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RU-2861466-C2 - NOVEL ENAVOGLIFLOZIN SOCRYSTALL

RU2861466C2RU 2861466 C2RU2861466 C2RU 2861466C2RU-2861466-C2

Abstract

FIELD: chemical industry. SUBSTANCE: invention relates to a socrystall of enavogliflozin/proline, which is characterised by an X-ray powder diffraction pattern with four or more diffraction peaks at 2[θ] values selected from 4.72±0.2, 6.81±0.2, 7.93±0.2, 8.59±0.2, 14.75±0.2, 15.21±0.2, 17.23±0.2, 18.80±0.2, 21.19±0.2, 24.42±0.2 and 27.29±0.2. The invention relates to a method for preparing the enavogliflozin/proline socrystall according to the invention, comprising (a) mixing enavogliflozin with ethanol in an amount of from 10 to 60 volumes per unit mass of solid enavogliflozin and adding proline to the resulting mixture; (b) stirring the resulting product of step (a) at a temperature of from 15 to 30°C for from 0.5 to 24 hours; and (c) vacuum drying the resulting product of step (b) at a temperature of from 30 to 65 °C to obtain the enavogliflozin/proline socrystall. The enavogliflozin/proline socrystall according to the invention is used for preparing a pharmaceutical composition for the treatment or prevention of diabetes. EFFECT: enavogliflozin/proline socrystall having stability and solubility. 7 cl, 7 dwg, 8 tbl, 7 ex

Inventors

  • YOON, YOUN JUNG
  • YOON, HEE KYOON
  • CHOI, JI SOO
  • JI, Hye Young
  • LIM, HYUN WOO

Dates

Publication Date
20260505
Application Date
20230927
Priority Date
20220928

Claims (9)

  1. 1. An enavogliflozin/proline co-crystal that is characterized by an X-ray powder diffraction pattern with four or more diffraction peaks at 2[θ] values selected from 4.72±0.2, 6.81±0.2, 7.93±0.2, 8.59±0.2, 14.75±0.2, 15.21±0.2, 17.23±0.2, 18.80±0.2, 21.19±0.2, 24.42±0.2, and 27.29±0.2.
  2. 2. The enavogliflozin/proline co-crystal of claim 1, wherein the X-ray powder diffraction pattern has a diffraction peak at a 2[θ] value selected from 6.81±0.2, 8.59±0.2, 14.75±0.2, 17.23±0.2, and 18.80±0.2.
  3. 3. The enavogliflozin/proline co-crystal of claim 1, which is characterized by X-ray powder diffraction patterns with peak positions corresponding to those listed in the following table:
  4. 2θ (±0.2°) d ( ) I/I o (%) 4.72 18.7 33.3 6.81 13.0 100.0 7.93 11.1 47.0 8.59 10.3 63.1 14.75 6.0 81.6 15.21 5.8 31.0 17.23 5.1 50.9 18.80 4.7 63.2 21.19 4.2 22.5 24.42 3.6 28.3 27.29 3.3 25.4
  5. 4. The enavogliflozin/proline co-crystal of claim 1, which exhibits an endothermic peak at an endothermic onset temperature of 217.71±3°C and an endothermic peak temperature of 219.42±3°C by differential scanning calorimetry (DSC).
  6. 5. The enavogliflozin/proline co-crystal of claim 1, wherein the enavogliflozin/proline co-crystal is in a form in which 1 equivalent of proline is bound to 1 equivalent of enavogliflozin.
  7. 6. A method for producing an enavogliflozin/proline co-crystal according to any one of claims 1-5, comprising:
  8. (a) mixing enavogliflozin with ethanol in an amount of 10 to 60 volumes per unit mass of solid enavogliflozin and adding proline to the resulting mixture; (b) stirring the resulting product of step (a) at a temperature of 15 to 30 °C for 0.5 to 24 hours and (c) vacuum drying the resulting product of step (b) at a temperature of 30 to 65 °C to obtain an enavogliflozin/proline co-crystal.
  9. 7. Use of the enavogliflozin/proline co-crystal according to any one of claims 1-5 for the preparation of a pharmaceutical composition for the treatment or prevention of diabetes.

Description

Field of technology to which the present invention relates The present invention relates to a co-crystal of enavogliflozin. Prior art of the present invention The selection of preferred solid forms of active ingredients, such as pharmaceutically acceptable salts, co-crystals, their polymorphs and pseudopolymorphs, has a very important impact on the development of the manufacturing process of the active pharmaceutical ingredient and on the design of the dosage form and composition of the drug product. In particular, salts and cocrystals of the active pharmaceutical ingredient and their polymorphs influence the final stage of active pharmaceutical ingredient production, i.e., the recrystallization yield, process speed, and purity during recrystallization and purification. Depending on the crystal size or shape, the crystallization process speed may vary, which impacts productivity and production costs. In addition, in pharmaceutical aspects, physicochemical properties such as hygroscopicity, stability, solubility, particle flowability and dissolution rate depend on the salt, cocrystal, their polymorph or pseudopolymorph or their polymorph, and thus become factors that determine the production method, production and storage conditions and shelf life of the drug product. However, when the bioavailability of a drug is affected by the physical properties of the active pharmaceutical ingredient, more attention is required when choosing its salt, co-crystal, polymorph or pseudo-polymorph, or their polymorph is very important from the point of view of drug development and registration. The aim of the present invention is to study a new co-crystal of enavogliflozin, to develop a co-crystal that can maximize the pharmacological activity by analyzing the physicochemical properties and thereby improve the low solubility which is a disadvantage of the existing polymorphs. Sodium glucose cotransporter 2 (SGLT-2) is a transporter that, along with sodium glucose cotransporter 1 (SGLT-1), is responsible for excess blood sugar reabsorption in the kidneys, with SGLT-2 playing a major role. Therefore, when an SGLT-2 inhibitor blocks SGLT-2, the amount of blood sugar excreted in urine increases, ultimately lowering blood sugar levels and releasing calories from blood sugar, leading to weight loss. One of the drugs developed as an SGLT-2 inhibitor that may be useful as a therapeutic agent for type 2 diabetes due to such effects is enavogliflozin, represented by the chemical formula 1 below, which is disclosed in Korean Unexamined Patent Application Publication No. 2014-0022086 (Patent Document 1). In addition, a crystalline form of enavogliflozin and a method for producing a crystalline form of enavogliflozin were disclosed in Korean Unexamined Patent Application Publication No. 2017-0142904 (Patent Document 2). However, the crystalline form of enavogliflozin disclosed in Korean Unexamined Patent Application Publication No. 2017-0142904 (Patent Document 2) has a drawback of low solubility of 0.25 mg/mL. Thus, the present inventors conducted a study on a co-crystal that can improve the solubility of enavogliflozin and confirmed that the specific form of the co-crystal also has excellent stability during preparation and is able to improve the solubility, thereby completing the present invention. Prior art documents Patent documents Patent Document 1. Publication of Korean Unexamined Patent Application No. 2014-0022086. Patent Document 2. Publication of Korean Unexamined Patent Application No. 2017-0142904. Disclosure of the present invention Technical challenge The present invention aims to provide a novel co-crystal of enavogliflozin with excellent stability and solubility, and a method for producing the same. The present invention also aims to provide a pharmaceutical composition comprising the novel co-crystal of enavogliflozin as the active ingredient. Technical solution One aspect of the present invention relates to a novel co-crystal of enavogliflozin represented by chemical formula 2 below and a method for preparing the same. The present inventors attempted to develop a co-crystal by selecting amino acids and organic acids that are highly soluble and rich in NH, N, O, and OH to overcome the low solubility of enavogliflozin. The amino acids and organic acids selected for obtaining the co-crystal include aspartic acid, acetylsalicylic acid, citric acid, nicotinic acid, nicotinamide, beta-cyclodextrin, propylene glycol, phenylalanine, lactose monohydrate, L-proline, urea, L-lysine, L-pyroglutamic acid, orotic acid monohydrate, maleic acid, malic acid, L-ascorbic acid, fumaric acid, succinic acid, malonic acid, oxalic acid trihydrate, L-tartrate, sodium chloride, L-serine, L-arginine, L-valine, L-methionine, threonine, glycine, L-alanine, L-cysteine, L-tryptophan, L-asparagine, L-isoleucine, L-glutamine, L-histidine and L-glutamic acid. The preparation of enavogliflozin co-crystals was attempted using the above-mentioned 38 type