraction angles of 8.8°, 9.7°, 14.3°, 14.8°, 16.0°, 17.2°, 19.3°, 20.4°, 21.5°, 23.2°, 24.1°, and 25.2° (2θ±0.2°), preferably having the X-ray powder diffraction pattern shown in Figure 4.

[0077] Example 3: Preparation of the crystalline form of tegoprazanhemiedisylate

[0078] 50 mL of acetone and 50 mL of isopropanol were added to the reaction vessel, and 10.0 g of free base of tegoprazan was added, followed by stirring at room temperature. A mixed solution of 2.89 g of 1,2-ethanedisulfonic acid dihydrate and 30 mL of acetone was slowly added to the reaction vessel. An additional 20 mL of acetone was added to the reaction vessel and stirred for 30 minutes to dissolve. 500 mg of crystalline tegoprazan hemiedisylate was added to the solution. The reaction mixture was stirred at 0-5°C for 1 hour, and then stirred at room temperature overnight to precipitate the solid. An additional 100 mL of acetone was slowly added to the reaction vessel to dilute the solution, and the mixture was stirred at 0-5°C for 1 hour. The suspension was filtered under nitrogen gas, and the filtered solid was washed with 50 mL of cooled acetone. The solid was vacuum-dried overnight at room temperature to obtain 10.7 g of white crystalline tegoprazan hemiedisylate.

[0079] ( 1 H NMR(400MHz,DMSO-d6)δ14.74(brs,1H), 7.42(d,J=14.4Hz,2H), 6.88(td,J=9.6,2.4Hz,1H), 6.75(d,J=10.4Hz,1H), 6.07(s,1H), 4.4 1(d,J=11.1Hz,1H), 4.24(t,J=11.2Hz,1H), 2.99(d,J=36.7Hz,6H), 2.71(s,3H), 2.66(s,2H), 2.31-2.21(m,1H), 2.21-2.09(m,1H)).

[0080] The crystalline form of the manufactured tegoprazan hemiedisylate is shown in Figure 5. 1 It is characterized by having H-NMR properties and, in the X-ray powder diffraction pattern (PXRD), having peaks at 2θ diffraction angles of 4.1°, 8.4°, 12.5°, 15.4°, 16.7°, 17.7°, 19.9°, 23.0°, 23.4°, and 25.9° (2θ±0.2°), preferably having the X-ray powder diffraction pattern shown in Figure 6.

[0081] Example 4: Preparation of the crystalline form of tegoprazanbesylate

[0082] 30 mL of acetone was added to the reaction vessel, followed by the addition of 10.0 g of free tegoprazan base, and the mixture was stirred at 0-5°C. A mixed solution of 4.00 g of benzenesulfonic acid and 20 mL of acetone was slowly added to the reaction vessel. The reaction mixture was stirred at 0-5°C for 1 hour to precipitate a solid. An additional 150 mL of methyl tert-butyl ether was slowly added to the reaction vessel, and the mixture was stirred at 0-5°C for 1 hour. The suspension was filtered under nitrogen gas, and the filtered solid was washed with 50 mL of cooled methyl tert-butyl ether. The solid was vacuum-dried overnight at room temperature to obtain 13.6 g of white crystalline tegoprazan besylate.

[0083] ( 1H NMR(400MHz,DMSO-d6)δ14.75(brs,1H), 7.64-7.55(m,2H), 7.44(s,1H), 7.39 (s,1H), 7.36-7.22(m,3H), 6.88(td,J=9.7,2.4Hz,1H), 6.75(d,J=10.4Hz,1H ), 6.07(s,1H), 4.41(d,J=11.1Hz,1H), 4.22(dd,J=17.6,6.6Hz,1H), 2.99(d, J=39.0Hz,6H), 2.71(s,3H), 2.25(dd,J=15.3,2.0Hz,1H), 2.21-2.10(m,1H)).

[0084] The crystalline form of the manufactured tegoprazan besylate is shown in Figure 7. 1 It is characterized by having H-NMR properties and, in its X-ray powder diffraction pattern (PXRD), having peaks at 2θ diffraction angles of 9.2°, 10.0°, 11.2°, 12.7°, 16.4°, 17.7°, 18.3°, 21.0°, 22.8°, 24.2°, 24.5°, and 25.6° (2θ±0.2°), preferably having the X-ray powder diffraction pattern shown in Figure 8.

[0085] Comparative Example 1: Production of amorphous tegoprazan mesylate

[0086] 20 mL of methanol was added to a reaction vessel, and 2.0 g of free tegoprazan base was added and dissolved. A mixed solution of 486 mg of methanesulfonic acid and 5 mL of MeOH was added to the solution. The solution was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure at 40°C. The concentrate was vacuum-dried for 30 minutes to obtain a white dry product, and then 30 mL of heptane was added and the slurry was stirred for 1 hour. The solid was filtered under nitrogen gas, and the filtered solid was washed with 10 mL of heptane. The solid was vacuum-dried overnight to obtain 2.0 g of white amorphous tegoprazan mesylate.

[0087] ( 1H NMR(400MHz,DMSO-d6)δ14.76(brs,1H), 7.51-7.34(m,2H), 6.88(td,J=9.7,2.5Hz,1H), 6.75(dd,J=10.4,1.7Hz,1H), 6.07(s,1H), 4.41(d,J= 11.2Hz,1H), 4.31-4.19(m,1H), 2.99(d,J=37.8Hz,6H), 2.71(s,3H), 2.32(s,3H), 2.26(dd,J=15.3,2.2Hz,1H), 2.15(tt,J=15.8,3.8Hz,1H)).

[0088] Comparative Example 2: Production of amorphous tegoprazan ethylate

[0089] 20 mL of methanol was added to a reaction vessel, and 1.23 g of crystalline tegoprazan ethylate was added and dissolved. The mixture was then concentrated under reduced pressure at 40°C. The concentrate was vacuum-dried for 1 hour, and 20 mL of heptane was added, and the slurry was stirred at room temperature for 1 hour. The suspension was filtered under nitrogen gas, and the filtered solid was washed with 20 mL of heptane. The solid was vacuum-dried overnight to obtain 1.0 g of white amorphous tegoprazan ethylate.

[0090] ( 1 H NMR(400MHz,DMSO-d6)δ14.74(brs,1H), 7.54-7.28(m,2H), 6.88(td,J=9.6, 2.5Hz,1H), 6.75(dd,J=10.4,1.7Hz,1H), 6.07(s,1H), 4.41(d,J=11.0Hz,1H ), 4.32-4.13(m,1H), 2.99(d,J=37.4Hz,6H), 2.71(s,3H), 2.39(q,J=7.4Hz, 2H), 2.25(dd,J=15.3,2.1Hz,1H), 2.21-2.10(m,1H), 1.05(t,J=7.4Hz,3H)).

[0091] Comparative Example 3: Production of amorphous tegoprazanhemiedisylate

[0092] 20 mL of methanol was added to a reaction vessel, and 1.20 g of crystalline tegoprazan hemiedisylate was added and dissolved. The mixture was then concentrated under reduced pressure at 40°C. The concentrate was vacuum-dried for 1 hour, and 20 mL of heptane was added, and the slurry was stirred at room temperature for 1 hour. The suspension was filtered under nitrogen gas, and the filtered solid was washed with 20 mL of heptane. The solid was vacuum-dried for 2 days to obtain 1.0 g of white amorphous tegoprazan hemiedisylate.

[0093] ( 1 H NMR(400MHz,DMSO-d6)δ14.74(brs,1H), 7.42(d,J=14.4Hz,2H), 6.88(td,J=9.6,2.4Hz,1H), 6.75(d,J=10.4Hz,1H), 6.07(s,1H), 4.4 1(d,J=11.1Hz,1H), 4.24(t,J=11.2Hz,1H), 2.99(d,J=36.7Hz,6H), 2.71(s,3H), 2.66(s,2H), 2.31-2.21(m,1H), 2.21-2.09(m,1H)).

[0094] Comparative Example 4: Production of amorphous tegoprazan besylate

[0095] 20 mL of methanol was added to a reaction vessel, and 1.20 g of crystalline tegoprazan besilate was added and dissolved. The mixture was then concentrated under reduced pressure at 40°C. The concentrate was vacuum-dried for 2 hours, and 20 mL of heptane was added, followed by slurry stirring at room temperature for 1 hour. The suspension was filtered under nitrogen gas, and the filtered solid was washed with 20 mL of heptane. The solid was vacuum-dried overnight to obtain 750 mg of white amorphous tegoprazan besilate.

[0096] ( 1H NMR(400MHz,DMSO-d6)δ14.75(brs,1H), 7.64-7.55(m,2H), 7.44(s,1H), 7.39 (s,1H), 7.36-7.22(m,3H), 6.88(td,J=9.7,2.4Hz,1H), 6.75(d,J=10.4Hz,1H ), 6.07(s,1H), 4.41(d,J=11.1Hz,1H), 4.22(dd,J=17.6,6.6Hz,1H), 2.99(d, J=39.0Hz,6H), 2.71(s,3H), 2.25(dd,J=15.3,2.0Hz,1H), 2.21-2.10(m,1H)).

[0097] Comparative Example 5: Production of Tegoprazanpyroglutamate

[0098] At 25°C, 3 g of free tegoprazan base and L-pyroglutamic acid (1.049 g, 1.05 eq.) were completely dissolved in 30 mL of methanol. The solution was then concentrated under reduced pressure and stirred at 50°C until a solid precipitated. A foamy solid precipitated, and a co-solvent of acetone / ethyl acetate = 1 / 4 (15 mL) was added to the concentrate at 25°C, followed by vigorous stirring for 30 minutes. As a result, the foamy solid agglomerated, and the solid could not be recovered.

[0099] Comparative Example 6: Production of Tegoprazan Malate

[0100] At 25°C, 3 g of free tegoprazan base and L-malic acid (1.090 g, 1.05 eq.) were completely dissolved in 30 mL of methanol. The solution was then concentrated under reduced pressure and stirred at 50°C until a solid precipitated. A foamy solid precipitated, and a cosolvent of acetone / ethyl acetate = 1 / 4 (15 mL) was added to the concentrate at 25°C, followed by vigorous stirring for 30 minutes. As a result, the foamy solid agglomerated, and the solid could not be recovered. <Example of experiment>

[0101] Experimental Example 1: Evaluation of Stability

[0102] The stability of the crystalline form of tegoprazan sulfonate produced in Examples 1-4 and the amorphous form of tegoprazan sulfonate produced in Comparative Examples 1-4 were compared.

[0103] Specifically, stability experiments were conducted under long-term, accelerated, and harsh conditions depending on the degree of generation of related substances. The results were then analyzed using high-performance liquid chromatography (HPLC) and are shown in Table 1.

[0104] As shown in Table 1, in the case of amorphous tegoprazan sulfonate, stability tests over 6 months showed a purity decrease of 0.12-16.1% under long-term conditions, 0.52-4.78% under accelerated conditions, and 2.09-45.87% under harsh conditions. In contrast, the crystalline forms of tegoprazan sulfonate according to the present invention all showed a purity change of 0.06% or less in stability tests over 12 months under the aforementioned storage conditions. This confirms that the crystalline form of tegoprazan sulfonate according to the present invention has extremely excellent stability.

[0105] Experimental Example 2: Evaluation of non-hygroscopic properties

[0106] Non-hygroscopicity is a crucial factor for the processing and preservation of pharmaceuticals. To confirm whether the compounds are suitable for use as pharmaceutical raw materials, hygroscopicity experiments were conducted on the crystalline forms of tegoprazan mesylate, tegoprazan esylate, tegoprazan hemiedisylate, and tegoprazan besylate produced in Examples 1-4.

[0107] Each dried sample was placed in chambers with relative humidity levels of 31%, 43%, 54%, 73%, and 86%, and the mass change rate of the samples after one and two weeks was measured by weighing. As a control group, the crystalline form of the free base of tegoprazan described in International Publication No. 2016-117814 was used.

[0108] JPEG2026533900000013.jpg134170

[0109] JPEG2026533900000014.jpg253170

[0110] As shown in Table 2, the crystalline forms of tegoprazan sulfonates according to the present invention, such as the crystalline form of tegoprazan mesylate, the crystalline form of tegoprazan esylate, the crystalline form of tegoprazan hemyedisylate, and the crystalline form of tegoprazan besylate, were all confirmed to exhibit low hygroscopicity with a mass change rate of 1.0% or less in a wide range of relative humidity levels.

[0111] Therefore, it has been confirmed that the crystalline form of tegoprazan sulfonate according to the present invention is highly advantageous in the processing and storage of pharmaceuticals due to its low hygroscopicity.

[0112] Experimental Example 3: Measurement of Melting Point

[0113] In order to evaluate whether or not there was an improvement in the physicochemical properties of the tetraprazan sulfonate crystalline form according to the present invention, the melting points of the conventional tetraprazan free base (chemical formula 1) and the tetraprazan sulfonate crystalline forms of chemical formulas 3 to 6 according to Examples 1 to 4 were measured using a melting point measuring device.

[0114] The measurement device used was the SRS OptiMelt MPA100. The sample was filled into a transparent capillary, and measurements were taken while increasing the temperature at a rate of 5°C per minute within a temperature range of 30°C to 300°C.

[0115] JPEG2026533900000015.jpg102170

[0116] As shown in Table 3, the crystalline form of tegoprazan sulfonate according to the present invention has a lower melting point than the crystalline form of the free base of tegoprazan, and does not change in properties even under general raw material storage conditions, making it easy to store the raw material.

[0117] Experimental Example 4: Confirmation of the properties of crystalline polymorphism (PXRD)

[0118] The X-ray powder diffraction pattern of the crystalline acid addition salt of tegoprazan according to the present invention was measured using a Bruker AXS D8 Advance X-ray diffractometer and Evaluation software system interface at a 2θ scan rate of 0.020° per minute. A standard line-focus copper X-ray tube (Siemens) equipped with a one-dimensional semiconductor X-ray detector using a silicon strip was used, and the X-ray generator operating at 40kV and 40mA was irradiated to scan in the range of 3 to 40° (2θ). The weighted average value of the X-ray wavelengths used in the calculation was Cu-Kα 1.541838A.

[0119] The measurement results showed that the crystalline forms of tegoprazan mesylate (Figure 2), tegoprazan esylate (Figure 4), tegoprazan hemyedisylate (Figure 6), and tegoprazan besylate (Figure 8) all exhibited characteristic X-ray powder diffraction patterns different from those of the conventional free base of tegoprazan, confirming that they possess completely different crystalline forms.

[0120] Experimental Example 5: Measurement of Differential Scanning Calorimetry (DSC)

[0121] The crystalline forms of the tegoprazan sulfonates produced in Examples 1-4 according to the present invention were compared with the amorphous tegoprazan sulfonates produced in Comparative Examples 1-4 using differential scanning calorimetry to confirm their physical properties. The calorimetry of the samples was performed using a differential scanning calorimeter (Hitachi Nexta DSC 600) at a heating rate of 10°C per minute. The amount of sample used was 3-5 mg.

[0122] Confirmation revealed that the amorphous sulfonates produced in Comparative Examples 1-4 did not exhibit specific endothermic peaks (see Figures 13-16), whereas the crystalline sulfonates produced in Examples 1-4 each showed their own unique endothermic peaks (see Figures 9-12).

[0123] Experimental Example 6: Confirmation of Solubility

[0124] To evaluate the solubility of the crystalline form of tegoprazan sulfonate represented by chemical formula 2 according to the present invention, the solubility of the crystalline form of the conventional free base of tegoprazan (chemical formula 1) and the crystalline forms of tegoprazan sulfonates of chemical formulas 3 to 6 prepared in Examples 1 to 4 were measured. 400 mg to 500 mg of each sample was added to purified water and solutions at pH 1.2, pH 4.0, and pH 6.8, and shaken for 24 hours at 37°C and 200 rpm. After 24 hours, each sample was filtered through a 0.45 μm filter, diluted with a 5 / 5 acetonitrile and water mixture, and then analyzed and quantified by high-performance liquid chromatography.

[0125] JPEG2026533900000016.jpg93170

[0126] As shown in Table 4, the crystalline form of tegoprazan sulfonate according to the present invention was confirmed to have high solubility in purified water and in all experimental ranges of pH 1.2, pH 4.0, and pH 6.8, and was found to have significantly superior solubility compared to the crystalline form of free tegoprazan base, which was the control group.

[0127] This demonstrates that the crystalline form of tegoprazan sulfonate according to the present invention significantly improves the physicochemical properties of tegoprazan, acting very favorably in drug absorption and dissolution, and ultimately proving highly advantageous in the commercialization of the drug.

[0128] Although specific parts of the present invention have been described in detail above, it will be clear to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention.

[0129] Therefore, the substantial scope of the present invention should be defined by the claims and their equivalents.

Claims

1. The crystalline form of tegoprazan sulfonate having the structure represented by chemical formula 2. [Chemical formula 2] In the above chemical formula 2, n and m are each independently 1 or 2, and R is hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl.

2. The crystalline form according to claim 1, wherein the tegoprazan sulfonate is tegoprazan mesylate represented by chemical formula 3. [Chemical formula 3]

3. The crystal form according to claim 2, characterized in that the X-ray powder diffraction pattern (PXRD) has peaks at 2θ diffraction angles of 8.8°, 9.7°, 14.5°, 15.9°, 17.5°, 19.3°, 20.6°, 21.4°, 23.4°, and 25.2° (2θ ± 0.2°).

4. The crystalline form according to claim 1, wherein the tegoprazan sulfonate is tegoprazan ethylate represented by chemical formula 4. [Chemical formula 4]

5. The crystal form according to claim 4, characterized in that the X-ray powder diffraction pattern (PXRD) has peaks at 2θ diffraction angles of 8.8°, 9.7°, 14.3°, 14.8°, 16.0°, 17.2°, 19.3°, 20.4°, 21.5°, 23.2°, 24.1°, and 25.2° (2θ ± 0.2°).

6. The crystalline form according to claim 1, wherein the tegoprazan sulfonate is tegoprazan hemyedisylate represented by chemical formula 5. [Chemical formula 5]

7. The crystal form according to claim 6, characterized in that the X-ray powder diffraction pattern (PXRD) has peaks at 2θ diffraction angles of 4.1°, 8.4°, 12.5°, 15.4°, 16.7°, 17.7°, 19.9°, 23.0°, 23.4°, and 25.9° (2θ ± 0.2°).

8. The crystalline form according to claim 1, wherein the tegoprazan sulfonate is tegoprazan besylate represented by chemical formula 6. [Chemical formula 6]

9. The crystal form according to claim 8, characterized in that the X-ray powder diffraction pattern (PXRD) has peaks at 2θ diffraction angles of 9.2°, 10.0°, 11.2°, 12.7°, 16.4°, 17.7°, 18.3°, 21.0°, 22.8°, 24.2°, 24.5°, and 25.6° (2θ ± 0.2°).

10. A pharmaceutical composition for the treatment of gastrointestinal diseases comprising the crystalline form of tegoprazan sulfonate according to any one of claims 1 to 9.

11. The pharmaceutically active composition according to claim 10, characterized in that the gastrointestinal disease is gastroesophageal disease, gastroesophageal reflux disease, peptic ulcer, gastric ulcer and duodenal ulcer, ulcer caused by nonsteroidal anti-inflammatory drugs, gastritis, Helicobacter pylori infection, indigestion and functional indigestion, Zollinger-Ellison syndrome, non-erosive gastroesophageal reflux disease, visceral-referred pain, heartburn, nausea, esophagitis, or dysphagia.

12. The pharmaceutical composition according to claim 10, further characterized by containing one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 12, characterized in that the excipient is one or more selected from the group consisting of fillers, disintegrants, binders, lubricants, preservatives, antioxidants, buffers, chelating agents, solubilizers, and sweeteners.

14. A pharmaceutical preparation comprising the pharmaceutical composition described in claim 10.

15. The pharmaceutical preparation according to claim 14, characterized in that it is a capsule, pellet or tablet.

16. The pharmaceutical preparation according to claim 15, characterized in that it is a film-coated tablet or orally disintegrating tablet containing a film coating layer.

17. A method for producing the crystalline form of tegoprazan sulfonate, represented by chemical formula 2, including the following steps: i) A step of preparing a solution by adding the free base of tegoprazan of chemical formula 1 to an organic solvent and then suspending and stirring it at 0-5°C or room temperature. ii) Adding a mixture of sulfonic acid and an organic solvent to the solution, dissolving it, and stirring, iii) A step of cooling the solution to a temperature of 0 to 5°C to precipitate crystals. [Chemical formula 1] [Chemical formula 2] In the above chemical formula 2, n and m are each independently 1 or 2, and R is hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl.

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