Salts of benzimidazole derivatives

Abstract

The present invention provides hydrochloride salts or hydrochloride hydrates of compounds of chemical formula 1, and pharmaceutical compositions containing the same.

Description

[Technical Field]

[0001] This invention relates to a novel acid addition salt of a benzimidazole derivative, and more specifically, to a novel acid addition salt of a benzimidazole derivative that has high stability, sufficient water solubility, and high bioavailability regardless of the presence or absence of food. [Background technology]

[0002] Acid pump inhibitors (H+ / K+ ATPase inhibitors) suppress acid secretion in the gastrointestinal tract through reversible potassium-competitive inhibition of H+ / K+ ATPase and are known to be effective in treating gastrointestinal diseases. To distinguish them from proton pump inhibitors, these acid pump inhibitors are also called potassium-competitive acid blockers (PCABs). Among the substances that are effective as such acid pump inhibitors, benzimidazole derivative compounds substituted with chromane are being studied (WO2007 / 072146). Among them, 4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide[(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide], represented by chemical formula 1, is a pharmaceutically active ingredient with a molecular weight of 387.39 and is also widely known by its generic name, tegoprazan.

[0003] [ka]

[0004] The compound has preventive and therapeutic effects on diseases mediated by acid pump inhibitory activity. These acid pump inhibitory-mediated gastrointestinal diseases include, but are not limited to, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcers, gastric ulcers and duodenal ulcers, NSAID-induced ulcers, gastritis, Helicobacter pylori infection, indigestion, functional indigestion, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral-referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, and asthma (WO2007 / 072146).

[0005] Crystalline form A of the free base of the compound of chemical formula 1 is disclosed in international patent publication WO2016 / 117814. According to this publication, crystalline form A has excellent photostability, low hygroscopicity and electrostatic induction, and is advantageous for formulation. Crystalline form A of the free base of the compound of chemical formula 1 is currently marketed with the approval of the Korea Food and Drug Administration (MFDS) in the form of oral tablets (product name: K-CAB Tablets (registered trademark)) and orally disintegrating tablets (product name: K-CAB Intraoral Disintegrating Tablets (registered trademark)).

[0006] International Patent Publication WO2018 / 056697 discloses pyrodrate and malate salts of the compound of chemical formula 1, which have superior water solubility and stability compared to the amorphous form of the free base of the compound of chemical formula 1, and are therefore advantageously usable as raw materials for oral and injectable formulations.

[0007] A large number of salts can be applied to a single compound, and polymorphs may exist. Depending on the type of salt and polymorph, the solubility, stability, and other properties when formulated as a pharmaceutical may differ. These physicochemical properties are important factors in determining the quality of a pharmaceutical product. Therefore, even if a conventional compound or a specific salt or crystal form is known, much research and effort is required to develop salts and crystal forms with superior physicochemical properties. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2007 / 072146 [Patent Document 2] International Publication No. 2016 / 117814 [Patent Document 3] International Publication No. 2018 / 056697 [Overview of the project] [Problems that the invention aims to solve]

[0009] One aspect of the present invention aims to solve is to provide an acid addition salt of a compound of chemical formula 1 that has excellent pharmaceutical properties such as water solubility and stability.

[0010] Another aspect of the present invention aims to solve is to provide a crystalline form of an acid addition salt of a compound of chemical formula 1 that has excellent pharmaceutical properties such as water solubility and stability.

[0011] Another aspect that the present invention aims to solve is to provide a pharmaceutical composition containing an acid addition salt or a crystalline form of the acid addition salt of the compound of chemical formula 1 as an active ingredient.

[0012] Other purposes and advantages of this application will be further clarified by the following detailed description, along with the attached claims. Matters not described herein are readily apparent and can be inferred by any person of ordinary skill in the art of this application or a similar art, and therefore no such description is provided. [Means for solving the problem]

[0013] One aspect of the present invention provides a salt which is a hydrochloride salt or hydrochloride hydrate of the compound of the following chemical formula 1.

[0014] [ka]

[0015] Another aspect of the present invention provides a pharmaceutical composition comprising a hydrochloride or a hydrochloride hydrate of a compound of Chemical Formula 1 and a pharmaceutically acceptable carrier.

[0016] Yet another aspect of the present invention provides a hydrochloride or a hydrochloride hydrate of a compound of Chemical Formula 1 for use in the prevention or treatment of diseases mediated by acid pump inhibitory activity. [Effect of the Invention]

[0017] The hydrochloride or the hydrochloride hydrate of the compound of Chemical Formula 1 according to one aspect of the present invention has been confirmed to have a solubility more than 10 times higher than that of the conventionally commercially available free base crystal form A, and is expected to ensure sufficient bioavailability upon administration to a living body. In fact, a formulation formulated in the same manner as a conventionally commercially available formulation was found to have a bioavailability equal to or higher than that of the conventionally commercially available formulation. Further, the hydrochloride or the hydrochloride hydrate has generally remarkably excellent liquid stability, solid stability, and photo stability as compared with other types of acid addition salts including known acid addition salts. In particular, the hydrochloride hydrate exhibits the most excellent stability in all aspects, and exhibits remarkably excellent stability as compared with other acid addition salts even when combined with pharmaceutically acceptable additives.

[0018] Furthermore, when orally disintegrating tablets of hydrochloride hydrate, prepared in the same manner as commercially available orally disintegrating tablets, were evaluated against a commercially available formulation (Keikabu® Oral Disintegrating Tablets), the test drug showed significantly faster disintegration characteristics. This suggests that when hydrochloride hydrate is prepared as an orally disintegrating tablet, it offers improved ease of administration and is expected to have an even faster effect. In addition, when dissolution tests were conducted comparing hydrochloride hydrate tablets, prepared in the same manner as the commercially available formulation, with commercially available tablets (Keikabu® Tablets), both showed similarly high immediate release rates of over 85% within 15 minutes under pH 1.2 conditions, which correspond to an empty stomach state. However, under pH 4.0, pH 6.8, and FaSSIF solution conditions, the dissolution of the control drug was significantly delayed, while the hydrochloride hydrate formulation (test drug) still showed high dissolution rates of over 85% within 15 minutes. Therefore, when preparing tablets using hydrochloride hydrate, it is expected that immediate release can be maintained regardless of changes in gastrointestinal pH due to meals or delays in gastrointestinal emptying time, and a stable and high bioavailability can be ensured regardless of the timing of administration, thereby improving the convenience of taking the medication. [Brief explanation of the drawing]

[0019] [Figure 1] This figure shows the results of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) for the free base crystal form A (WO2016 / 117814) of the conventional compound of chemical formula 1.

[0020] [Figure 2] This figure shows the PXRD and DSC results for crystalline form A of the hydrochloride hydrate of the compound of chemical formula 1.

[0021] [Figure 3] This figure shows the PXRD and DSC results for the hydrochloride salt (amorphous) of the compound of chemical formula 1.

[0022] [Figure 4] This figure shows the PXRD and DSC results for the hydrobromide salt of the compound of chemical formula 1.

[0023] [Figure 5]This figure shows the PXRD and DSC results for the maleate salt of the compound of chemical formula 1.

[0024] [Figure 6] This figure shows the PXRD and DSC results for the pyrodolate salt of the compound of chemical formula 1.

[0025] [Figure 7] This figure shows the PXRD results (Figure 7A), DSC results (Figure 7B), and PXRD results (Figure 7C) before (top) and after (bottom) 1 month of storage under severe stability (RH90%) conditions for the sulfate of the compound of chemical formula 1.

[0026] [Figure 8] This figure shows the PXRD and DSC results for the phosphate of the compound of chemical formula 1.

[0027] [Figure 9] This figure shows the PXRD and DSC results for the maleate of the compound of chemical formula 1.

[0028] [Figure 10] This figure shows the PXRD and DSC results for the hydrochloride salt (amorphous) of the compound of chemical formula 1.

[0029] [Figure 11] This figure shows the PXRD and DSC results for the methanesulfonate (crystalline form) of the compound of chemical formula 1.

[0030] [Figure 12] This figure shows the PXRD and DSC results for the hemisalicylate of the compound of chemical formula 1.

[0031] [Figure 13] This graph shows the results of measuring the total amount of related substances after conducting a severe stability test (60°C or 90% RH) on tegopranoate addition salts.

[0032] [Figure 14]This figure shows the results of measuring the total amount of related substances after compatibility testing of tegoprazan hydrochloride hydrate crystalline form with various pharmaceutical additives (1 or 3 weeks at 60°C or 90% RH).

[0033] [Figure 15] This figure shows the results of measuring the total amount of related substances after conducting compatibility tests (1 or 3 weeks at 60°C or 90% RH) on tegoprazan sulfate with various pharmaceutical additives.

[0034] [Figure 16] This figure shows the results of measuring the total amount of related substances after compatibility testing of tegoprazan methanesulfonate crystalline form with various pharmaceutical additives (1 or 3 weeks at 60°C or 90% RH).

[0035] [Figure 17] This graph shows the weight change after preparing tablets and orally disintegrating tablets for each tegoprazanate addition salt, and then leaving them under harsh storage conditions (90% RH) for three weeks.

[0036] [Figure 18] This graph shows the results of measuring the total amount of related substances after preparing tablets for each tegoprazanate addition salt and conducting a harsh stability test (60°C or 90% RH).

[0037] [Figure 19] This graph shows the results of measuring the total amount of related substances after preparing orally disintegrating tablets for each tegoprazanate addition salt and conducting a harsh stability test (60°C or 90% RH).

[0038] [Figure 20] This figure shows a photograph taken at the time when an orally disintegrating tablet was prepared for each tegoprazanate addition salt, and then placed in 18 mL of physiological saline solution at approximately 37°C and pH 6.8, and the entire surface of the orally disintegrating tablet was wetted with the solution (wetting time).

[0039] [Figure 21] This graph shows the results of a comparative dissolution test conducted on tegoprazan hydrochloride hydrate (crystalline form) tablets in pH 1.2 and pH 4.0 solutions, using Keikabu Tablets (registered trademark) 50 mg as a control drug.

[0040] [Figure 22] This graph shows the results of a comparative dissolution test conducted on tegoprazan hydrochloride hydrate (crystalline form) tablets in pH 6.8 solution and FaSSiF solution, using Keikabu Tablets (registered trademark) 50 mg as a control drug.

[0041] [Figure 23] This graph shows the results of a pharmacokinetic study conducted in beagle dogs using tegoprazan hydrochloride hydrate (crystalline form) tablets, with Keikabu tablets (registered trademark) 50 mg as the control drug. [Modes for carrying out the invention]

[0042] The present invention will be described in more detail below.

[0043] All technical terms used in this invention are used in the same sense as those generally understood by those skilled in the art, unless otherwise specified. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of this invention.

[0044] One aspect of the present invention provides a salt which is a hydrochloride salt or hydrochloride hydrate of the compound of the following chemical formula 1:

[0045] [ka]

[0046] In this specification, the compound of chemical formula 1 is also referred to as "4-[((4S)-5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide" or by its generic name "tegoprazan".

[0047] The free base of the compound of chemical formula 1 can be prepared by the method described in WO2007 / 072146 or WO2016 / 117814 (Patent Document 2), the entirety of which is incorporated herein by reference. The salt according to the above embodiment can be prepared by any method for preparing a hydrochloride salt or hydrochloride hydrate after preparing the free base of the compound of chemical formula 1, in one specific example, by the method disclosed in Example 1 (hydrochloride hydrate) or Example 2 (hydrochloride salt) below.

[0048] The term "freebase" is used herein for convenience to distinguish it from any salt, and refers to the parent compound represented by Chemical Formula 1.

[0049] The hydrochloride salt of the compound of chemical formula 1 has the following chemical formula 2: [ka]

[0050] The hydrochloride salt of the chemical formula 2 is amorphous.

[0051] In one specific example, the amorphous material may exhibit a single endothermic peak at approximately 189.91°C during DSC measurement (scan speed 10°C / min) (Figure 3B).

[0052] In one specific example, the amorphous hydrochloride salt exhibits an endothermic peak with an onset temperature of approximately 179.64°C during DSC measurement (scan speed 10°C / min) (Figure 3B).

[0053] In one specific example, the amorphous hydrochloride salt is characterized by containing an endothermic peak that starts at approximately 179.64°C and has its lowest point at approximately 189.91°C during DSC measurement (scan speed 10°C / min) (Figure 3B).

[0054] The amorphous hydrochloride salt showed significantly less formation of related substances compared to other salts in accelerated stability tests (40±2℃ / RH75±5%) and severe stability tests (60℃ or 90%RH), demonstrating superior stability. Therefore, the amorphous hydrochloride salt is suitable for pharmaceutical use and is expected to ensure the stability of pharmaceuticals when prepared as such.

[0055] The hydrate of tegoprazan hydrochloride has the following chemical formula 3:

[0056] [ka]

[0057] The hydrochloride hydrate of chemical formula 3 is in crystalline form. In one specific example, the hydrochloride hydrate of chemical formula 3 is in crystalline form A.

[0058] In one specific example, the hydrochloride hydrate crystal form A has a powder X-ray diffraction (PXRD) pattern that includes peaks at diffraction angles 2θ of 18.4±0.2°, 22.5±0.2°, and 25.6±0.2°.

[0059] In one specific example, the hydrochloride hydrate crystal form A has a powder X-ray diffraction (PXRD) pattern that includes peaks at diffraction angles 2θ of 13.4±0.2°, 15.2±0.2°, 18.4±0.2°, 18.9±0.2°, 22.5±0.2°, 23.7±0.2°, 25.6±0.2°, 26.2±0.2°, and 27.7±0.2°.

[0060] In one specific example, the hydrochloride hydrate crystalline form A has a powder X-ray diffraction (PXRD) pattern that includes peaks at diffraction angles 2θ of 8.7±0.2°, 13.4±0.2°, 15.2±0.2°, 18.1±0.2°, 18.4±0.2°, 18.9±0.2°, 19.9±0.2°, 20.3±0.2°, 21.4±0.2°, 22.5±0.2°, 23.7±0.2°, 25.2±0.2°, 25.6±0.2°, 26.2±0.2°, 26.6±0.2°, 27.7±0.2°, 28.3±0.2°, 28.8±0.2°, and 37.5±0.2°.

[0061] The peak at the diffraction angle 2θ is the powder X-ray diffraction (PXRD) pattern when irradiated with X-rays (Cu(ka), 1.54056 Å).

[0062] In one specific example, when the hydrochloride hydrate crystal form A is irradiated with X-rays (Cu(ka)), it has a powder X-ray diffraction (PXRD) pattern that substantially matches that of Figure 2A.

[0063] In one specific example, when the hydrochloride hydrate crystal form A is irradiated with X-rays (Cu(ka)), it has a powder X-ray diffraction (PXRD) pattern similar to that shown in Figure 2A.

[0064] In one specific example, when the hydrochloride hydrate crystal form A is irradiated with X-rays (Cu(ka)), it has a powder X-ray diffraction (PXRD) pattern that substantially matches that of Table 1 below.

[0065] [Table 1]

[0066] In one specific example, the hydrochloride hydrate crystal form A may exhibit an endothermic peak at approximately 181.94°C during DSC measurement (scan speed 10°C / min) (Figure 2B).

[0067] In one specific example, the hydrochloride hydrate crystal form A shows a sharp endothermic peak starting at approximately 176.5°C during DSC measurement (scan speed 10°C / min) (Figure 2B).

[0068] In one specific example, the hydrochloride hydrate crystal form A is characterized by containing an endothermic peak that has an initiation point at approximately 176.5°C and a minimum point at approximately 181.94°C during DSC measurement (scan speed 10°C / min) (Figure 2B).

[0069] An example of the analytical instrument and measurement method for the PXRD analysis described above is as follows:

[0070] (1) Powder X-ray Diffraction (PXRD)

[0071] Powder X-ray diffraction (PXRD) analysis was performed using continuous θ-2θ scans at a scan speed of 5° / min (step size 0.02° 2θ) over a 2θ angle range of approximately 2° to 60°.

[0072] (2) Differential scanning calorimetry (DSC)

[0073] Differential scanning calorimetry (DSC) was performed from 25°C to 400°C. 1-2 mg of the sample was weighed and added to an aluminum DSC pan, and the sample was heated from 25°C to 400°C at a scanning rate of 10°C / min. The resulting heat flow reaction (DSC) was monitored.

[0074] In one specific example, the hydrochloride hydrate crystalline form A can be stored stably under general pharmaceutical storage conditions without conversion to other crystalline forms.

[0075] In one specific example, the hydrochloride hydrate crystalline form A allows for the stable storage of pharmaceuticals under accelerated stability testing (40±2℃ / RH75±5%) and harsh stability testing conditions (60℃ or 90%RH).

[0076] The compound of chemical formula 1, i.e., tegoprazan, is known to produce related substances, including the degradation product of chemical formula 4, during storage or formulation processes, particularly under acidic conditions where solubility increases (WO2018 / 056697). Therefore, the smaller the amount of the degradation product of chemical formula 4 and the total amount of related substances containing it, the more pharmaceutically stable the compound is considered to be.

[0077] [ka]

[0078] In this specification, the compound of chemical formula 4 is also referred to as the "decomposition product of chemical formula 4" or simply as the "decomposition product."

[0079] The test results confirmed that tegoprazan hydrochloride hydrate crystalline form and tegoprazan hydrochloride amorphous form, based on one specific example, have at least 10 times higher solubility than tegoprazan free base crystalline form, which is commercially available as Keikabu Tablets (registered trademark), suggesting that sufficient absorption can be achieved when administered to the body (see Experimental Example 1). Furthermore, the liquid stability test confirmed that the hydrochloride hydrate crystalline form and tegoprazan hydrochloride amorphous form showed an increase of only 0.5% or less in the decomposition product of chemical formula 4, demonstrating significantly superior stability compared to other acid addition salts (see Experimental Example 2). The solid stability test also showed that the hydrochloride hydrate crystalline form exhibited significantly superior stability compared to other acid addition salts across both accelerated and severe stability tests, with extremely low total related substance content and an increase in the decomposition product of chemical formula 4 (see Experimental Example 3). In addition, the hydrochloride hydrate crystalline form showed significantly superior stability compared to other acid addition salts in the photostability test (see Experimental Example 4). Furthermore, the amorphous hydrochloride salt was found to have generally superior liquid stability, solid stability, and photostability compared to other acid addition salts (see Experimental Examples 2, 3, and 4).

[0080] Methanesulfonates (amorphous and crystalline) were found to be very stable in liquid stability tests, with an increase in degradation products of only 0.5% or less. However, in solid stability tests, they showed low stability, with a significant increase in the content of total related substances and degradation products, and melting due to moisture absorption. Conventionally disclosed maleate and pyroderate salts, although having high solubility, precipitated solids after 24 hours in liquid stability tests, melted within 24 hours of the start of solid stability tests under harsh 90% RH conditions, and were unstable in photostability tests, producing significantly larger amounts of total related substances and degradation products compared to tegoprazan hydrochloride hydrate. In contrast, amorphous hydrochloride and crystalline hydrochloride hydrate did not exhibit phenomena such as solid precipitation or melting under the same conditions, and degradation products were produced at remarkably low levels, indicating stability (see Experimental Examples 2, 3, and 4). Therefore, the stability tests showed that tegoprazan hydrochloride amorphous and hydrochloride hydrate crystalline forms generally exhibited significantly superior stability compared to other acid addition salts. In particular, tegoprazan hydrochloride hydrate crystalline forms showed significantly superior stability compared to other acid addition salts, and were found to have significantly superior stability compared to conventionally disclosed maleate and pyrodrate salts. Furthermore, when comprehensively comparing and judging solubility, liquid stability, solid stability, and photostability, hydrochloride hydrate crystalline forms and hydrochloride amorphous forms can be said to be pharmaceutically superior acid addition salts that are easy to store as active pharmaceutical ingredients and maintain stability even after being formulated into pharmaceuticals.

[0081] Another aspect of the present invention provides hydrochloride salts or hydrochloride hydrates of the compound of chemical formula 1 for use in the prevention or treatment of diseases mediated by acid pump inhibitory activity.

[0082] Yet another aspect of the present invention provides a pharmaceutical composition comprising a hydrochloride salt or hydrochloride hydrate of the compound of chemical formula 1, and a pharmaceutically acceptable additive. The hydrochloride salt or hydrochloride hydrate of chemical formula 1 may specifically be an amorphous hydrochloride salt of chemical formula 2 or a crystalline hydrochloride hydrate of chemical formula 3. The hydrochloride salt or hydrochloride hydrate of chemical formula 1 is as described above for the hydrochloride salt or hydrochloride hydrate of the compound of chemical formula 1 according to one aspect.

[0083] The aforementioned pharmaceutical composition may be used for the prevention or treatment of diseases mediated by acid pump inhibitory activity.

[0084] The diseases mediated by the aforementioned acid pump inhibitory activity are selected from the group consisting of gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcers, gastric ulcers, duodenal ulcers, NSAID-induced ulcers, gastritis, Helicobacter pylori infection, indigestion, functional indigestion, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral-referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, and asthma.

[0085] The aforementioned pharmaceutical composition may be formulated in a dosage form selected from the group consisting of powders, granules, tablets, orally disintegrating tablets, capsules, suspensions, emulsions, syrups, aerosols, ointments, creams, suppositories, and injections.

[0086] In one specific example, the pharmaceutical composition is an oral tablet or an orally disintegrating tablet.

[0087] In one specific example, the pharmaceutical composition is a tablet or orally disintegrating tablet containing a hydrochloride hydrate crystalline form represented by chemical formula 3 as the active ingredient.

[0088] In one specific example, the pharmaceutical composition is an orally disintegrating tablet containing a hydrochloride hydrate crystalline form represented by chemical formula 3 as the active ingredient.

[0089] As a result of the study, when the hydrochloride hydrate crystalline form was formulated in the same manner as the commercially available tegoprazan free base orally disintegrating tablets (Kei-kabu® Orally Disintegrating Tablets), and the disintegration time was evaluated against the commercially available formulation (Kei-kabu® Orally Disintegrating Tablets), it showed significantly faster disintegration characteristics. Therefore, when the hydrochloride hydrate is prepared as an orally disintegrating tablet, it disintegrates more rapidly in the mouth, improving the convenience of administration and allowing for a more rapid effect (see Experimental Example 7-4).

[0090] In one specific example, the pharmaceutical composition is an oral tablet containing a crystalline form of a hydrochloride salt hydrate represented by chemical formula 3 as an active ingredient.

[0091] After the hydrochloride hydrate crystalline form was formulated using the same method as a commercially available tablet containing tegoprazan free base crystalline form A (Keikabu Tablets®), dissolution tests were conducted comparing it with the commercially available tablet (Keikabu Tablets®). The results showed that both drugs exhibited similarly high immediate release rates of over 85% within 15 minutes under pH 1.2 conditions, which correspond to a fasting state. However, under pH 4.0, pH 6.8, and FaSSIF solution conditions, the dissolution of the control drug (Keikabu Tablets®) was significantly delayed, while the hydrochloride hydrate crystalline form formulation still showed a high immediate release rate of over 85% within 15 minutes (see Experimental Examples 7-5 and 7-6). This indicates that even under conditions where dissolution is delayed due to fluctuations (increases) in gastric pH after a meal, or when drug release is delayed as a result, causing the formulation to leave the gastric environment and reach the intestinal (duodenum or small intestine) environment, the hydrochloride hydrate crystalline form formulation exhibits immediate release, demonstrating rapid efficacy and high bioavailability. Therefore, when preparing tablets using hydrochloride hydrate crystalline form, rapid release can be maintained regardless of pH changes due to food intake, ensuring stable and high bioavailability. Consequently, rapid effects and high bioavailability can be achieved not only on an empty stomach but also when administered after meals (i.e., regardless of whether it is administered after a meal). Thus, it is expected that the convenience of administration will be improved.

[0092] Furthermore, in animal studies, the hydrochloride hydrate crystalline tablets achieved a similar bioavailability (total body exposure) to the control drug while exhibiting improved solubility. max It has been confirmed that this shortens the time required for drug absorption, which enables rapid drug absorption and leads to a quick onset of drug effects (see Experimental Example 7-7).

[0093] In one specific example, the pharmaceutically acceptable additives may vary depending on the intended formulation, and the specific additives used depending on the formulation are well known in the relevant art.

[0094] In one specific example, the pharmaceutical composition is an oral tablet, and specifically, the pharmaceutically acceptable additive may further include one or more substances selected from the group consisting of diluents, binders, disintegrants, and lubricants. Any known additive commonly used in the art may be used as the diluent, binder, disintegrant, and lubricant, but the stability and dissolution rate of the active ingredient can be further improved by the selection of specific additives. As the additive, the diluent may be selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof, but is not limited thereto. The binder may be selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and any combination thereof, but is not limited thereto. The disintegrant may be selected from the group consisting of crospovidone, croscarmellose sodium, starch glycolate sodium, low-substituted hydroxypropylcellulose, and any combination thereof, but is not limited thereto. The lubricant may be selected from, but is not limited to, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and any combination thereof.

[0095] In one specific example, the oral tablet may contain, but is not limited to, hydroxypropylcellulose, mannitol, microcrystalline cellulose, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate.

[0096] In one specific example, the pharmaceutical composition is an orally disintegrating tablet and includes a diluent, a binder, a disintegrant, a lubricant, etc. In one specific example, the oral tablet may, but is not limited to, mannitol, sucralose, perlitol® flush, crospovidone, maltitol, enzyme-treated stevia, peppermint, light anhydrous silicic acid, and magnesium stearate.

[0097] The amount of active ingredient per unit formulation contained in the pharmaceutical composition varies depending on the condition of the patient being administered the drug, the desired level of treatment, and so on. Preferably, the composition of the present invention contains the compound represented by chemical formula 1 as an active ingredient in an amount of 1 to 100 mg as a free base, and more preferably in an amount of 1 to 50 mg, for example, about 50 mg.

[0098] The selection of additives and specific preparation methods for the urban pharmaceutical composition can be appropriately carried out by those skilled in the art using knowledge known in the art, for example, by referring to "Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA".

[0099] The configuration and effects of the present invention will be described in more detail below with reference to embodiments. However, the following embodiments are merely illustrative of the present invention, and the content of the present invention is not limited to the following embodiments.

[0100] Test method

[0101] Powder X-ray Diffraction (PXRD) Test Method

[0102] PXRD measurements were performed using an X-ray diffractometer (Rigaku MiniFlex 600). The measurements were performed under the following conditions:

[0103] [Table A]

[0104] Measurement method: Add the sample to the glass holder and measure according to the analysis conditions described above.

[0105] DSC Test Method

[0106] Differential scanning calorimeter (DSC) measurements were performed using a temperature differential scanning calorimeter (SCINCO DSC N-650). The measurements were performed under the following conditions:

[0107] [Table B]

[0108] Measurement method: Weigh 1-2 mg of the sample onto an aluminum sample pan, cover with the lid, and seal it to use as the sample. Cover an empty aluminum DSC pan with the lid and seal it to use as the reference. Place the sample and reference into the furnace, cover with the lid, and start the measurement once the analysis start temperature is stably maintained.

[0109] Related Substance Testing Method (HPLC)

[0110] The amounts of the decomposition product of chemical formula 4 and all related substances were measured using high-performance liquid chromatography (HPLC), and in this invention, an infinity 1260 (manufactured by Agilent) was used. The analytical conditions were as follows:

[0111] [Solution preparation]

[0112] Blank solution (diluent)

[0113] Mix 400 mL of water with 600 mL of acetonitrile.

[0114] Standard solution

[0115] Accurately weigh out 50.0 mg of tegoprazan free base, place it in a 50 mL volumetric flask, dissolve it with the diluent, and then dilute it to the mark with the diluent. Take 1 mL of this solution and dilute it to 25 mL to prepare the standard solution (0.04 mg / mL).

[0116] Test solution

[0117] Accurately weigh out the sample (100.0 mg as tegoprazan free base), dissolve it in a 25 mL volumetric flask, and then dilute it with diluent to the mark to use as the test solution (4.0 mg / mL).

[0118] [Table C]

[0119] Procedure and Calculation: The blank solution, standard solution, and test solution are tested in that order under the aforementioned instrument operating conditions, in accordance with the "Liquid Chromatography Method for General Test Methods, 12th Revision of the Korean Pharmacopoeia," and the amount of related substances is calculated using the following formula.

[0120]

number

[0121] A T = Area of ​​each related substance peak obtained from the test solution A S = Area of ​​the tegoprazan peak obtained from the standard solution C S =Concentration of standard solution (mg / mL) C T =Concentration of the test solution (mg / mL) P = Purity / Assay / Potency (%) of the standard product RRF = Relative Sensitivity Factor (1.0)

[0122] The total amount of related substances is calculated as the sum of the amounts of each individual related substance.

[0123] Examples

[0124] Tegoprazan acid addition salts were prepared using the various acids shown in Table 2 below. Tegoprazan malate salt and tegoprazan pyridolate salt were prepared according to the method disclosed in Korean Patent Registration No. 1829706.

[0125] [Table 2]

[0126] Preparation Example 1. Preparation of Tegoprazan Free Base Crystal Form A

[0127] 1.5 kg of 7-hydroxy-N,N,2-trimethyl-3-(p-tolylsulfonyl)benzimidazole-5-carboxamide, 822.5 g (1.1 equivalents) of (4R)-5,7-difluorochromen-4-ol, and 15 L of tetrahydrofuran were added to the reactor, and a solution of 1.04 kg (1.2 equivalents) of diisopropyl azodicarboxylate dissolved in 3 L of tetrahydrofuran was gradually added dropwise. After the addition was complete, the mixture was stirred for 2 hours and concentrated under reduced pressure at an external temperature of 40°C. After the concentrate was cooled to room temperature, 7.5 L of ethyl ether was added, and the mixture was stirred at room temperature for 18 hours. The solid was filtered and washed with 5 L of ethyl ether to obtain a wet product (3.26 kg), which was then added to the reactor along with 6.52 L of isopropyl alcohol and 9.78 L of ethyl ether. The mixture was stirred at room temperature for 3 hours. The solid was filtered, washed with 5 L of ethyl ether, and then vacuum-dried at 40°C to obtain 7-[(4S)-5,7-difluorochromen-4-yl]oxy-N,N,2-trimethyl-3-(p-tolylsulfonyl)benzimidazole-5-carboxamide (1.43 kg, yield 64.86%).

[0128] 1.43 kg of 7-[(4S)-5,7-difluorochromen-4-yl]oxy-N,N,2-trimethyl-3-(p-tolylsulfonyl)benzimidazole-5-carboxamide, 3.85 L of tetrahydrofuran, 12.97 L of isopropyl alcohol, and 12.97 L of 2N sodium hydroxide aqueous solution were added to a reactor and stirred at room temperature for 4 hours. 14.3 L of ethyl acetate was added to the reaction mixture, stirred for 10 minutes, and then allowed to stand for 10 minutes before the layers were separated. 14.3 L of 10% ammonium chloride aqueous solution was added to the obtained organic layer, stirred for 10 minutes, and then allowed to stand for 10 minutes before the layers were separated. 142.5 g of magnesium sulfate was added to the obtained organic layer, stirred for 5 minutes, and then filtered. The mixture was concentrated at an external temperature of 50°C until the volume of ethyl acetate remained approximately 3 times the volume of the starting material. After stirring at room temperature for 18 hours, the solid was filtered, washed with 7.13 L of ethyl acetate, and then vacuum-dried at 40°C to obtain crude tegoprazan (746.56 g, yield 73.24%).

[0129] Crude tegoprazan 746.56 g was dissolved in 2.24 L of methanol and filtered. The mixture was stirred and concentrated at an external temperature of 50°C, and after adding 2.24 L of ethyl acetate, it was stirred for 12 hours while gradually cooling to room temperature. The solid was filtered, washed with 1.49 L of ethyl acetate, and then vacuum-dried at 40°C to obtain tegoprazan free base crystalline form A (665.26 g, yield: 89.11%). The PXRD and DSC results of the prepared tegoprazan hydrochloride hydrate are shown in Figure 1.

[0130] [Table D]

[0131] Using the prepared tegoprazan free base crystalline form A (hereinafter referred to as "tegoprazan") as a starting material, acid addition salts were prepared in the following examples and comparative examples.

[0132] Example 1. Preparation of hydrochloride hydrate of the compound of chemical formula 1

[0133] 20 g of tegoprazan and 660 mL of acetonitrile were placed in a reactor and cooled to 0-5°C. 4.878 mL (1.1 equivalents) of hydrochloric acid was gradually added dropwise. After the solid was completely dissolved and precipitation of the solid began, the mixture was stirred at 0-5°C for 2 hours. The solid was filtered, washed with 100 mL of acetonitrile, and then vacuum-dried at room temperature to obtain tegoprazan hydrochloride hydrate as a white powder (20.16 g, yield 88.21%). The PXRD and DSC results of the prepared tegoprazan hydrochloride hydrate are shown in Figure 2.

[0134] [Table E]

[0135] Example 2. Preparation of the hydrochloride salt (amorphous) of the compound of chemical formula 1.

[0136] 20 g of tegoprazan was dissolved in 660 mL of methanol and cooled to 0-5°C. 4.434 mL (1.0 equivalent) of hydrochloric acid was gradually added at 0-5°C, and the mixture was concentrated at an external temperature of 50°C until a solid precipitate formed. 200 mL of acetone and 400 mL of ethyl ether were added, and the mixture was vigorously stirred at room temperature for 1 hour. The solid was filtered, washed with 100 mL of an acetone:ethyl ether (1:2, v / v) mixture, and then vacuum-dried at 40°C to obtain tegoprazan hydrochloride (amorphous) as a white powder (20.32 g, yield 92.86%). The PXRD and DSC results of the prepared tegoprazan hydrochloride amorphous are shown in Figure 3.

[0137] [Table F]

[0138] Comparative Example 1. Preparation of hydrobromide salt of the compound of chemical formula 1.

[0139] 30 g of tegoprazan and 900 mL of acetonitrile were placed in a reactor and cooled to 0-5°C. 20.07 mL (1.1 equivalents) of hydrobromic acid was gradually added dropwise. After the solid was completely dissolved and precipitation of the solid began, the mixture was stirred at 0-5°C for 17 hours. The solid was filtered, washed with 150 mL of acetonitrile, and dried at 40°C to obtain tegoprazan hydrobromide as a white powder (24.66 g, yield 67.87%). The PXRD and DSC results of the prepared tegoprazan hydrobromide are shown in Figure 4.

[0140] [Table G]

[0141] Comparative Example 2. Preparation of the maleate salt of the compound of chemical formula 1.

[0142] 15 g of tegoprazan and 5.45 g (1.05 equivalents) of L-marusan were completely dissolved in 600 mL of methanol, and the mixture was concentrated at an external temperature of 50°C until a solid precipitate formed. 600 mL of ethyl ether was added, and the mixture was vigorously stirred at room temperature for 30 minutes. The solid was filtered, washed with 75 mL of ethyl ether, and then vacuum-dried at 40°C to obtain tegoprazan malate salt as a white powder (18.79 g, yield 93.06%). The PXRD and DSC results of the prepared tegoprazan malate salt are shown in Figure 5.

[0143] [Table H]

[0144] Comparative Example 3. Preparation of pyrodrate salt of the compound of chemical formula 1

[0145] 15 g of tegoprazan and 5.25 g (1.05 equivalents) of L-pyroglutamic acid were completely dissolved in 600 mL of methanol, and the mixture was concentrated at an external temperature of 50°C until a solid precipitate formed. 600 mL of n-hexane was added, and the mixture was vigorously stirred at room temperature for 30 minutes. The solid was filtered, washed with 75 mL of n-hexane, and then vacuum-dried at 40°C to obtain tegoprazan pyridolate salt as a white powder (19.18 g, yield 95.91%). The PXRD and DSC results of the prepared tegoprazan pyridolate salt are shown in Figure 6.

[0146] [Table I]

[0147] Comparative Example 4. Preparation of sulfate salt of the compound of chemical formula 1.

[0148] 20 g of tegoprazan and 400 mL (1 equivalent) of acetone were placed in a reactor and cooled to 15°C. 2.767 mL (1.0 equivalent) of sulfuric acid was gradually added dropwise at 15°C, and the mixture was stirred at 15°C for 19 hours. The solid was filtered, washed with 100 mL of acetone, and then vacuum-dried at 40°C to obtain tegoprazan sulfate as an apricot-colored powder (24.25 g, yield 96.58%). The PXRD and DSC results of the prepared tegoprazan sulfate, as well as the crystal transition results at initial and 1 month in the severe stability (90% RH) test, are shown in Figure 7.

[0149] [Table J]

[0150] Comparative Example 5. Preparation of phosphate of the compound of chemical formula 1

[0151] 20 g of tegoprazan and 1,000 mL of isopropyl alcohol were placed in a reactor. After the solid was completely dissolved, 2.65 mL (0.84 equivalents) of phosphoric acid was gradually added dropwise. The mixture was concentrated at an external temperature of 50°C until the solid precipitated, then 200 mL of acetone and 400 mL of ethyl ether were added, and the mixture was vigorously stirred at room temperature for 1 hour. The solid was filtered, washed with 100 mL of an acetone:ethyl ether (1:2, v / v) mixture, and then vacuum-dried at 40°C to obtain tegoprazan phosphate as a white powder (19.62 g, yield 85.16%). The PXRD and DSC results of the prepared tegoprazan phosphate are shown in Figure 8.

[0152] [Table K]

[0153] Comparative Example 6. Preparation of maleate salt of the compound of chemical formula 1

[0154] 20 g of tegoprazan and 800 mL of dichloromethane were placed in a reactor and cooled to 0-5°C. After the solid was completely dissolved, 5.99 g (1.0 equivalent) of maleic acid was added, and the temperature was raised to room temperature to completely dissolve it. After concentrating at room temperature until the solid precipitated, 800 mL of ethyl ether was added, and the mixture was vigorously stirred at room temperature for 2 hours. The solid was filtered, washed with 100 mL of ethyl ether, and vacuum-dried at 60°C to obtain tegoprazan maleate as a white powder (24.87 g, yield 95.50%). The PXRD and DSC results of the prepared tegoprazan maleate are shown in Figure 9.

[0155] [Table L]

[0156] Comparative Example 7. Preparation of methanesulfonate (amorphous) of the compound of chemical formula 1.

[0157] 20 g of tegoprazan was completely dissolved in 200 mL of methanol, and 3.35 mL (1.0 equivalent) of methanesulfonic acid was added dropwise. The mixture was concentrated at an external temperature of 40°C until a solid precipitate formed, and after adding 800 mL of ethyl ether, it was vigorously stirred at room temperature for 1 hour. The solid was filtered, washed with 100 mL of ethyl ether, and then vacuum-dried at 40°C to obtain tegoprazan methanesulfonate (amorphous) as a white powder (24.45 g, yield 97.95%). The PXRD and DSC results of the prepared tegoprazan methanesulfonate (amorphous) are shown in Figure 10.

[0158] [Table M]

[0159] Comparative Example 8. Preparation of methanesulfonate (crystalline form) of the compound of chemical formula 1.

[0160] 50 g of tegoprazan and 1,000 mL of acetonitrile were placed in a reactor, and 8.4 mL (1.0 equivalent) of methanesulfonic acid was added dropwise at room temperature. After the solid was completely dissolved and precipitation began, the mixture was stirred at room temperature for 1 hour. The solid was filtered, washed with 250 mL of acetonitrile, and then vacuum-dried at 40°C to obtain tegoprazan methanesulfonate (crystalline form) as a white powder (59.41 g, yield 95.20%). The PXRD and DSC results of the prepared tegoprazan methanesulfonate (crystalline form) are shown in Figure 11.

[0161] [Table N]

[0162] Comparative Example 9. Preparation of hemisalicylate of the compound of chemical formula 1

[0163] 20 g of tegoprazan was completely dissolved in 200 mL of methanol, and 4.272 g (0.6 equivalents) of salicylic acid was added. After the solid was completely dissolved, the mixture was concentrated at an external temperature of 40°C until the solid precipitated, and 400 mL of ethyl ether was added and the mixture was vigorously stirred for 1 hour. The solid was filtered, washed with 100 mL of ethyl ether, and then vacuum-dried at 40°C to obtain tegoprazan hemisalicylate as a white powder (18.82 g, yield 79.86%). The PXRD and DSC results of the prepared tegoprazan hemisalicylate are shown in Figure 12.

[0164] [Table O]

[0165] Experimental example

[0166] The following tests were performed on the tegopranoate addition salt prepared as described above.

[0167] Solubility tests and stability tests were conducted, and the conditions are as shown in Table 3 below.

[0168] [Table 3]

[0169] Experimental Example 1: Solubility Comparison Test

[0170] The solubility of the nine tegoprazan acid addition salts prepared as described above was measured. The measurements were performed according to the method described in the "Solubility" section of the general rules in Appendix 1 of the 12th revision of the Korean Pharmacopoeia. The solubility of each salt is shown as the solubility of the acid addition salt itself, not on a basis of tegoprazan free base.

[0171] [Table 4]

[0172] As can be seen from Table 4 above, of the nine acid addition salts, seven, excluding maleate and hemisalicylate, showed solubility at least 10 times greater than that of commercially available tegoprazan free base. In the case of maleate and hemisalicylate, they showed solubility of 1.0 mg / mL or less, similar to that of the free base of the compound of chemical formula 1. Therefore, tegoprazan hydrochloride (amorphous) and hydrochloride hydrate crystalline form A show higher solubility than conventionally commercially available organic bases and are expected to be advantageous for drug absorption in the body.

[0173] Experimental Example 2: Liquid Stability Comparison Test

[0174] Using the acid addition salts (hydrochloride hydrate, sulfate, hydrochloride (amorphous), phosphate, methanesulfonate (amorphous), and methanesulfonate (crystalline)) that showed a water solubility of 30 mg / mL or more in Experimental Example 1 as a control group, tests were conducted to confirm the liquid stability of Comparative Examples 2 and 3 (malate salt and pyrodate salt).

[0175] Each sample was dissolved in purified water to prepare a 20 mg / mL solution. These solutions were stored at an external temperature of 40°C, and their purity was measured by HPLC analysis at the initial stage and after 24 hours. The change in the amount of decomposition product (chemical formula 4) was also measured. For the analysis of the total amount of related substances and decomposition products, a sample was taken from the 20 mg / mL solution, diluted to a concentration of 4 mg / mL using the diluent for the related substance test method (HPLC), measured as a test solution, and analyzed according to the related substance test method (HPLC). The results are shown in Table 5 below.

[0176] [Table 5]

[0177] The test results showed that when the maleate salt, pyrodrate salt, and phosphate salt were stored at 40°C for 24 hours, solid precipitates formed, while the other acid addition salts maintained a homogeneous solution state. Furthermore, it was confirmed that the sulfate salt formed more than 5% of decomposition products after 24 hours of storage, and its purity decreased by approximately 6%. On the other hand, the hydrochloride hydrate, hydrochloride salt, and methanesulfonate (amorphous and crystalline) showed relatively high stability, with the increase in decomposition products remaining below 0.5%.

[0178] Experimental Example 3: Solid Stability Comparison Test

[0179] A solid stability comparison test was conducted for each of the tegopranoate addition salts prepared as described above. The stability comparison test was carried out for one month under the conditions shown in Table 6 below, in accordance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. The purity of the acid addition salt, the total amount of related substances, and the content of degradation products were measured by HPLC at the initial stage and after one month. The amount of total related substances and degradation products were measured according to the related substances test method (HPLC) described above.

[0180] [Table 6]

[0181] 1) Accelerated stability test (40±2℃ / RH75±5%)

[0182] [Table 7]

[0183] According to the results of the accelerated stability test in Table 7, the maleate salt, pyrodate salt, hydrochloride hydrate, and hemisalicylate showed a purity change of less than 0.1% after one month, indicating their stability. In contrast, the hydrobromide salt, sulfate, maleate salt, methanesulfonate (amorphous), and methanesulfonate (crystalline) showed an increase of more than 0.3% in total related substance content after one month, and in the case of sulfate, a change in properties such as discoloration of the solid was observed.

[0184] Powder X-ray diffraction (PXRD) analysis was performed on all acid addition salts initially and one month later, and no crystal transitions were observed.

[0185] 2) Severe stability test (temperature 60°C) [Table 8]

[0186] According to the results of the severe stability test (temperature 60°C) in Table 8, it was confirmed that hydrobromide, maleate, methanesulfonate (amorphous), and methanesulfonate (crystalline) increased by more than 5.0% in total related substances after one month, and that the decomposition products of chemical formula 4 also increased significantly. Furthermore, in the case of hydrobromide, sulfate, methanesulfonate (amorphous), and methanesulfonate (crystalline), a change in the solid's color was observed. In contrast, maleate, pyridolate, hydrochloride hydrate, and hemisalicylate showed significantly low levels of total related substances and decomposition products of chemical formula 4 even after one month, indicating their stability.

[0187] Powder X-ray diffraction (PXRD) analysis was performed on all acid addition salts initially and one month later, and no crystal transitions were observed.

[0188] 3) Severe stability (humidity 90%RH)

[0189] [Table 9]

[0190] According to the results of the severe stability test (90% RH humidity) shown in Table 9, the hydrochloride hydrate showed a change of less than 0.1%, demonstrating its superior stability, followed by the amorphous hydrochloride, which showed a low change of less than 0.15%. In contrast, the maleate salt, pyrodate salt, phosphate salt, maleate salt, amorphous methanesulfonate, and crystalline methanesulfonate all melted due to moisture absorption within two days of the start of the test, indicating extremely low stability to humidity.

[0191] After one month, powder X-ray diffraction (PXRD) analysis was performed on five acid addition salts that had maintained their solid properties. The sulfates were found to exist in a mixture of the initial and new crystalline forms, indicating a crystal transition (see Figure 7C).

[0192] Experimental Example 4: Photostability Comparison Test

[0193] A comparative photostability test was conducted on each of the tegopranoate addition salts prepared as described above. The test was conducted in accordance with the guidelines of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), using 200W UV light at hr / m². 2 The tests were conducted by exposing the samples to light with an energy of 1.2 Mlux hr in the visible light spectrum. The samples were packaged in a single PE bag to ensure stability against humidity, and spread thinly to allow exposure to the light source. The purity of the acid addition salts and the changes in degradation products were measured by HPLC both initially and after exposure to ultraviolet or visible light.

[0194] 1) Ultraviolet light (200W hr / m 2 ) Exposure test

[0195] [Table 10]

[0196] 2) Visible light (1.2 Mlux hr) exposure test

[0197] [Table 11]

[0198] According to the results of the photostability tests in Tables 10 and 11, when the purity and changes in degradation products of the acid addition salts were examined after exposure to ultraviolet and visible light, the hydrochloride hydrate was found to be the most stable, with degradation products of 0.1% or less under both light sources. In contrast, hydrobromide discolored and showed changes in properties under visible light exposure conditions, while hemisalicylate discolored and showed changes in properties under both ultraviolet and visible light exposure conditions.

[0199] Based on the combined results of the liquid stability test and the solid stability test (Table 12), it was found that the hydrochloride hydrate and hydrochloride (amorphous) are highly stable acid addition salts that are resistant to humidity, and the hydrochloride hydrate in particular exhibits remarkably superior stability.

[0200] [Table 12]

[0201] Experimental Example 5. Powder X-ray Diffraction (PXRD) Analysis

[0202] PXRD analysis was performed to analyze the changes in crystallinity of each of the tegopranoate addition salts prepared as described above. In the solid stability (accelerated stability, severe stability (60°C), severe stability (90%RH)) tests in Experimental Example 3, PXRD analysis was performed on each acid addition salt initially and after storage for one month after the test. The PXRD analysis was performed according to the PXRD test method described above.

[0203] As a result, it was confirmed that no crystallization transitions were observed under any other conditions, except for tegoprazan sulfate after storage for one month under harsh stability conditions (90% RH) (see Figure 7C).

[0204] Experimental Example 6. Differential Scanning Calorimetry (DSC) Analysis

[0205] DSC analysis was performed on each of the tegopranoate addition salts prepared as described above. The DSC analysis was performed in a sealed pan using a differential scanning calorimeter (SCINCO DSCN-650) under nitrogen purification at a scanning rate of 10°C / min from 25°C to 400°C.

[0206] As a result, it was confirmed that each acid addition salt was successfully synthesized from the free base of the compound with chemical formula 1 in crystalline form (see Figure 1B). DSC analysis was performed according to the DSC test method described above.

[0207] conclusion

[0208] Tegoprazan hydrochloride hydrate and hydrochloride salt were confirmed to have at least 10 times higher solubility than commercially available tegoprazan free base, suggesting that sufficient absorption can be achieved upon administration to the body. Furthermore, liquid stability tests confirmed that the hydrochloride hydrate and hydrochloride salt showed significantly superior stability compared to other acid addition salts, with an increase in degradation products of only 0.5% or less. Solid stability tests also showed that the hydrochloride hydrate exhibited significantly superior stability compared to other acid addition salts across both accelerated and harsh stability tests. In addition, the hydrochloride hydrate showed significantly superior stability compared to other acid addition salts in photostability tests. Moreover, the hydrochloride salt was found to have generally superior liquid stability, solid stability, and photostability compared to other acid addition salts.

[0209] Methanesulfonates (amorphous and crystalline) were found to be very stable in liquid stability tests, with only a 0.5% or less increase in degradation products. However, in solid stability tests, they showed a significant increase in the content of total related substances and degradation products, and melted due to moisture absorption, indicating low stability. Conventionally disclosed maleate and pyroderate salts, while having high solubility, precipitated solids after 24 hours in liquid stability tests, melted within 24 hours under harsh 90% RH conditions in solid stability tests, and were unstable in photostability tests, generating significantly larger amounts of total related substances and degradation products compared to tegoprazan hydrochloride hydrate. In contrast, hydrochloride and hydrochloride hydrate did not exhibit phenomena such as solid precipitation or melting under the same conditions, and degradation products were generated at significantly lower levels, indicating stability. Therefore, the stability tests showed that tegoprazan hydrochloride and hydrochloride hydrate generally exhibited significantly superior stability compared to other acid addition salts. In particular, tegoprazan hydrochloride hydrate was found to exhibit significantly superior stability compared to other acid addition salts, and also significantly superior stability compared to conventionally disclosed maleate and pyrodrate salts. Furthermore, when comprehensively comparing and judging solubility, liquid stability, solid stability, and photostability, hydrochloride hydrate and hydrochloride (amorphous) can be said to be pharmaceutically superior acid addition salts that are easy to store as active pharmaceutical ingredients and maintain stability even after being formulated into pharmaceuticals.

[0210] Experimental Example 7. Comparative Test for Formulation

[0211] The analytical methods for related substances used in the following experimental examples 7-1 to 7-3 are as follows:

[0212] <Testing method for related substances (HPLC)>

[0213] The total amount of related substances under harsh storage conditions (temperature / humidity) was measured using high-performance liquid chromatography (HPLC) with an Agilent Infinity 1260. The analytical conditions were as follows:

[0214] [Solution preparation]

[0215] Blank solution (diluent) Mix TFA:ACN:Water in a volume ratio of 1:70:30.

[0216]

Table P

[0217] Operation and calculation: Prepare the standard solution and the test solution so that their concentrations are 0.2 mg / mL, conduct tests according to the liquid chromatography method, and calculate the amount of related substances using the following calculation formula.

[0218]

Number

[0219] A T = Area of each related substance peak obtained from the test solution A S = Area of the tegoprazan peak obtained from the standard solution C S = Concentration of the standard solution (mg / mL) C T = Concentration of the test solution (mg / mL) The total amount of related substances is calculated as the sum of the amounts of individual related substances.

[0220] Experimental Example 7-1. Raw material stability test (comparative test with tegoprazan free base)

[0221] For the tegoprazan hydrochloride hydrate prepared in Example 1 above, a comparative test was conducted with tegoprazan free base crystal form A contained in the control drugs (Keikabu tablets 50 mg and Keikabu (registered trademark) orally disintegrating tablets 50 mg) published in the Pharmaceutical Integrated Information System of the Ministry of Food and Drug Safety (MFDS), and the product obtained in Production Example 1 was used. As acid addition salts for additional comparison, the sulfate and methanesulfonate crystal forms produced in the above Comparative Example, which were found to have high solubility, were used.

[0222] To compare the stability of the main raw materials themselves, we compared the degree of change in properties and the generation of related substances under harsh conditions. Stability tests were conducted under the harsh temperature and humidity conditions shown in Table 13 below.

[0223] [Table 13]

[0224] (1) Observation of characteristics

[0225] The changes in properties of tegoprazan free base and tegoprazanate addition salt after 3 weeks were examined under initial conditions and harsh storage conditions (temperature / humidity). The results are shown in Table 14 below.

[0226] [Table 14]

[0227] As shown in Table 14 above, sulfates exhibited a persistent pungent odor due to the acidic properties of the initial raw material. For methanesulfonates, significant moisture adsorption of the raw material occurred under harsh humidity conditions, leading to melting of the raw material. Therefore, hydrochloride hydrates were found to be the most suitable acid addition salt for ensuring stability and excellent functional properties in the development of orally disintegrating tablets.

[0228] As shown in Figure 13, when the amount of related substances generated under harsh temperature / humidity storage conditions was examined, the amount of related substances generated increased significantly with tegoprazan sulfate and methanesulfonate (crystalline form) compared to tegoprazan free base. However, tegoprazan hydrochloride hydrate showed a similar level of related substance generation as tegoprazan free base, indicating its stability.

[0229] Experimental Example 7-2. Testing of Formulation Compatibility

[0230] To confirm the interaction (impact on stability) between potentially usable additives with tegoprazan acid addition salts, we evaluated their compatibility for different formulation purposes. To confirm the influence of excipients used in actual control drugs, we selected excipients used in control drugs (Keikabu Tablets 50 mg and Keikabu® Orally Disintegrating Tablets 50 mg), which are publicly available on the Ministry of Food and Drug Safety's Integrated Drug Information System, as candidate groups. For other excipients, we selected excipients commonly used in tablet and orally disintegrating tablet formulations. The compatibility test design is described in Table 15 below. Stability tests were conducted by leaving the samples under harsh temperature conditions of 60°C and harsh humidity conditions of 90% RH for 1 week and 3 weeks, respectively, and measuring the total amount of related substances. The results are shown in Figures 14 to 16. The results for tegoprazan hydrochloride hydrate are shown in Figure 14, the results for sulfate in Figure 15, and the results for methanesulfonate (crystalline form) in Figure 16. For convenience, the combined samples are denoted as -1, -2, and -3, respectively.

[0231] [Table 15]

[0232] As a result of confirming the compatibility of tegoprazan acid addition salts and additives under severe temperature / humidity storage conditions, in the combination with the hydrochloride hydrate, the generation amount of related substances increased only in C12 (Copovidone) used as an internal binder in tablets and C*07 (Acesulfame potassium) used as a sweetening agent in orally disintegrating tablets, and it was found that the blending stability was not good. However, since the generation amount of related substances also increased from the initial stage when this combination was mixed with other acid addition salts, it is judged that the influence of the peak derived from the excipient itself detected at the HPLC analysis wavelength is greater than the increase in related substances due to the interaction with the main component. On the other hand, it was confirmed that the total generation amount of related substances in other additive combinations was clearly improved compared to the combination of tegoprazan hydrochloride hydrate and the combination of tegoprazan sulfate and methanesulfonate (crystalline form). Therefore, it was found that tegoprazan hydrochloride hydrate has little interaction with the additives to be mixed, and when formulated into tablets and orally disintegrating tablets, it can ensure significantly better stability than other acid addition salts.

[0233] Experimental Example 7-3. Stability Test for Different Formulations

[0234] To confirm the stability according to the formulation, tablets and orally disintegrating tablets with different tegoprazan acid addition salts were prepared, and the property changes and the generation amount of related substances under severe conditions were compared. The formulations of each test preparation were selected to be the same as those of the additives of the control drugs (Keikabu tablets 50 mg, Keikabu (registered trademark) orally disintegrating tablets 50 mg) publicly available in the Pharmaceutical Integrated Information System of the Ministry of Food and Drug Safety in order to minimize the influence of additives, and were manufactured by the simple mixing (direct pressing) method to minimize the differences in the granule manufacturing process. Each formulation was as shown in Tables 16 and 17 below, and the stability conditions were carried out for each formulation under the storage conditions of 60 °C, which is a severe temperature condition, and 90% RH, which is a severe humidity condition.

[0235]

Table 16

[0236] [Table 17]

[0237] (1) Observation of characteristics

[0238] The changes in properties of the control drugs (Keikabu Tablets 50 mg and Keikabu® Orally Disintegrating Tablets 50 mg) and tablets and orally disintegrating tablets prepared with tegoprazanate addition salt were observed after being left for 3 weeks under harsh storage conditions (60°C / 90%RH), and are shown in Figure 17.

[0239] As shown in Figure 17, weight increase was observed under harsh humidity conditions, regardless of the type of formulation or acid addition salt. The degree of weight increase was even greater for sulfates and methanesulfonates (crystalline form) compared to the control drug, while for hydrochloride hydrates it was similar to the control drug, and even smaller for tablet formulations. Therefore, hydrochloride hydrates are expected to minimize the degree of moisture absorption even under high humidity conditions, which is advantageous for ensuring formulation stability.

[0240] (2) Analysis of related substances

[0241] Stability tests were conducted under harsh storage conditions (temperature / humidity) for each formulation. The total amount of related substances was measured after leaving the products under harsh conditions for one or three weeks, and the results are shown in Figures 18 and 19.

[0242] As shown in Figures 18 and 19, when the amount of related substances generated under harsh storage conditions of temperature and humidity was examined, the amount of total related substances generated in both formulations prepared with sulfate and methanesulfonate (crystalline form) increased significantly compared to the control drug. However, when prepared with hydrochloride hydrate, both formulations showed the same amount of related substances generated as the control drug, and hydrochloride hydrate showed significantly superior stability during formulation compared to other acid addition salts.

[0243] Experimental Example 7-4. Evaluation of decay time

[0244] Orally disintegrating tablets can be taken without water and disintegrate in the mouth, making them easy to administer to patients with impaired swallowing ability. Therefore, rapid disintegration in the mouth is essential. To confirm the disintegration time, 18 mL of physiological saline solution with a pH of 6.8, warmed to approximately 37°C (most similar to saliva), was placed in a petri dish. The orally disintegrating tablets prepared in Experimental Example 7-3 were then placed on top, and the time it took for the entire surface of the orally disintegrating tablet to be moistened by the solution (wetting time) was measured. The results are shown in Figure 20.

[0245] As shown in Figure 20, the hydrochloride hydrate was confirmed to be absorbed most rapidly from the solution, demonstrating a significantly shorter absorption time compared to commercially available orally disintegrating tablets. Therefore, when formulated as an orally disintegrating tablet, hydrochloride hydrate exhibits the fastest disintegration, offering greater convenience for administration and a faster onset of efficacy.

[0246] Experimental Example 7-5. Evaluation of elution rate under acidic conditions

[0247] The control drug (Keikabu 50mg tablets) is known to exhibit rapid drug release in the gastric juice environment of the body upon administration. Therefore, under acidic conditions that take into account the gastric juice environment, the drug dissolution rates of the control drug (Keikabu 50mg tablets) and the test drug (tegoprazan hydrochloride hydrate tablets) prepared in Experimental Example 7-3 were compared.

[0248] The dissolution test was conducted according to Method 2 (Paddle Method) of the General Test Methods of the 12th Revision of the Korean Pharmacopoeia, as shown in Table 18 below. The results are shown in Figure 21.

[0249] [Table 18]

[0250] According to the results in Figure 21, both tegoprazan hydrochloride hydrate tablets and the control drug, Keikabu 50 mg tablets, exhibited rapid release, releasing 85% within 15 minutes without delay at pH 1.2. In particular, tegoprazan hydrochloride hydrate tablets released 85% within 15 minutes under both pH 1.2 and pH 4.0 conditions. In contrast, the control drug, Keikabu tablets, showed rapid release, releasing 85% within 15 minutes at pH 1.2, but the release was slightly delayed at pH 4.0, reaching 85% release after 15 minutes.

[0251] Experimental Example 7-6. Dissolution Test in the Intestinal Environment

[0252] In general, food can alter the bioavailability of drugs by delaying gastric emptying time or changing the acidity of the gastrointestinal tract. In a postprandial state, the pH of the gastrointestinal tract increases, which can affect the drug dissolution rate. This delay in the release of the active ingredient in the stomach may cause it to migrate to the intestinal environment rather than the gastric environment and dissolve there. Therefore, dissolution tests were conducted under intestinal fluid conditions rather than gastric fluid conditions.

[0253] Dissolution tests were performed on commercially available Keikabu 50 mg tablets (control drug) and the test drug prepared in Experimental Example 7-3 (tegoprazan hydrochloride hydrate tablets) containing the same amount of tegoprazan. As the dissolution test solution, a FaSSiF solution (pH 6.5) simulating fasting artificial intestinal fluid was selected with a pH of 6.8. The dissolution test was carried out according to Dissolution Test Method 2 (Paddle Method) of the General Test Methods of the 12th Revision of the Korean Pharmacopoeia, as shown in Table 19 below. The results are shown in Figure 22.

[0254] [Table 19]

[0255] The test results showed that the dissolution rate of tegoprazan hydrochloride hydrate tablets was high, exceeding 85% within 15 minutes in both pH 6.8 and FaSSiF solutions, while the control drug (Keikabu tablets®) showed a relatively significantly lower dissolution rate.

[0256] Traditionally, when tegoprazan free base is administered after a meal, it has a higher T than when administered on an empty stomach. max It is known that absorption can be delayed by up to 8 hours (Clin Transl Sci. 2021;14:934-941). This can be explained by differences in solubility due to pH changes before and after meals, which lead to differences in the drug absorption profile. In contrast, tegoprazan hydrochloride hydrate, when measured according to the method described in the General Test Methods of the Korean Pharmacopoeia "Solubility," has at least 10 times the solubility of tegoprazan free base (see Experimental Example 1 above), and it is thought that this high solubility can minimize changes in dissolution due to pH changes. Therefore, tegoprazan hydrochloride hydrate is expected to minimize the impact of meals on drug absorption compared to conventional commercially available Keikeb tablets, and ensure high bioavailability regardless of whether food is consumed, i.e., consistently high bioavailability. Furthermore, since tegoprazan hydrochloride hydrate can be administered regardless of whether food is consumed, it offers significantly improved convenience of medication administration.

[0257] Experimental Example 7-7. Evaluation of pharmacokinetic absorption effects in Beagle dogs.

[0258] To evaluate the pharmacokinetic properties of tegoprazan hydrochloride hydrate, pharmacokinetic studies were conducted on commercially available Keikabu 50 mg tablets (control drug) and the test drug prepared in Experimental Example 7-3 (tegoprazan hydrochloride hydrate tablets) containing the same amount of tegoprazan.

[0259] A total of 18 male Beagle dogs (17-20 months old) were included in the study, with 9 dogs in each test group. The study was conducted under fasting conditions using a crossover design. After fasting for at least 16 hours the day before administration, the drugs were administered orally.

[0260] One tablet each of the test drug and the control drug was administered orally. Blood samples were collected before administration (0 hours) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. Two mL of blood was collected from the jugular vein and immediately centrifuged to separate the plasma, which was then frozen and stored until analysis. Tegoprazan was analyzed in the plasma using LC-MS / MS, with Tegoprazan-d6 as the internal standard. The results are shown in Table 20 and Figure 23 below.

[0261] [Table 20]

[0262] According to the results in Table 20 and Figure 23, the test drug showed a rapid T1c level compared to the control drug. max Ensure the highest blood concentration of the drug after administration (C max The area under the blood drug concentration-time curve (AUC) showed similar results. This indicates that the test drug maintained a similar drug bioavailability (total exposure) to the control drug in a fasted state, while the improved solubility allowed for T max This demonstrates that shortening the time required for drug absorption allows for rapid drug absorption, which is expected to lead to a more rapid onset of therapeutic effects.

Claims

1. A salt that is the hydrochloride salt or hydrochloride hydrate of the compound of the chemical formula 1 below. 【Chemistry 1】

2. The salt according to claim 1, wherein the hydrochloride salt is represented by the following chemical formula 2. 【Chemistry 2】

3. The salt according to claim 1, wherein the hydrochloride hydrate is represented by the following chemical formula 3. 【Transformation 3】

4. The salt according to claim 2, wherein the salt is amorphous.

5. The salt according to claim 3, wherein the salt is in crystalline form.

6. The salt according to claim 5, wherein the crystalline form A has a powder X-ray diffraction (PXRD) pattern that includes peaks at diffraction angles 2θ of 18.4±0.2°, 22.5±0.2°, and 25.6±0.2°.

7. The salt according to claim 6, wherein the crystalline form A has a powder X-ray diffraction (PXRD) pattern that includes peaks at diffraction angles 2θ of 13.4±0.2°, 15.2±0.2°, 18.4±0.2°, 18.9±0.2°, 22.5±0.2°, 23.7±0.2°, 25.6±0.2°, 26.2±0.2° and 27.7±0.2°.

8. The salt according to claim 7, wherein the crystalline form A has a powder X-ray diffraction (PXRD) pattern including peaks at diffraction angles 2θ of 8.7±0.2°, 13.4±0.2°, 15.2±0.2°, 18.1±0.2°, 18.4±0.2°, 18.9±0.2°, 19.9±0.2°, 20.3±0.2°, 21.4±0.2°, 22.5±0.2°, 23.7±0.2°, 25.2±0.2°, 25.6±0.2°, 26.2±0.2°, 26.6±0.2°, 27.7±0.2°, 28.3±0.2°, 28.8±0.2° and 37.5±0.2°.

9. The salt according to claim 8, having substantially the same powder X-ray diffraction (PXRD) pattern as that shown in Figure 2A.

10. A pharmaceutical composition comprising a salt according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, wherein the composition is for the prevention or treatment of diseases mediated by acid pump inhibitory activity.

12. The pharmaceutical composition according to claim 11, wherein the disease mediated by the acid pump inhibitory activity is selected from the group consisting of gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, indigestion, functional indigestion, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral-referred pain, heartburn, nausea, esophagitis, dysphagia, salivation, airway disorders, and asthma.

13. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is formulated in a formulation selected from the group consisting of powders, granules, tablets, orally disintegrating tablets, capsules, suspensions, emulsions, syrups, aerosols, ointments, creams, suppositories, and injections.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is a tablet or an orally disintegrating tablet.

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