KR-102964632-B1 - Cocrystal of 2-((2-Oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic Acid with Ferulic Acid and Preparation Method Thereof

Abstract

The present invention relates to a cocrystalline compound in which 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid and ferulic acid form a cocrystalline structure, and a method for manufacturing the same. The cocrystalline compound according to the present invention exhibits improved physicochemical stability against heat, moisture, and light compared to a free compound, and possesses the characteristic of maintaining a stable drug content even during long-term storage. Furthermore, when the cocrystalline compound according to the present invention is administered orally, it exhibits pharmacokinetic characteristics in which the area under the absorption curve (AUC) of the active drug in the body is significantly increased compared to a free compound, thereby improving drug delivery efficiency. In addition, since the cocrystalline compound according to the present invention can be stably manufactured with high purity using ferulic acid, which is utilized as a food additive, it can be usefully applied as an active ingredient in pharmaceutical compositions in the pharmaceutical industry.

Inventors

• 정혜경
• 서명원
• 한인규

Assignees

• 주식회사 카이저바이오

Dates

Publication Date

20260513

Application Date

20260115

Claims (6)

1. 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid; and ferulic acid It is characterized by forming a co-crystal structure, Represented by the following chemical formula 1, As a co-crystal compound, The above co-crystal compound is a co-crystal compound that exhibits at least three diffraction peaks among 2θ diffraction angles of 8.9°, 12.7°, 15.5°, 17.3°, 18.0°, 23.0°, and 32.7° when analyzed by X-ray powder diffraction (XRPD): [Chemical Formula 1] ; In the above chemical formula 1, m:n is 2:1 to 3:1.
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4. (a) a step of preparing a first mixture by dissolving 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid in an organic solvent; (b) a step of preparing a second mixture by adding ferulic acid to the first mixture and mixing so that the molar ratio of 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid to ferulic acid is 2:1 to 3:1; and (c) The solvent is evaporated and crystallized without applying heat to the second mixture to obtain 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid Step of obtaining a ferulic acid co-crystal compound A method for preparing a co-crystal compound comprising, The above organic solvent is ethyl acetate, and A method for preparing a cocrystalline compound, wherein the cocrystalline compound exhibits at least three diffraction peaks among 2θ diffraction angles of 8.9°, 12.7°, 15.5°, 17.3°, 18.0°, 23.0°, and 32.7° when analyzed by X-ray powder diffraction (XRPD).
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6. A pharmaceutical composition for the prevention or treatment of neurological diseases comprising a co-crystal compound according to claim 1 as an active ingredient, A pharmaceutical composition for the prevention or treatment of neurological diseases, wherein the neurological disease is dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, Pick's disease, and Creutzfeldt-Jakob disease.

Description

Cocrystal of 2-((2-Oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid with Ferulic Acid and Preparation Method Thereof The present invention relates to a novel co-crystallized compound of 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid and a method for preparing the same. Specifically, the invention relates to a crystalline co-crystallized compound of 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid and ferulic acid prepared by reacting 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid with ferulic acid, a method for preparing the same, and a pharmaceutical composition containing the same. 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid is a compound known as an active ingredient in pharmaceutical compositions useful for the treatment of brain diseases. For example, Korean Registered Patent Publication (B1) No. 10-1061764 discloses that the said compound can be used as an active ingredient in pharmaceutical compositions for the treatment of brain diseases. However, the said compound exhibits unstable characteristics under acidic conditions, light (UV/Vis), and heat, and there were significant limitations in its direct use as a drug due to the problem of rapid deterioration of purity caused by these environmental factors. Although Korean Registered Patent No. 10-1061764 discloses that acid addition salts containing organic or inorganic acids can be prepared from the said compound, the said compound lacks sufficient proton-bearing or electrophilic centers capable of giving and receiving protons, making it difficult to form a stable salt in the form of a conventional salt, for example, a chloride. In addition, even when attempting to manufacture inorganic salts using inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH), there was a problem in that the corresponding compounds decomposed easily, making them practically unusable. In other words, it was confirmed that preparing inorganic salts using pharmaceutically viable and stable acid addition salts or inorganic bases is practically difficult due to the structural characteristics and decomposition tendencies of the aforementioned compounds. Furthermore, studies on the recrystallization of the free form of the compounds using various organic solvents revealed that the purification effect was insufficient; in particular, it was confirmed that producing high-purity compounds is not easy when recrystallization is performed under conditions above room temperature for the purpose of improving purity, as the amount of certain impurities that are difficult to remove increases. Furthermore, since the free form of the above compound tends to gradually decrease in purity due to the influence of temperature, light, or humidity during long-term storage, this low stability not only leads to a reduction in the content of the active ingredient due to decomposition, thereby lowering its efficacy, but also carries the potential to cause unexpected side effects due to an increase in impurities; thus, it has acted as a significant limiting factor in manufacturing the compound as a pharmaceutical or storing it for a long period. Meanwhile, International Patent Publication WO 2010-072776 discloses acid addition salts of the above compounds, in particular pharmaceutically acceptable inorganic or organic acid addition salts. The document lists inorganic acids such as hydrochloric acid, hydrobromide, phosphoric acid, nitric acid, and sulfuric acid, as well as numerous organic acids including acetic acid, benzenesulfonic acid, citric acid, gentisic acid, and tartaric acid, such as 63 types of organic acids; however, this is merely a simple list of acids, and there is no specific description of how the acid addition salts exhibit improvements in physicochemical properties or stability compared to the free form of the above compounds. Furthermore, the aforementioned international patent publication only contains analytical data to identify the substances, and no description of differentiated properties compared to the free form is confirmed. In addition, the aforementioned prior art does not mention the cocrystal of 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid at all, nor has there been any attempt to simultaneously improve physicochemical stability and pharmaceutical utility through cocrystallization. Meanwhile, ferulic acid is a compound that was first extracted from plant resin and named in 1866 (H. Hlasiwetz et al., Annalen der Chemie , Vol. 138, p. 61, 1866), and is known as a natural organic acid abundant in plant cell walls. Ferulic acid has an antioxidant effect that neutralizes free radicals, and in addition, it has been reported to exhibit blood sugar-lowering and cholesterol-lowering effects. In addition, ferulic acid has been reported to have an LD 50 value of approximately 2,133 mg/kg to 2,445 mg/kg upon oral administration to rats, and as a substance utilized as a food additive, it has been confirmed to be a rel