[go: up one dir, main page]

WO2025121965A1 - Novel crystal form of tegoprazan sulfonic acid salt and pharmaceutical composition comprising the same - Google Patents

Novel crystal form of tegoprazan sulfonic acid salt and pharmaceutical composition comprising the same Download PDF

Info

Publication number
WO2025121965A1
WO2025121965A1 PCT/KR2024/020014 KR2024020014W WO2025121965A1 WO 2025121965 A1 WO2025121965 A1 WO 2025121965A1 KR 2024020014 W KR2024020014 W KR 2024020014W WO 2025121965 A1 WO2025121965 A1 WO 2025121965A1
Authority
WO
WIPO (PCT)
Prior art keywords
tegoprazan
crystal form
sulfonic acid
acid salt
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2024/020014
Other languages
French (fr)
Inventor
Jaemin Lee
Dong Hyuk Nam
Su Jin Kim
Sung Kwon Kang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chong Kun Dang Corp
Original Assignee
Chong Kun Dang Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chong Kun Dang Corp filed Critical Chong Kun Dang Corp
Publication of WO2025121965A1 publication Critical patent/WO2025121965A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/05—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing at least two sulfo groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a novel crystal form of a tegoprazan sulfonic acid salt, a pharmaceutical composition containing the same, and a method of preparing the novel crystal form of tegoprazan sulfonic acid salt and the pharmaceutical composition containing the same, and more specifically, to a novel crystal form of a tegoprazan sulfonic acid salt which greatly improves the stability of raw materials, non-hygroscopicity and solubility, and exhibits pharmacological effects comparable to conventional tegoprazan free base forms, a pharmaceutical composition containing the same, and a method of preparing the same.
  • the proton pump called “H+/K+-ATPase” of the parietal cells present in the gastric mucosa causes potassium ions (K + ) to flow into the cells and releases protons (H + ) into the stomach, resulting in gastric acid secretion. Then, the protons (H+) released into the stomach combine with chloride ions (Cl - ) to secrete gastric acid, causing gastrointestinal diseases.
  • PPIs Proton pump inhibitors
  • tegoprazan which is a benzimidazole derivative that has a chemical name of [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide] and a structure of Formula 1, competitively binds to potassium ions and inhibits the release of protons (H+) into the stomach, thereby inhibiting gastric acid secretion (see International Patent Publication No. 2007/072146, or the like). For this reason, tegoprazan, which is called a “potassium competitive acid blocker (P-CAB)”, is known to have a faster onset of pharmaceutical effect than PPI drugs.
  • P-CAB potassium competitive acid blocker
  • tegoprazan has preventive and therapeutic effects on gastrointestinal diseases, for example, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, and diseases caused by proton pump antagonist activity, such as drooling, airway disorders, and asthma, and K-CAB tablets or K-CAB orally disintegrating tablets, which are medicines containing tegoprazan as an active ingredient, are approved and are currently being marketed for the treatment of erosive gastroesophageal reflux diseases, the treatment of non-erosive gastroesophageal reflux diseases, the
  • tegoprazan has low stability and still a problem of requiring improved solubility.
  • International Patent Publication No. 2016/117814 discloses, as a crystal form of tegoprazan, a crystal form of tegoprazan free base and a method of preparing the same.
  • This crystal form of tegoprazan free base has a relatively low denaturation rate and electrostatic induction ability even under harsh light conditions, thus having advantages of easy formulation and improved stability of the crystal form.
  • this crystal form of tegoprazan free base has a disadvantage of low bioavailability due to low aqueous solubility thereof (0.02 mg/ml, pH 6.8).
  • the crystal form of tegoprazan free base has relatively excellent stability and is relatively easy to prepare as a sustained-release preparation, but has disadvantages of low bioavailability and difficulty in formulation due to low solubility.
  • amorphous tegoprazan acid addition salts have advantages of relatively high solubility and excellent bioavailability, but have disadvantages of low stability, short distribution period, and difficulty in controlling drug release rate and blood concentration.
  • the present invention provides a crystal form of tegoprazan sulfonic acid salt represented by Formula 2 and a method of preparing the same:
  • n and m are each independently 1 or 2;
  • R is hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl, but is not limited thereto.
  • the crystal form of tegoprazan sulfonic acid salt according to the present invention may be a crystal form of tegoprazan mesylate of Formula 3, a crystal form of tegoprazan esylate of Formula 4, a crystal form of tegoprazan hemiedisylate of Formula 5, or a crystal form of tegoprazan besylate of Formula 6, but is not limited thereto.
  • the present invention provides a pharmaceutical composition containing the crystal form of tegoprazan sulfonic acid salt, preferably the crystal forms of tegoprazan sulfonic acid salts represented by Formulas 3 to 6, and a method of preparing the same.
  • the crystal form of tegoprazan sulfonic acid salt according to the present invention is non-hygroscopic and has high stability and excellent solubility compared to a conventional crystal form of a tegoprazan free base, thus having a remarkable effect of simultaneously providing excellent bioavailability and high stability.
  • the tegoprazan sulfonic acid salt and a crystal form thereof according to the present invention have advantages of reproducibility and ease of mass production in terms of the preparation method.
  • FIG. 1 shows the 1 H-NMR result of the crystal form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
  • FIG. 2 shows the PXRD result of the crystal form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
  • FIG. 3 shows the 1 H-NMR result of the crystal form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
  • FIG. 4 shows the PXRD result of the crystal form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
  • FIG. 5 shows the 1 H-NMR result of the crystal form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
  • FIG. 6 shows the PXRD result of the crystal form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
  • FIG. 7 shows the 1 H-NMR result of the crystal form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
  • FIG. 8 shows the PXRD result of the crystal form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
  • FIG. 9 shows the DSC result of the crystal form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
  • FIG. 10 shows the DSC result of the crystal form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
  • FIG. 11 shows the DSC result of the crystal form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
  • FIG. 12 shows the DSC result of the crystal form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
  • FIG. 13 shows the DSC result of the amorphous form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
  • FIG. 14 shows the DSC result of the amorphous form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
  • FIG. 15 shows the DSC result of the amorphous form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
  • FIG. 16 shows the DSC result of the amorphous form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
  • the crystal form of tegoprazan sulfonic acid salt represented by Formula 2 according to the present invention has low hygroscopicity and excellent stability, and thus has an effect comparable to conventional tegoprazan free bases in terms of storage of raw materials.
  • the crystal form of tegoprazan sulfonic acid salt has an advantage of high bioavailability upon administration because of excellent solubility compared to conventional tegoprazan free bases.
  • the present invention relates to a crystal form of tegoprazan sulfonic acid salt represented by 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, but is not limited thereto.
  • the crystal form of tegoprazan sulfonic acid salt according to Formula 2 of the present invention may be a crystal form of tegoprazan mesylate of Formula 3, a crystal form of tegoprazan esylate of Formula 4, a crystal form of tegoprazan hemiedisylate of Formula 5, or a crystal form of tegoprazan besylate of Formula 6, but is not limited thereto.
  • the crystal form of tegoprazan mesylate of Formula 3 has characteristic peaks at 2 ⁇ diffraction angles of 8.8°, 9.7°, 14.5°, 15.9°, 17.5°, 19.3°, 20.6°, 21.4°, 23.4°, and 25.2° (2 ⁇ 0.2°) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG.
  • PXRD powder X-ray diffraction pattern
  • the crystal form of the tegoprazan esylate of Formula 4 has characteristic peaks at 2 ⁇ 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° (2 ⁇ 0.2°) in a powder X-ray diffraction pattern (PXRD), and preferably has an X-ray powder diffraction pattern of FIG. 4.
  • PXRD powder X-ray diffraction pattern
  • the crystal form of tegoprazan hemiedisylate salt of Formula 5 has characteristic peaks at 2 ⁇ diffraction angles of 4.1°, 8.4°, 12.5°, 15.4°, 16.7°, 17.7°, 19.9°, 23.0°, 23.4°, and 25.9° (2 ⁇ ⁇ 0.2°) in a powder X-ray diffraction pattern (PXRD), and preferably has an X-ray powder diffraction pattern of FIG.
  • crystal form of tegoprazan besylate of Formula 6 has characteristic peaks at 2 ⁇ 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° (2 ⁇ ⁇ 0.2°) in a powder X-ray diffraction pattern (PXRD), and preferably has an X-ray powder diffraction pattern of FIG. 8.
  • PXRD powder X-ray diffraction pattern
  • the present invention also relates to a pharmaceutical composition containing a crystal form of tegoprazan sulfonic acid salt of Formula 2, preferably a crystal form of tegoprazan mesylate of Formula 3, a crystal form of tegoprazan esylate of Formula 4, a crystal form of tegoprazan hemiedisylate salt of Formula 5, or a crystal form of tegoprazan besylate of Formula 6.
  • the pharmaceutical composition containing the crystal form of tegoprazan sulfonic acid salt of Formula 2, preferably Formulas 3 to 6 according to the present invention may further contain at least one pharmaceutically acceptable excipient, and such an excipient may include at least one selected from the group consisting of fillers (diluents), disintegrants, binders, lubricants (glidants), preservatives, antioxidants, buffers, chelating agents, solubilizers, and sweeteners.
  • the filler (diluent) contained in the pharmaceutical composition according to the present invention may include at least one selected from the group consisting of microcrystalline cellulose, D-mannitol, anhydrous lactose, lactose monohydrate, lactose dihydrate, lactose trihydrate, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, sorbitol, starch, sucrose, talc, xylitol, maltose maltodextrin and maltitol, but is not limited thereto.
  • the disintegrant contained in the pharmaceutical composition according to the present invention may include at least one selected from the group consisting of croscarmellose sodium, crospovidone, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, powdered cellulose, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, and pregelatinized starch, but is not limited thereto.
  • the binder contained in the pharmaceutical composition according to the present invention may include at least one selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, acacia mucilage, alginic acid, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, and sucrose, but is not limited thereto.
  • the lubricant (glidant) contained in the pharmaceutical composition according to the present invention may include at least one 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 thereto.
  • the pharmaceutical composition may further contain, as an additive, at least one selected from the group consisting of Pearlitol Flash, maltitol, sucralose, enzyme-treated stevia, and peppermint micron, but is not limited thereto.
  • the present invention is directed to a pharmaceutical formulation containing the pharmaceutical composition according to the present invention.
  • the pharmaceutical formulation may be a solid formulation such as a tablet, a pill, a powder, a granule, or a capsule, or a liquid formulation such as a suspension, a solution, an emulsion, a syrup, or the like, and preferably a solid formulation.
  • the pharmaceutical formulation may be in the form of a pellet, a granule, a capsule, or a tablet, and more preferably, the tablet is a film-coated tablet including a film coating layer or an orally disintegrating tablet.
  • the film coating layer may be formed using at least one coating agent selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, a methacrylic acid copolymer, polyethylene oxide, and xanthan gum, and accordingly, the film coating layer may include at least one film coating agent selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, a methacrylic acid copolymer, polyethylene oxide, and xanthan gum, but is not limited thereto.
  • Polyvinyl alcohol and the copolymer of polyvinyl alcohol and polyethylene that may be contained in the film coating agent may have a weight average molecular weight of about 2,500 to 1,000,000, preferably about 2,500 to 500,000, and xanthan gum used herein may have a weight average molecular weight of about 2,000,000, but is not limited thereto.
  • water-soluble film coating agents such as commercially available Opadry IITM or Opadry AMBTM (Colorcon, USA), or Collicort IRTM (BASF, Germany) may be used, but is not limited thereto.
  • the content of the water-soluble film coating agent may be 0.5 to 5 wt%, preferably 0.8 to 3 wt%, and more preferably 1 to 2 wt%, based on the total weight of the formulation, but is not limited thereto.
  • the pharmaceutical composition and pharmaceutical formulation according to the present invention may be used for the treatment of gastrointestinal diseases, and examples of gastrointestinal diseases include gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, and dysphagia.
  • gastroesophageal diseases gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux
  • the pharmaceutical composition and pharmaceutical formulation may be used for the treatment of erosive gastroesophageal reflux diseases, the treatment of non-erosive gastroesophageal reflux diseases, the treatment of gastric ulcer, combination therapy with antibiotics for eradication of Helicobacter pylori in patients with peptic ulcer and/or chronic atrophic gastritis, and maintenance therapy after treatment of erosive gastroesophageal reflux disease.
  • the present invention is directed to the use of the pharmaceutical composition or pharmaceutical formulation according to the present invention for the treatment of the gastrointestinal disease, and a method of treating a gastrointestinal disease including administering the pharmaceutical composition or pharmaceutical formulation according to the present invention to a patient in need of treatment.
  • the present invention is directed to a method of preparing a crystal form of tegoprazan sulfonic acid salt of Formula 2, preferably Formulas 3 to 6, according to the present invention.
  • the method of preparing a crystal form of tegoprazan sulfonic acid salt according to the present invention includes:
  • the organic solvent in steps i) and ii) 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 thereto.
  • the organic solvent is more preferably acetone or a mixed solution of acetone and isopropanol.
  • the method of preparing a crystal form of the tegoprazan sulfonic acid salt of the present invention may include:
  • the method may optionally include producing a secondary crystal using the seed crystal formed in step iii).
  • room temperature means a temperature range of 15 to 30°C, preferably 17 to 27°C, and more preferably 20 to 25°C.
  • the tegoprazan free base used in the preparation method of the present invention may be directly prepared using a method known in International Patent Publication No. 2016/117814, or the like or may be commercially available.
  • the organic solvent is preferably used in an amount of 10 to 30 mL with respect to 1 g of tegoprazan in the preparation method of the present invention.
  • the stirring in steps i), ii), and iii) may be performed at a temperature of 0 to 5°C or at room temperature, but is not limited thereto.
  • the crystal form of the prepared tegoprazan mesylate has the 1 H-NMR characteristics described in FIG. 1, and has characteristic peaks at 2 ⁇ diffraction angles of 8.8°, 9.7°, 14.5°, 15.9°, 17.5°, 19.3°, 20.6°, 21.4°, 23.4°, and 25.2° (2 ⁇ ⁇ 0.2°) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 2.
  • PXRD powder X-ray diffraction pattern
  • the crystal form of the prepared tegoprazan esylate has the 1H-NMR characteristics described in FIG. 3, and has characteristic peaks at 2 ⁇ diffraction angles of 8.8o, 9.7o, 14.3o, 14.8o, 16.0o, 17.2o, 19.3o, 20.4o, 21.5o, 23.2o, 24.1o and 25.2o (2 ⁇ ⁇ 0.2o) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 4.
  • PXRD powder X-ray diffraction pattern
  • the crystal form of the prepared tegoprazan hemiedisylate has the 1H-NMR characteristics described in FIG. 5, and has characteristic peaks at 2 ⁇ diffraction angles of 4.1°, 8.4°, 12.5°, 15.4°, 16.7°, 17.7°, 19.9°, 23.0°, 23.4°, and 25.9° (2 ⁇ ⁇ 0.2°) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 6.
  • PXRD powder X-ray diffraction pattern
  • the crystal form of the prepared tegoprazan besylate has the 1H-NMR characteristics described in FIG. 7, and has characteristic peaks at 2 ⁇ 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° (2 ⁇ ⁇ 0.2°) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 8.
  • PXRD powder X-ray diffraction pattern
  • the amorphous tegoprazan sulfonic acid salt exhibit purity decreases of 0.12 to 16.1%, 0.52 to 4.78%, and 2.09 to 45.87%, respectively, in a 6-month stability test under long-term, accelerated, and severe conditions, whereas all crystal forms of tegoprazan sulfonic acid salts of the present invention exhibited a purity change of 0.06% or less in a 12-month stability test under the storage conditions, which indicates that the stability of the crystal forms of tegoprazan sulfonic acid salt of the present invention was excellent.
  • Each dried sample was placed in a chamber with a relative humidity of 31%, 43%, 54%, 73%, and 86%, and the mass change rate of the sample was measured using a balance after 1 week and 2 weeks.
  • the crystal form of tegoprazan free base disclosed in International Patent Publication No. 2016-117814 was used as a control group.
  • crystal forms of tegoprazan sulfonic acid salt according to the present invention exhibit low hygroscopicity with a mass change rate of 1.0% or less in various relative humidity ranges.
  • the crystal form of tegoprazan sulfonic acid salt of the present invention is highly advantageous in processing and storing pharmaceuticals based on low hygroscopicity thereof.
  • the melting points of the crystal form of conventional tegoprazan free base (Formula 1) and the crystal forms of tegoprazan sulfonic acid salt salts of Formulas 3 to 6 according to Examples 1 to 4 were measured using an MP meter.
  • the measuring device used herein was an SRS OptiMelt MPA100 and the sample was placed in a transparent capillary tube. Measurements were performed by increasing the temperature by 5°C per minute in the temperature range from a starting temperature of 30°C to an ending temperature of 300°C.
  • the crystal form of the tegoprazan sulfonic acid salt of the present invention has a lower melting point than conventional tegoprazan free base crystal forms, and does not undergo change in properties even under general storage conditions of raw materials and thus is easy to store.
  • the X-ray powder diffraction pattern of the tegoprazan crystalline acid addition salt of the present invention was measured at a scan speed of 0.020° 2 ⁇ per minute using a D8 Advance X-ray diffraction detector from Bruker AXS and an Evaluation software system interface. The scan was performed at 2 ⁇ between 3 and 40° by exposure to an X-ray generator operating at 40 kV and 40 mA using a standard line focus copper X-ray tube (Siemens) equipped with a one-dimensional semiconductor X-ray detector using a silicon strip. The weighted average of the X-ray wavelength used in the calculation was Cu-Ka 1.541838A.
  • the crystal form of tegoprazan mesylate (FIG. 2), the crystal form of tegoprazan esylate (FIG. 4), the crystal form of tegoprazan hemiedisylate (FIG. 6), and the crystal form of tegoprazan besylate (FIG. 8) showed characteristic X-ray powder diffraction patterns different from the crystal form of conventional tegoprazan free bases, which indicates that they had completely different crystal forms.
  • the physical properties of the crystalline tegoprazan sulfonic acid salt of the present invention prepared in Examples 1 to 4 were compared with the amorphous tegoprazan sulfonic acid salt prepared in Comparative Examples 1 to 4 using differential scanning calorimetry.
  • the calorimetric analysis of the samples was performed using a differential injection calorimeter (Hitachi; Nexta DSC 600) at a scan rate of 10°C/min.
  • the amount of the sample used was 3 to 5 mg.
  • the solubility of the crystal form of tegoprazan sulfonic acid salt according to Formula 2 of the present invention was measured. 400 mg to 500 mg of each sample was added to purified water, and pH 1.2, pH 4.0, and pH 6.8 solutions, and shaken at 37°C and 200 rpm for 24 hours. After 24 hours, each sample was filtered through a 0.45 ⁇ m filter, diluted with a mixed solution of acetonitrile and water (5/5), and analyzed by high-performance liquid chromatography (HPLC) for quantification.
  • HPLC high-performance liquid chromatography
  • the crystal of tegoprazan sulfonic acid salt according to the present invention has high solubility in purified water and in all experimental ranges of pH 1.2, pH 4.0, and pH 6.8, and has significantly better solubility than the crystal form of tegoprazan free base as a control.
  • the crystal form of tegoprazan sulfonic acid salt of the present invention greatly improves the physicochemical properties of tegoprazan, thus acting very favorably on the absorption and dissolution of the drug, and ultimately being very advantageous for the commercialization of the drug.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are a novel crystal form of tegoprazan sulfonic acid salt and a method of preparing a pharmaceutical composition containing the same. More specifically, disclosed are a novel crystal form of tegoprazan sulfonic acid salt, which greatly improves raw material stability, non-hygroscopicity and solubility, and exhibits pharmacological effects comparable to conventional tegoprazan free base forms, and a method of preparing the same. The novel crystal form of tegoprazan sulfonic acid salt has excellent raw material stability, non-hygroscopicity, and solubility and is thus useful for the development of a novel tegoprazan formulation.

Description

NOVEL CRYSTAL FORM OF TEGOPRAZAN SULFONIC ACID SALT AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
The present invention relates to a novel crystal form of a tegoprazan sulfonic acid salt, a pharmaceutical composition containing the same, and a method of preparing the novel crystal form of tegoprazan sulfonic acid salt and the pharmaceutical composition containing the same, and more specifically, to a novel crystal form of a tegoprazan sulfonic acid salt which greatly improves the stability of raw materials, non-hygroscopicity and solubility, and exhibits pharmacological effects comparable to conventional tegoprazan free base forms, a pharmaceutical composition containing the same, and a method of preparing the same.
The proton pump called “H+/K+-ATPase” of the parietal cells present in the gastric mucosa causes potassium ions (K+) to flow into the cells and releases protons (H+) into the stomach, resulting in gastric acid secretion. Then, the protons (H+) released into the stomach combine with chloride ions (Cl-) to secrete gastric acid, causing gastrointestinal diseases.
Proton pump inhibitors (PPIs) which are administered orally as prodrugs are converted to active forms through absorption and metabolism, and then irreversibly inhibit the proton pump, thus having the disadvantage of being slow in onset of pharmaceutical effect.
Unlike proton pump inhibitors, tegoprazan, which is a benzimidazole derivative that has a chemical name of [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide] and a structure of Formula 1, competitively binds to potassium ions and inhibits the release of protons (H+) into the stomach, thereby inhibiting gastric acid secretion (see International Patent Publication No. 2007/072146, or the like). For this reason, tegoprazan, which is called a “potassium competitive acid blocker (P-CAB)”, is known to have a faster onset of pharmaceutical effect than PPI drugs.
Figure PCTKR2024020014-appb-img-000001
Based on this mode-of-action, tegoprazan has preventive and therapeutic effects on gastrointestinal diseases, for example, gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, and diseases caused by proton pump antagonist activity, such as drooling, airway disorders, and asthma, and K-CAB tablets or K-CAB orally disintegrating tablets, which are medicines containing tegoprazan as an active ingredient, are approved and are currently being marketed for the treatment of erosive gastroesophageal reflux diseases, the treatment of non-erosive gastroesophageal reflux diseases, the treatment of gastric ulcer, combination therapy with antibiotics for eradication of Helicobacter pylori in patients with peptic ulcer and/or chronic atrophic gastritis, and maintenance therapy after treatment of erosive gastroesophageal reflux disease.
However, tegoprazan has low stability and still a problem of requiring improved solubility.
To solve these problems, research has been conducted on salts of tegoprazan, and International Patent Publication No. 2018/056697, or the like discloses pidolate and malate as acid addition salts of tegoprazan. Although the pidolate or malate of tegoprazan has relatively excellent water solubility and precipitation stability, it has the disadvantage of being difficult to formulate due to the problem of low stability because it is in an amorphous form.
In addition, International Patent Publication No. 2007/072146 discloses pharmaceutically acceptable salts of tegoprazan including acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate, but does not disclose the physicochemical properties of the salts of tegoprazan, as well as preparation examples thereof.
Meanwhile, International Patent Publication No. 2016/117814 discloses, as a crystal form of tegoprazan, a crystal form of tegoprazan free base and a method of preparing the same. This crystal form of tegoprazan free base has a relatively low denaturation rate and electrostatic induction ability even under harsh light conditions, thus having advantages of easy formulation and improved stability of the crystal form. However, this crystal form of tegoprazan free base has a disadvantage of low bioavailability due to low aqueous solubility thereof (0.02 mg/ml, pH 6.8).
As discussed above, the crystal form of tegoprazan free base has relatively excellent stability and is relatively easy to prepare as a sustained-release preparation, but has disadvantages of low bioavailability and difficulty in formulation due to low solubility. On the other hand, amorphous tegoprazan acid addition salts have advantages of relatively high solubility and excellent bioavailability, but have disadvantages of low stability, short distribution period, and difficulty in controlling drug release rate and blood concentration.
Therefore, the demand for tegoprazan forms, i.e. raw materials, that have excellent physicochemical properties, especially excellent stability, and high solubility and thus excellent bioavailability is continuously increasing.
Under this technical background, as a result of efforts to develop a raw material of tegoprazan that has excellent stability and non-hygroscopicity, and excellent solubility while being in a crystal form, the present inventors identified that the crystal form of tegoprazan sulfonic acid salt has non-hygroscopicity and excellent stability and solubility, and completed the present invention based on this finding.
SUMMARY OF THE INVENTION
Therefore, it is one object of the present invention to provide a crystal form of tegoprazan sulfonic acid salt having excellent physical properties such as raw material stability, non-hygroscopicity, and solubility, and a method of preparing the same.
It is another object of the present invention to provide a pharmaceutical composition containing the crystal form of tegoprazan sulfonic acid salt, a method of treating a patient in need of treatment using the crystal form of tegoprazan sulfonic acid salt and the pharmaceutical composition containing the same, and a method of preparing a drug therefor.
In one aspect, the present invention provides a crystal form of tegoprazan sulfonic acid salt represented by Formula 2 and a method of preparing the same:
Figure PCTKR2024020014-appb-img-000002
wherein n and m are each independently 1 or 2; and
R is hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl, but is not limited thereto.
More preferably, the crystal form of tegoprazan sulfonic acid salt according to the present invention may be a crystal form of tegoprazan mesylate of Formula 3, a crystal form of tegoprazan esylate of Formula 4, a crystal form of tegoprazan hemiedisylate of Formula 5, or a crystal form of tegoprazan besylate of Formula 6, but is not limited thereto.
Figure PCTKR2024020014-appb-img-000003
In another aspect, the present invention provides a pharmaceutical composition containing the crystal form of tegoprazan sulfonic acid salt, preferably the crystal forms of tegoprazan sulfonic acid salts represented by Formulas 3 to 6, and a method of preparing the same.
EFFECT OF THE INVENTION
The crystal form of tegoprazan sulfonic acid salt according to the present invention is non-hygroscopic and has high stability and excellent solubility compared to a conventional crystal form of a tegoprazan free base, thus having a remarkable effect of simultaneously providing excellent bioavailability and high stability.
In addition, the tegoprazan sulfonic acid salt and a crystal form thereof according to the present invention have advantages of reproducibility and ease of mass production in terms of the preparation method.
FIG. 1 shows the 1H-NMR result of the crystal form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
FIG. 2 shows the PXRD result of the crystal form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
FIG. 3 shows the 1H-NMR result of the crystal form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
FIG. 4 shows the PXRD result of the crystal form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
FIG. 5 shows the 1H-NMR result of the crystal form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
FIG. 6 shows the PXRD result of the crystal form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
FIG. 7 shows the 1H-NMR result of the crystal form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
FIG. 8 shows the PXRD result of the crystal form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
FIG. 9 shows the DSC result of the crystal form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
FIG. 10 shows the DSC result of the crystal form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
FIG. 11 shows the DSC result of the crystal form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
FIG. 12 shows the DSC result of the crystal form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
FIG. 13 shows the DSC result of the amorphous form of tegoprazan mesylate of Formula 3 prepared in accordance with Example 1 of the present invention.
FIG. 14 shows the DSC result of the amorphous form of tegoprazan esylate of Formula 4 prepared in accordance with Example 2 of the present invention.
FIG. 15 shows the DSC result of the amorphous form of tegoprazan hemiedisylate of Formula 5 prepared in accordance with Example 3 of the present invention.
FIG. 16 shows the DSC result of the amorphous form of tegoprazan besylate of Formula 6 prepared in accordance with Example 4 of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as appreciated by those skilled in the field to which the present invention pertains. In general, the nomenclature used herein and the experimental method described below are well-known in the art and is ordinarily used.
Certain terms are defined herein for convenience in order to provide a better understanding of the present invention. Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. It will be further understood that the terms “comprise” and/or “comprising”, when used herein, specify the presence of another component, but do not preclude the presence or addition of one or more other components, unless otherwise defined herein.
The crystal form of tegoprazan sulfonic acid salt represented by Formula 2 according to the present invention has low hygroscopicity and excellent stability, and thus has an effect comparable to conventional tegoprazan free bases in terms of storage of raw materials. In addition, the crystal form of tegoprazan sulfonic acid salt has an advantage of high bioavailability upon administration because of excellent solubility compared to conventional tegoprazan free bases.
Accordingly, the present invention relates to a crystal form of tegoprazan sulfonic acid salt represented by Formula 2.
Figure PCTKR2024020014-appb-img-000004
wherein n and m are each independently 1 or 2, and R is hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl, but is not limited thereto.
More preferably, the crystal form of tegoprazan sulfonic acid salt according to Formula 2 of the present invention may be a crystal form of tegoprazan mesylate of Formula 3, a crystal form of tegoprazan esylate of Formula 4, a crystal form of tegoprazan hemiedisylate of Formula 5, or a crystal form of tegoprazan besylate of Formula 6, but is not limited thereto.
Figure PCTKR2024020014-appb-img-000005
More preferably, the crystal form of tegoprazan mesylate of Formula 3 has characteristic 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°) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 2, and the crystal form of the tegoprazan esylate of Formula 4 has characteristic 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°) in a powder X-ray diffraction pattern (PXRD), and preferably has an X-ray powder diffraction pattern of FIG. 4.
In addition, the crystal form of tegoprazan hemiedisylate salt of Formula 5 has characteristic 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 a powder X-ray diffraction pattern (PXRD), and preferably has an X-ray powder diffraction pattern of FIG. 6, and the crystal form of tegoprazan besylate of Formula 6 has characteristic 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°) in a powder X-ray diffraction pattern (PXRD), and preferably has an X-ray powder diffraction pattern of FIG. 8.
The present invention also relates to a pharmaceutical composition containing a crystal form of tegoprazan sulfonic acid salt of Formula 2, preferably a crystal form of tegoprazan mesylate of Formula 3, a crystal form of tegoprazan esylate of Formula 4, a crystal form of tegoprazan hemiedisylate salt of Formula 5, or a crystal form of tegoprazan besylate of Formula 6.
The pharmaceutical composition containing the crystal form of tegoprazan sulfonic acid salt of Formula 2, preferably Formulas 3 to 6 according to the present invention may further contain at least one pharmaceutically acceptable excipient, and such an excipient may include at least one selected from the group consisting of fillers (diluents), disintegrants, binders, lubricants (glidants), preservatives, antioxidants, buffers, chelating agents, solubilizers, and sweeteners.
As a non-limiting example, the filler (diluent) contained in the pharmaceutical composition according to the present invention may include at least one selected from the group consisting of microcrystalline cellulose, D-mannitol, anhydrous lactose, lactose monohydrate, lactose dihydrate, lactose trihydrate, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, sorbitol, starch, sucrose, talc, xylitol, maltose maltodextrin and maltitol, but is not limited thereto.
As a non-limiting example, the disintegrant contained in the pharmaceutical composition according to the present invention may include at least one selected from the group consisting of croscarmellose sodium, crospovidone, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, powdered cellulose, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, and pregelatinized starch, but is not limited thereto.
As a non-limiting example, the binder contained in the pharmaceutical composition according to the present invention may include at least one selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, acacia mucilage, alginic acid, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, and sucrose, but is not limited thereto.
As a non-limiting example, the lubricant (glidant) contained in the pharmaceutical composition according to the present invention may include at least one 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 thereto.
In addition, the pharmaceutical composition may further contain, as an additive, at least one selected from the group consisting of Pearlitol Flash, maltitol, sucralose, enzyme-treated stevia, and peppermint micron, but is not limited thereto.
In another aspect, the present invention is directed to a pharmaceutical formulation containing the pharmaceutical composition according to the present invention. The pharmaceutical formulation may be a solid formulation such as a tablet, a pill, a powder, a granule, or a capsule, or a liquid formulation such as a suspension, a solution, an emulsion, a syrup, or the like, and preferably a solid formulation. Preferably, the pharmaceutical formulation may be in the form of a pellet, a granule, a capsule, or a tablet, and more preferably, the tablet is a film-coated tablet including a film coating layer or an orally disintegrating tablet.
The film coating layer may be formed using at least one coating agent selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, a methacrylic acid copolymer, polyethylene oxide, and xanthan gum, and accordingly, the film coating layer may include at least one film coating agent selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, a methacrylic acid copolymer, polyethylene oxide, and xanthan gum, but is not limited thereto.
Polyvinyl alcohol and the copolymer of polyvinyl alcohol and polyethylene that may be contained in the film coating agent may have a weight average molecular weight of about 2,500 to 1,000,000, preferably about 2,500 to 500,000, and xanthan gum used herein may have a weight average molecular weight of about 2,000,000, but is not limited thereto.
For example, water-soluble film coating agents such as commercially available Opadry II™ or Opadry AMB™ (Colorcon, USA), or Collicort IR™ (BASF, Germany) may be used, but is not limited thereto.
The content of the water-soluble film coating agent may be 0.5 to 5 wt%, preferably 0.8 to 3 wt%, and more preferably 1 to 2 wt%, based on the total weight of the formulation, but is not limited thereto.
The pharmaceutical composition and pharmaceutical formulation according to the present invention may be used for the treatment of gastrointestinal diseases, and examples of gastrointestinal diseases include gastroesophageal diseases, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, and dysphagia. The pharmaceutical composition and pharmaceutical formulation according to the present invention may be used for the prevention and treatment of drooling, airway disorders, and asthma.
Preferably, the pharmaceutical composition and pharmaceutical formulation may be used for the treatment of erosive gastroesophageal reflux diseases, the treatment of non-erosive gastroesophageal reflux diseases, the treatment of gastric ulcer, combination therapy with antibiotics for eradication of Helicobacter pylori in patients with peptic ulcer and/or chronic atrophic gastritis, and maintenance therapy after treatment of erosive gastroesophageal reflux disease.
Accordingly, the present invention is directed to the use of the pharmaceutical composition or pharmaceutical formulation according to the present invention for the treatment of the gastrointestinal disease, and a method of treating a gastrointestinal disease including administering the pharmaceutical composition or pharmaceutical formulation according to the present invention to a patient in need of treatment.
In addition, in another aspect, the present invention is directed to a method of preparing a crystal form of tegoprazan sulfonic acid salt of Formula 2, preferably Formulas 3 to 6, according to the present invention.
Specifically, the method of preparing a crystal form of tegoprazan sulfonic acid salt according to the present invention, but is not limited thereto, includes:
i) adding a tegoprazan free base represented by Formula 1 to an organic solvent, followed by stirring the resulting solution;
ii) adding a mixture of sulfonic acid and an organic solvent to the solution, followed by stirring the resulting solution; and
iii) cooling the solution, followed by stirring the solution to induce crystal precipitation.
In the method of preparing a crystal form of tegoprazan sulfonic acid salt according to the present invention, the organic solvent in steps i) and ii) 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 thereto. The organic solvent is more preferably acetone or a mixed solution of acetone and isopropanol.
More specifically, the method of preparing a crystal form of the tegoprazan sulfonic acid salt of the present invention may include:
i) preparing a solution by adding tegoprazan free base of Formula 1 to an organic solvent, followed by stirring the solution to a suspension at 0 to 5°C or room temperature;
ii) adding a mixture of sulfonic acid and an organic solvent to the solution, followed by dissolving and stirring; and
iii) cooling the solution to a temperature of 0 to 5°C to precipitate a crystal.
After the step iii), the method may optionally include producing a secondary crystal using the seed crystal formed in step iii).
As used herein, the term “room temperature” means a temperature range of 15 to 30°C, preferably 17 to 27°C, and more preferably 20 to 25°C.
The tegoprazan free base used in the preparation method of the present invention may be directly prepared using a method known in International Patent Publication No. 2016/117814, or the like or may be commercially available. In addition, the organic solvent is preferably used in an amount of 10 to 30 mL with respect to 1 g of tegoprazan in the preparation method of the present invention.
In the preparation method of the present invention, the stirring in steps i), ii), and iii) may be performed at a temperature of 0 to 5°C or at room temperature, but is not limited thereto.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, it will be obvious to those skilled in the art that the following examples are provided only for illustration of the present invention, and should not be construed as limiting the scope of the present invention.
[Example]
Hereinafter, in the example, 1H NMR measurement was performed using Bruker UltraShieldTM 400 (400 MHz), HPLC analysis was performed using Agilent 1200 series, melting point measurement was performed using SRS OptiMelt MPA100, and PXRD measurement was performed using Bruker AXS D8 Advance X-ray diffractometer.
Example 1: Preparation of crystal form of tegoprazan mesylate
70 ml of acetone was injected into a reaction chamber and 10.0 g of tegoprazan free base was added thereto, followed by stirring at 0 to 5°C. A mixed solution of 2.43 g of methanesulfonic acid and 30 ml of acetone was slowly injected into the suspension while maintaining the temperature below 10°C. The reaction solution was stirred at 0 to 5°C and solid precipitation was confirmed after 30 minutes. 2 ml of methanol was added to the suspension, followed by stirring 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 a white crystal form of tegoprazan mesylate of Formula 3.
(1H NMR (400 MHz, DMSO-d6) δ 14.76 (brs, 1H), 7.51 - 7.34 (m, 2H), 6.88 (td, J = 9.7, 2.5 Hz, 1H), 6.75 (dd, J = 10.4, 1.7 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.2 Hz, 1H), 4.31 - 4.19 (m, 1H), 2.99 (d, J = 37.8 Hz, 6H), 2.71 (s, 3H), 2.32 (s, 3H), 2.26 (dd, J = 15.3, 2.2 Hz, 1H), 2.15 (tt, J = 15.8, 3.8 Hz, 1H)).
The crystal form of the prepared tegoprazan mesylate has the 1H-NMR characteristics described in FIG. 1, and has characteristic 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°) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 2.
Example 2: Preparation of crystal form of tegoprazan esylate
70 ml of acetone was injected into a reaction chamber and 10.0 g of tegoprazan free base was added thereto, followed by stirring at 0 to 5°C. A mixed solution of 3.98 g of 70 wt% ethanesulfonic acid and 30 ml of acetone was slowly injected into the suspension while maintaining the temperature below 10°C. The reaction solution was stirred at 0 to 5°C and 2 ml of methanol was added thereto. The resulting reaction 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 12.4 g of a white crystal form of tegoprazan esylate of Formula 4.
(1H NMR (400 MHz, DMSO-d6) δ 14.74 (brs, 1H), 7.54 - 7.28 (m, 2H), 6.88 (td, J = 9.6, 2.5 Hz, 1H), 6.75 (dd, J = 10.4, 1.7 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.0 Hz, 1H), 4.32 - 4.13 (m, 1H), 2.99 (d, J = 37.4 Hz, 6H), 2.71 (s, 3H), 2.39 (q, J = 7.4 Hz, 2H), 2.25 (dd, J = 15.3, 2.1 Hz, 1H), 2.21 - 2.10 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H)).
The crystal form of the prepared tegoprazan esylate has the 1H-NMR characteristics described in FIG. 3, and has characteristic peaks at 2θ diffraction angles of 8.8o, 9.7o, 14.3o, 14.8o, 16.0o, 17.2o, 19.3o, 20.4o, 21.5o, 23.2o, 24.1o and 25.2o (2θ ± 0.2o) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 4.
Example 3: Preparation of crystal form of tegoprazan hemiedisylate
50 ml of acetone and 50 ml of isopropanol were injected into a reaction chamber and 10.0 g of tegoprazan free base was added thereto, 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 injected into the reaction chamber. An additional 20 ml of acetone was injected into the reaction chamber and the reaction solution was dissolved in the acetone by stirring for 30 minutes. 500 mg of a crystalline salt of tegoprazan hemiedisylate was added to the solution. The reaction solution was stirred at 0 to 5°C for 1 hour, and stirred at room temperature overnight to precipitate a solid. An additional 100 ml of acetone was slowly injected into the reaction chamber to perform dilution, followed by stirring at 0 to 5°C for 1 hour. The suspension was filtered under nitrogen gas and the filtered solid was washed with 50 ml of cold acetone. The solid was dried under vacuum overnight at room temperature to obtain 10.7 g of white crystalline tegoprazan hemiedisylate.
(1H NMR (400 MHz, DMSO-d6) δ 14.74 (brs, 1H), 7.42 (d, J = 14.4 Hz, 2H), 6.88 (td, J = 9.6, 2.4 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.1 Hz, 1H), 4.24 (t, J = 11.2 Hz, 1H), 2.99 (d, J = 36.7 Hz, 6H), 2.71 (s, 3H), 2.66 (s, 2H), 2.31 - 2.21 (m, 1H), 2.21 - 2.09 (m, 1H)).
The crystal form of the prepared tegoprazan hemiedisylate has the 1H-NMR characteristics described in FIG. 5, and has characteristic 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 a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 6.
Example 4: Preparation of crystal form of tegoprazan besylate
30 ml of acetone was injected into a reaction chamber, 10.0 g of tegoprazan free base was added thereto, and the mixture was stirred at 0 to 5°C. A mixed solution of 4.00 g of benzenesulfonic acid and 20 ml of acetone was slowly injected into the reaction chamber. The reaction solution was stirred at 0 to 5°C for 1 hour to precipitate a solid. An additional 150 ml of methyl tert-butyl ether was slowly injected into the reaction chamber and the mixture was stirred at 0 to 5°C for 1 hour. The suspension was filtered under nitrogen gas and the filtered solid was washed with 50 ml of cold methyl tert-butyl ether. The solid was vacuum-dried overnight at room temperature to obtain 13.6 g of a white crystal form of tegoprazan besylate.
(1H NMR (400 MHz, DMSO-d6) δ 14.75 (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, 2.4 Hz), 6.75 (d, J = 10.4 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.1 Hz, 1H), 4.22 (dd, J = 17.6, 6.6 Hz, 1H), 2.99 (d, J = 39.0 Hz, 6H), 2.71 (s, 3H), 2.25 (dd, J = 15.3, 2.0 Hz, 1H), 2.21 - 2.10 (m, 1H)).
The crystal form of the prepared tegoprazan besylate has the 1H-NMR characteristics described in FIG. 7, and has characteristic 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°) in a powder X-ray diffraction pattern (PXRD), and preferably has the X-ray powder diffraction pattern of FIG. 8.
Comparative Example 1: Preparation of amorphous tegoprazan mesylate
20 ml of methanol was injected into a reaction chamber and 2.0 g of a tegoprazan free base was added and dissolved in the methanol. A mixed solution of 486 mg of methanesulfonic acid and 5 ml of methanol was injected into 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 dried product, 30 ml of heptane was injected 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.
(1H NMR (400 MHz, DMSO-d6) δ 14.76 (brs, 1H), 7.51 - 7.34 (m, 2H), 6.88 (td, J = 9.7, 2.5 Hz, 1H), 6.75 (dd, J = 10.4, 1.7 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.2 Hz, 1H), 4.31 - 4.19 (m, 1H), 2.99 (d, J = 37.8 Hz, 6H), 2.71 (s, 3H), 2.32 (s, 3H), 2.26 (dd, J = 15.3, 2.2 Hz, 1H), 2.15 (tt, J = 15.8, 3.8 Hz, 1H)).
Comparative Example 2: Preparation of amorphous tegoprazan esylate
20 ml of methanol was injected into a reaction chamber and 1.23 g of a tegoprazan esylate crystalline salt was added and dissolved and concentrated under reduced pressure at 40° C. The concentrate was vacuum-dried for one hour to obtain a white dried product, and 20 ml of heptane was injected 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 esylate.
(1H NMR (400 MHz, DMSO-d6) δ 14.74 (brs, 1H), 7.54 - 7.28 (m, 2H), 6.88 (td, J = 9.6, 2.5 Hz, 1H), 6.75 (dd, J = 10.4, 1.7 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.0 Hz, 1H), 4.32 - 4.13 (m, 1H), 2.99 (d, J = 37.4 Hz, 6H), 2.71 (s, 3H), 2.39 (q, J = 7.4 Hz, 2H), 2.25 (dd, J = 15.3, 2.1 Hz, 1H), 2.21 - 2.10 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H)).
Comparative Example 3: Preparation of amorphous tegoprazan hemiedisylate
20 ml of methanol was injected into a reaction chamber, and 1.20 g of a crystal salt of tegoprazan hemiedisylate was added thereto, and dissolved and concentrated under reduced pressure at 40°C. The concentrate was vacuum-dried for one hour, 20 ml of heptane was injected 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 hemiedisylate.
(1H NMR (400 MHz, DMSO-d6) δ 14.74 (brs, 1H), 7.42 (d, J = 14.4 Hz, 2H), 6.88 (td, J = 9.6, 2.4 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.1 Hz, 1H), 4.24 (t, J = 11.2 Hz, 1H), 2.99 (d, J = 36.7 Hz, 6H), 2.71 (s, 3H), 2.66 (s, 2H), 2.31 - 2.21 (m, 1H), 2.21 - 2.09 (m, 1H)).
Comparative Example 4: Preparation of amorphous tegoprazan besylate
20 ml of methanol was injected into a reaction chamber and 1.20 g of a crystal salt of tegoprazan besylate was added and dissolved and concentrated under reduced pressure at 40°C. The concentrate was vacuum-dried for 2 hours and 20 ml of heptane was injected 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 750 mg of white amorphous tegoprazan besylate.
(1H NMR (400 MHz, DMSO-d6) δ 14.75 (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, 2.4 Hz, 1H), 6.75 (d, J = 10.4 Hz, 1H), 6.07 (s, 1H), 4.41 (d, J = 11.1 Hz, 1H), 4.22 (dd, J = 17.6, 6.6 Hz, 1H), 2.99 (d, J = 39.0 Hz, 6H), 2.71 (s, 3H), 2.25 (dd, J = 15.3, 2.0 Hz, 1H), 2.21 - 2.10 (m, 1H)).
Comparative Example 5: Preparation of tegoprazan pidolate
3 g of a tegoprazan free base and L-pyroglutamic acid (1.049 g, 1.05 eq.) were completely dissolved in 30 ml of methanol at 25°C, and the solution was concentrated at 50°C under reduced pressure while stirring 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 vigorously stirring for 30 minutes. As a result, the foamy solid coagulated, making it impossible to obtain a solid.
Comparative Example 6: Preparation of tegoprazan malate
3 g of a tegoprazan free base and malic acid (1.090 g, 1.05 eq.) were completely dissolved in 30 ml of methanol at 25°C, and the solution was concentrated under reduced pressure at 50°C while stirring 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 vigorously stirring for 30 minutes. As a result, the foamy solid coagulated, making it impossible to obtain a solid.
[Experimental Example]
Experimental Example 1: Stability Evaluation
The stability of the crystal form tegoprazan sulfonic acid salt of the present invention prepared in Examples 1 to 4 was compared with that of the amorphous tegoprazan sulfonic acid salt prepared in Comparative Examples 1 to 4.
Specifically, stability tests were conducted under long-term, accelerated, and harsh conditions depending on the degree of occurrence of flexible substances, and the results were analyzed using high-performance liquid chromatography (HPLC) and are shown in Table 1.
As can be seen from Table 1, the amorphous tegoprazan sulfonic acid salt exhibit purity decreases of 0.12 to 16.1%, 0.52 to 4.78%, and 2.09 to 45.87%, respectively, in a 6-month stability test under long-term, accelerated, and severe conditions, whereas all crystal forms of tegoprazan sulfonic acid salts of the present invention exhibited a purity change of 0.06% or less in a 12-month stability test under the storage conditions, which indicates that the stability of the crystal forms of tegoprazan sulfonic acid salt of the present invention was excellent.
Experimental Example 2: Evaluation of non-hygroscopicity
Non-hygroscopicity is one very important factor for processing and storage of pharmaceuticals. In order to determine whether or not the compound is useful as a pharmaceutical raw material, a hygroscopicity test was conducted on the crystal form of tegoprazan mesylate, the crystal form of tegoprazan esylate, the crystal form of tegoprazan hemiedisylate, and the crystal form of tegoprazan besylate prepared in Examples 1 to 4.
Each dried sample was placed in a chamber with a relative humidity of 31%, 43%, 54%, 73%, and 86%, and the mass change rate of the sample was measured using a balance after 1 week and 2 weeks. The crystal form of tegoprazan free base disclosed in International Patent Publication No. 2016-117814 was used as a control group.
Figure PCTKR2024020014-appb-img-000006
Figure PCTKR2024020014-appb-img-000007
As can be seen from Table 2, all of the crystal forms of tegoprazan sulfonic acid salt according to the present invention, such as the crystal form of tegoprazan mesylate, the crystal form of tegoprazan esylate, the crystal form of tegoprazan hemiedisylate, and the crystal form of tegoprazan besylate exhibit low hygroscopicity with a mass change rate of 1.0% or less in various relative humidity ranges.
Therefore, it can be seen that the crystal form of tegoprazan sulfonic acid salt of the present invention is highly advantageous in processing and storing pharmaceuticals based on low hygroscopicity thereof.
Experimental Example 3: Melting point measurement
In order to determine whether or not the physicochemical properties of the crystal form of tegoprazan sulfonic acid salt according to the present invention were improved, the melting points of the crystal form of conventional tegoprazan free base (Formula 1) and the crystal forms of tegoprazan sulfonic acid salt salts of Formulas 3 to 6 according to Examples 1 to 4 were measured using an MP meter.
The measuring device used herein was an SRS OptiMelt MPA100 and the sample was placed in a transparent capillary tube. Measurements were performed by increasing the temperature by 5°C per minute in the temperature range from a starting temperature of 30°C to an ending temperature of 300°C.
Figure PCTKR2024020014-appb-img-000008
As can be seen from Table 3, the crystal form of the tegoprazan sulfonic acid salt of the present invention has a lower melting point than conventional tegoprazan free base crystal forms, and does not undergo change in properties even under general storage conditions of raw materials and thus is easy to store.
Experimental Example 4: Confirmation of characteristics of crystal polymorph (PXRD)
The X-ray powder diffraction pattern of the tegoprazan crystalline acid addition salt of the present invention was measured at a scan speed of 0.020° 2θ per minute using a D8 Advance X-ray diffraction detector from Bruker AXS and an Evaluation software system interface. The scan was performed at 2θ between 3 and 40° by exposure to an X-ray generator operating at 40 kV and 40 mA using a standard line focus copper X-ray tube (Siemens) equipped with a one-dimensional semiconductor X-ray detector using a silicon strip. The weighted average of the X-ray wavelength used in the calculation was Cu-Ka 1.541838A.
As a result of the measurement, the crystal form of tegoprazan mesylate (FIG. 2), the crystal form of tegoprazan esylate (FIG. 4), the crystal form of tegoprazan hemiedisylate (FIG. 6), and the crystal form of tegoprazan besylate (FIG. 8) showed characteristic X-ray powder diffraction patterns different from the crystal form of conventional tegoprazan free bases, which indicates that they had completely different crystal forms.
Experimental Example 5: Differential scanning calorimetry (DSC) measurement
The physical properties of the crystalline tegoprazan sulfonic acid salt of the present invention prepared in Examples 1 to 4 were compared with the amorphous tegoprazan sulfonic acid salt prepared in Comparative Examples 1 to 4 using differential scanning calorimetry. The calorimetric analysis of the samples was performed using a differential injection calorimeter (Hitachi; Nexta DSC 600) at a scan rate of 10°C/min. The amount of the sample used was 3 to 5 mg.
As a result of the test, the amorphous sulfonic acid salts prepared in Comparative Examples 1 to 4 did not show any particular endothermic peak (see FIGS. 13 to 16), but each of the crystalline sulfonic acid salts prepared in Examples 1 to 4 showed its own unique endothermic peak (see FIGS. 9 to 12).
Experimental Example 6: Solubility Verification
In order to evaluate the solubility of the crystal form of tegoprazan sulfonic acid salt according to Formula 2 of the present invention, the solubility of the crystal form of a conventional tegoprazan free base (Formula 1) and the crystal forms of tegoprazan sulfonic acid salt of Formulas 3 to 6 prepared in Examples 1 to 4 was measured. 400 mg to 500 mg of each sample was added to purified water, and pH 1.2, pH 4.0, and pH 6.8 solutions, and shaken at 37°C and 200 rpm for 24 hours. After 24 hours, each sample was filtered through a 0.45 μm filter, diluted with a mixed solution of acetonitrile and water (5/5), and analyzed by high-performance liquid chromatography (HPLC) for quantification.
Figure PCTKR2024020014-appb-img-000009
As can be seen from Table 4, the crystal of tegoprazan sulfonic acid salt according to the present invention has high solubility in purified water and in all experimental ranges of pH 1.2, pH 4.0, and pH 6.8, and has significantly better solubility than the crystal form of tegoprazan free base as a control.
Accordingly, it can be seen that the crystal form of tegoprazan sulfonic acid salt of the present invention greatly improves the physicochemical properties of tegoprazan, thus acting very favorably on the absorption and dissolution of the drug, and ultimately being very advantageous for the commercialization of the drug.
Although specific configurations of the present invention have been described in detail, those skilled in the art will appreciate that this detailed description is provided as preferred embodiments for illustrative purposes, and should not be construed as limiting the scope of the present invention.
Therefore, the substantial scope of the present invention is defined by the accompanying filed claims and equivalents thereto.

Claims (17)

  1. A crystal form of tegoprazan sulfonic acid salt represented by Formula 2:
    Figure PCTKR2024020014-appb-img-000010
    wherein 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 crystal form of tegoprazan sulfonic acid salt of claim 1, wherein the tegoprazan sulfonic acid salt is tegoprazan mesylate represented by Formula 3:
    Figure PCTKR2024020014-appb-img-000011
  3. The crystal form of tegoprazan sulfonic acid salt of claim 2, wherein the tegoprazan mesylate of Formula 3 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°) in a powder X-ray diffraction pattern (PXRD).
  4. The crystal form of tegoprazan sulfonic acid salt of claim 1, wherein the tegoprazan sulfonic acid salt is tegoprazan esylate represented by Formula 4:
    Figure PCTKR2024020014-appb-img-000012
  5. The crystal form of tegoprazan sulfonic acid salt of claim 4, wherein the crystal form of tegoprazan esylate of Formula 4 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°) in a powder X-ray diffraction pattern (PXRD).
  6. The crystal form of tegoprazan sulfonic acid salt of claim 1, wherein the tegoprazan sulfonic acid salt is tegoprazan hemiedisylate represented by Formula 5:
    Figure PCTKR2024020014-appb-img-000013
  7. The crystal form of tegoprazan sulfonic acid salt of claim 6, wherein the crystal form of tegoprazan hemiedisylate of Formula 5 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°) in a powder X-ray diffraction pattern (PXRD).
  8. The crystal form of tegoprazan sulfonic acid salt of claim 1, wherein the tegoprazan sulfonic acid salt is tegoprazan besylate represented by Formula 6:
    Figure PCTKR2024020014-appb-img-000014
  9. The crystal form of tegoprazan sulfonic acid salt of claim 8, wherein the crystal form of tegoprazan besylate represented by Formula 6 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°) in a powder X-ray diffraction pattern (PXRD).
  10. A pharmaceutical composition for treating a gastrointestinal disease comprising the crystal form of tegoprazan sulfonic acid salt of any one of claims 1 to 9.
  11. The pharmaceutical composition of claim 10, wherein the gastrointestinal disease is a gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, or dysphagia.
  12. The pharmaceutical composition of claim 10, further comprising at least one pharmaceutically acceptable excipient.
  13. The pharmaceutical composition of claim 12, wherein the excipient is at least one selected from the group consisting of fillers, disintegrants, binders, lubricants, preservatives, antioxidants, buffers, chelating agents, solubilizers, and sweeteners.
  14. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 10 to 13.
  15. The pharmaceutical formulation of claim 14, wherein the pharmaceutical formulation is a capsule, a pellet or a tablet.
  16. The pharmaceutical formulation of claim 15, wherein the pharmaceutical formulation is a film-coated tablet including a film coating layer or an orally disintegrating tablet.
  17. A method of preparing a crystal form of tegoprazan sulfonic acid salt represented by Formula 2, the method comprising:
    i) preparing a solution by adding a tegoprazan free base of Formula 1 to an organic solvent, followed by stirring to a suspension at 0 to 5°C or room temperature;
    ii) adding a mixture of sulfonic acid and an organic solvent to the solution, followed by dissolving and stirring; and
    iii) cooling the solution to a temperature of 0 to 5°C to precipitate a crystal.
    Figure PCTKR2024020014-appb-img-000015
    Figure PCTKR2024020014-appb-img-000016
    wherein n and m are each independently 1 or 2; and
    R is hydrogen, methyl, ethyl, propyl, methylsulfonic acid, ethylsulfonic acid, 4-methylbenzene, or phenyl.
PCT/KR2024/020014 2023-12-08 2024-12-09 Novel crystal form of tegoprazan sulfonic acid salt and pharmaceutical composition comprising the same Pending WO2025121965A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20230177835 2023-12-08
KR10-2023-0177835 2023-12-08

Publications (1)

Publication Number Publication Date
WO2025121965A1 true WO2025121965A1 (en) 2025-06-12

Family

ID=95979705

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2024/020014 Pending WO2025121965A1 (en) 2023-12-08 2024-12-09 Novel crystal form of tegoprazan sulfonic acid salt and pharmaceutical composition comprising the same

Country Status (2)

Country Link
KR (1) KR20250088407A (en)
WO (1) WO2025121965A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060103997A (en) * 2005-03-29 2006-10-09 종근당바이오 주식회사 Novel crystalline sibutramine organic acid salt and preparation method thereof
WO2009080365A1 (en) * 2007-12-21 2009-07-02 Synthon B.V. Pregabalin salts
WO2016117814A2 (en) * 2015-01-20 2016-07-28 씨제이헬스케어 주식회사 Novel crystal form of benzimidazole derivative and preparation method thereof
WO2017012771A1 (en) * 2015-07-23 2017-01-26 Ratiopharm Gmbh Crystalline filgotinib sulfonic acid addition salts
KR101829706B1 (en) * 2016-09-21 2018-02-19 씨제이헬스케어 주식회사 Acid addition salts of (S)-4-(5,7-difluorochroman-4-yloxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide
WO2024228133A1 (en) * 2023-05-02 2024-11-07 Metrochem Api Pvt Ltd Novel salts of tegoprazan and its polymorphs

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060103997A (en) * 2005-03-29 2006-10-09 종근당바이오 주식회사 Novel crystalline sibutramine organic acid salt and preparation method thereof
WO2009080365A1 (en) * 2007-12-21 2009-07-02 Synthon B.V. Pregabalin salts
WO2016117814A2 (en) * 2015-01-20 2016-07-28 씨제이헬스케어 주식회사 Novel crystal form of benzimidazole derivative and preparation method thereof
WO2017012771A1 (en) * 2015-07-23 2017-01-26 Ratiopharm Gmbh Crystalline filgotinib sulfonic acid addition salts
KR101829706B1 (en) * 2016-09-21 2018-02-19 씨제이헬스케어 주식회사 Acid addition salts of (S)-4-(5,7-difluorochroman-4-yloxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide
WO2024228133A1 (en) * 2023-05-02 2024-11-07 Metrochem Api Pvt Ltd Novel salts of tegoprazan and its polymorphs

Also Published As

Publication number Publication date
KR20250088407A (en) 2025-06-17

Similar Documents

Publication Publication Date Title
WO2018056697A1 (en) Acid addition salt of benzimidazole derivative
US12053463B2 (en) Solid forms of ((s)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
KR20080064908A (en) Carvedilol
WO2023182869A1 (en) Novel salt of glp-1 receptor agonist compound, preparation method thereof and pharmaceutical composition comprising thereof
WO2018194416A1 (en) Novel crystalline solid compound of 3-phenyl-4-propyl-1-(pyridin-2-yl)-1h-pyrazol-5-ol hydrochloride
US11820772B2 (en) Polymorphs of the hydrochloride salt of linaprazan glurate
WO2020067735A1 (en) 3-azabicyclo[3,1,1]heptane derivative and pharmaceutical composition comprising same
WO2020231146A1 (en) Novel salt of pelubiprofen, preparation method therefor and pharmaceutical composition comprising same
WO2022098057A1 (en) Method for preparing crystalline particles of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid, and pharmaceutical composition comprising same
WO2018124700A1 (en) Novel preparation containing benzimidazole derivative
WO2021137369A1 (en) Novel cocrystal of empagliflozin
WO2014003400A1 (en) Aripiprazole-organic acid cocrystal, preparation or composition containing same, and preparation method therefor
WO2025121965A1 (en) Novel crystal form of tegoprazan sulfonic acid salt and pharmaceutical composition comprising the same
WO2009030106A1 (en) 7-(4-oximino-3-amino-1-piperidyl)quinolinecarboxylic acid derivatives and their preparation methods
US20060148878A1 (en) Pseudopolymorphic forms of carvedilol
WO2017116193A1 (en) Crystalline forms of thienopyrimidine compound
WO2023113458A1 (en) Novel salt of 1-sulfonyl pyrrole derivative, preparation method thereof and pharmaceutical composition comprising thereof
WO2021125474A1 (en) Novel crystalline form of edoxaban and preparation method therefor
WO2024210689A1 (en) Salt of benzimidazole derivative
WO2021060949A1 (en) Co-crystalline efinaconazole, and method for producing same
WO2011152657A2 (en) Acetyl-l-carnitine malate, process for preparing the same, and pharmaceutical composition comprising the same
WO2023229322A1 (en) Method for preparing 6-methoxypyridin-3-yl derivatives
WO2020111524A1 (en) Salt and crystalline form of puropyrimidine compound and pharmaceutical use thereof
WO2025244393A1 (en) Pharmaceutical composition containing amorphous tegoprazan and method for preparing same
WO2017091041A1 (en) Novel salt of fimasartan

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24901151

Country of ref document: EP

Kind code of ref document: A1