WO2021137369A1 - Nouveau co-cristal d'empagliflozine - Google Patents

Nouveau co-cristal d'empagliflozine Download PDF

Info

Publication number
WO2021137369A1
WO2021137369A1 PCT/KR2020/008488 KR2020008488W WO2021137369A1 WO 2021137369 A1 WO2021137369 A1 WO 2021137369A1 KR 2020008488 W KR2020008488 W KR 2020008488W WO 2021137369 A1 WO2021137369 A1 WO 2021137369A1
Authority
WO
WIPO (PCT)
Prior art keywords
empagliflozin
crystal
acid
present
pyruglutamic
Prior art date
Application number
PCT/KR2020/008488
Other languages
English (en)
Korean (ko)
Inventor
안지훈
Original Assignee
유니셀랩 주식회사
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 유니셀랩 주식회사 filed Critical 유니셀랩 주식회사
Priority to JP2021515504A priority Critical patent/JP2023509242A/ja
Priority to CN202080006768.3A priority patent/CN113544127A/zh
Publication of WO2021137369A1 publication Critical patent/WO2021137369A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • 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 is to provide a new empagliflozin co-crystal with improved stability and water solubility, which are problems of empagliflozin.
  • Cocrystals are rich in functional groups capable of forming hydrogen bonds such as O, OH, N, etc., or coformers with a difference of 3 or less in pKa, which combine in a regular ratio through hydrogen bonds to form a new crystal structure.
  • functional groups capable of forming hydrogen bonds such as O, OH, N, etc., or coformers with a difference of 3 or less in pKa, which combine in a regular ratio through hydrogen bonds to form a new crystal structure.
  • these co-crystals contain two or more molecules of a compound, they can be expressed in the form of a complex.
  • the solubility and dissolution rate of the drug can be increased. This can change the absorption rate of the drug in the human body, thereby changing the bioavailability.
  • the co-molecules of the co-crystal must be water-friendly molecules that are well soluble in water. If the co-molecule is not water-friendly and has poor solubility, it does not overcome the poor solubility of the drug, but rather causes the solubility to decrease. Therefore, the selection of co-molecules is a very important requirement.
  • co-crystals include amorphous polymorphs, hydrates, solvates, and the like.
  • crystals generally prefer to precipitate metastable crystals during the crystallization process and then transition to a more stable crystal structure in a solvent-mediated and solid state to maintain thermodynamic stability, in general, phase transition (phase) in a solvent Through transformation), the molecules are rearranged to form a more stable crystal structure.
  • the crystal structure of the co-molecules of the co-crystal is changed through a phase transition phenomenon in which they are generally replaced with the solvent molecules in the solvent, or the existence of a polymorph of the co-crystal itself can be confirmed.
  • the co-crystal may undergo a phase change as a hydrate in water, which may cause a phenomenon in which the solubility of the co-crystal is changed to that of the hydrate.
  • phase transition can be inhibited or promoted (Crystal Growth & Design (2011) 11, 887-895, Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74, Drug Discovery Today ( 2008) 13, 440-446).
  • the co-crystallization method is a solvent evaporation technique, an anti-solvent method, a solvent drop grinding method, a slurry technique, a solid state grinding method, etc. (Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74).
  • Amorphous refers to a solid state in which molecular interactions exist but do not form a crystal arrangement. Therefore, it has a higher energy level than that of the crystalline form and therefore has higher solubility than the crystalline form.
  • thermodynamic stability is low, so it has a problem of very rapidly changing the phase to the crystalline form.
  • Amorphous co-crystals form an amorphous solid through new hydrogen bonds between two or more molecules, which can have the effect of suppressing the phenomenon of phase change to a crystalline form, and can overcome poor solubility through high solubility. solid state.
  • phase transition to the crystalline form can be suppressed is because the glass transition temperature of the amorphous form is higher than that of the amorphous drug itself (Advanced Drug Delivery Reviews (2016) 100, 116-125).
  • a crystallization method must be used to quickly reach a high degree of supersaturation by controlling the crystallization rate very quickly.
  • a method of inducing a very extremely rapid crystallization rate such as vacuum evaporation crystallization, supercritical crystallization, liquid nitrogen crystallization, and freeze evaporation crystallization is used.
  • Tg glass transition temperature
  • DSC temperature differential scanning calorimetry
  • SGLT-2 sodium/glucose cotransporter 2
  • SGLT-1 sodium/glucose cotransporter 1
  • SGLT-2 plays most roles. Therefore, when the SGLT-2 inhibitor inhibits the SGLT-2 transporter, the blood glucose excreted in the urine increases, eventually lowering the blood sugar and furthermore, the calories in the blood glucose are discharged, resulting in the effect of weight loss.
  • one of the drugs developed as a SGLT-2 inhibitor that can be usefully used as a treatment for type 2 diabetes is Empagliflozin, which was developed by Boehringer Ingelheim and is currently under the trade name Jardien Tablet. is sold on
  • empagliflozin As for empagliflozin, a crystallization method for preparing empagliflozin crystal form is disclosed in International Patent Publication No. WO 2006/117359, and an empagliflozin crystal form in International Patent Publication No. WO 2011/039107. .
  • empagliflozin has a disadvantage that it is not useful pharmaceutically because it is difficult to maintain a constant quality due to poor stability as a drug substance.
  • an empagliflozin co-crystal was developed using an easier and more productive crystallization method in order to overcome the poor stability of empagliflozin that does not maintain a constant quality and low solubility in water.
  • Patent Document 1 International Patent Publication No. WO 2005/092877
  • Patent Document 2 International Patent Publication No. WO 2006/117359
  • Patent Document 3 International Patent Publication No. WO 2011/039107
  • empagliflozin/fumaric acid co-crystal empagliflozin/citric acid amorphous co-crystal
  • empagliflozin/ An L-pyruglutamic acid co-crystal was developed.
  • Another object of the present invention is to provide a method for preparing the novel empagliflozin/fumaric acid, empagliflozin/citric acid, and empagliflozin/L-pyruglutamic acid co-crystals of the present invention described above.
  • a co-crystal in which one molecule of empagliflozin and one molecule of fumaric acid are combined.
  • the present invention provides an amorphous co-crystal in which one molecule of empagliflozin and one molecule of citric acid are combined.
  • a co-crystal in which one molecule of empagliflozin and one molecule of L-pyruglutamic acid are combined.
  • the present inventors have developed empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, empagliflozin using fumaric acid, citric acid, and L-pyruglutamic acid, which are amino acids or organic acids that are not basic inorganic salts.
  • a gin/L-pyruglutamic acid co-crystal was prepared.
  • the present inventors have very high water solubility to overcome the low stability and water solubility of empagliflozin, and L-proline, L-arginine, L-lysine, fumaric acid, oxalic acid, L rich in NH, N, O, OH -Pyroglutamic acid and citric acid were selected to design and manufacture co-crystals.
  • empagliflozin/fumaric acid co-crystal empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal were developed.
  • empagliflozin/fumaric acid co-crystal empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal through experimental optimization.
  • the empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal prepared in this way have higher water solubility and higher water solubility than the existing empagliflozin crystal form.
  • the solubility of the pH of the small intestine has been increased by more than 120 times, and since it can be sufficiently dissolved in 250ml of water injected during oral intake, oral absorption can be improved, and hygroscopicity and stability are also improved.
  • empagliflozin/fumaric acid co-crystal empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal of the present invention are used, empagliflozin stability and acceptance It is suitable for use as an improved new drug with improved sea charts.
  • the empagliflozin/fumaric acid co-crystal is a compound represented by the following formula 2:
  • one molecule of empagliflozin and one molecule of fumaric acid form a co-crystal in a 1:1 ratio by hydrogen bonding.
  • empagliflozin/fumaric acid co-crystal of the present invention is a novel solid form that has not been reported anywhere.
  • the empagliflozin/fumaric acid co-crystal has 2 ⁇ diffraction angles of 14.703 ⁇ 0.2, 15.747 ⁇ 0.2, 17.958 ⁇ 0.2, 18.859 ⁇ 0.2, 19.192 ⁇ in X-ray diffraction (PXRD) analysis.
  • Empagliflozin / fumaric acid co-crystal represented by the following formula 2, characterized in that it has a powder X-ray diffraction pattern having characteristic peaks at 0.2, 19.518 ⁇ 0.2, 20.367 ⁇ 0.2, 25.23 ⁇ 0.2 and 28.794 ⁇ 0.2 to provide.
  • the intensity and peak position of powder X-ray diffraction of an embodiment of the empagliflozin/fumaric acid co-crystal according to the present invention may be as shown in [Table 1] below.
  • the present invention is shown at the endothermic temperature of 145.78 °C ⁇ 3 °C when the temperature increase rate is 10 °C / min in the temperature differential scanning calorimetry (DSC) analysis using a closed fan, and appears at the endothermic temperature of 148.10 °C ⁇ 3 °C, An empagliflozin/fumaric acid co-crystal formed in a ratio of molecules of 1:1 is provided.
  • DSC temperature differential scanning calorimetry
  • 1 H-NMR spectrum in nuclear magnetic resonance spectroscopy (NMR) analysis provides an empagliflozin/fumaric acid co-crystal in which the ratio of one molecule of empagliflozin and one molecule of fumaric acid is clear to 1:1. .
  • the empagliflozin/citric acid co-crystal in the amorphous form is a compound represented by the following Chemical Formula 3:
  • one molecule of empagliflozin and one molecule of citric acid forms a co-crystal in a 1:1 ratio by hydrogen bonding. Since citric acid having such a high water solubility forms an amorphous form due to hydrogen bonding with empagliflozin, when citric acid is dissolved due to interaction with citric acid, empagliflozin is also dissolved in water, so water solubility and Small intestine pH 6.8 will increase solubility.
  • the amorphous form of empagliflozin/citric acid co-crystal of the present invention is a novel solid form that has not been reported anywhere.
  • the empagliflozin / citric acid co-crystal or composite agent in the amorphous form exhibits an amorphous 2 ⁇ diffraction angle in X-ray diffraction (PXRD) analysis, and in temperature differential scanning calorimetry (DSC) analysis It is an amorphous co-crystal or composite agent in which the ratio of molecules whose calorific curve shows an amorphous form is 1:1.
  • 1 H-NMR spectrum shows an amorphous empagliflozin/citric acid co-crystal in which the ratio of one molecule of empagliflozin and one molecule of citric acid is clear to 1:1.
  • the empagliflozin/L-pyruglutamic acid co-crystal is a compound represented by the following formula (4):
  • empagliflozin/L-pyruglutamic acid co-crystal of Formula 4 one molecule of empagliflozin and one molecule of L-pyruglutamic acid forms a co-crystal in a 1:1 ratio by hydrogen bonding.
  • L-pyruglutamic acid with such high water solubility forms a co-crystal due to hydrogen bonding with empagliflozin
  • empagliflozin is also Because it is soluble in water, the solubility in water and small intestine pH 6.8 is increased.
  • the empagliflozin/L-pyruglutamic acid co-crystal of the present invention is a novel solid form that has not been reported anywhere.
  • the empagliflozin/L-pyruglutamic acid co-crystal has 2 ⁇ diffraction angles of 14.738 ⁇ 0.2, 18.001 ⁇ 0.2, 18.892 ⁇ 0.2, 20.418 ⁇ 0.2 in X-ray diffraction (PXRD) analysis. , 22.226 ⁇ 0.2, 23.041 ⁇ 0.2, 24.878 ⁇ 0.2, 25.712 ⁇ 0.2 and 27.306 ⁇ 0.2 empagliflozin / L- represented by formula 4, characterized in that it has a powder X-ray diffraction pattern having characteristic peaks A pyruglutamic acid co-crystal is provided.
  • PXRD X-ray diffraction
  • the intensity and peak position of powder X-ray diffraction of an embodiment of the empagliflozin/L-pyruglutamic acid co-crystal according to the present invention may be as shown in [Table 2] below.
  • the present invention when the temperature increase rate is 10 °C / min in the temperature differential scanning calorimetry (DSC) analysis using a sealed fan, it appears at the endothermic temperature of 122.98 °C ⁇ 3 °C, the endothermic temperature 127.09 °C ⁇ 3 °C, An empagliflozin/L-pyruglutamic acid co-crystal formed in a ratio of molecules of 1:1 is provided.
  • DSC temperature differential scanning calorimetry
  • the present invention provides a method for producing a co-crystal of empagliflozin comprising the following steps.
  • step (a) mixing empagliflozin and an organic solvent and adding an organic acid thereto, respectively; (b) raising the temperature and refluxing the resultant of step (a); (c) cooling and stirring the resultant of step (b); (d) evaporating 1/2 of the solvent of step (c); and (e) vacuum drying the resultant of step (d) to obtain empagliflozin co-crystals.
  • the present inventors have established a method for preparing a new pharmaceutically useful co-crystal of empagliflozin in high yield without adding and removing a separate salt during the manufacturing process. .
  • This method is called solvent evaporation during co-crystallization.
  • the method of the present invention is to prepare the empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal of the present invention as described above, , descriptions of common content between them are omitted in order to avoid excessive complexity of the specification due to repeated descriptions.
  • the method of the present invention includes mixing empagliflozin and an organic solvent in a solid powder and adding an organic acid thereto, respectively.
  • empagliflozin in step (a) is added in an amount of 1-30 (w/v)% based on the volume of the organic solvent, more preferably 6-25 (w/v) v)%, and even more preferably 10-20 (w/v)%.
  • Organic solvents that produce empagliflozin co-crystals in high yield during the preparation of the empagliflozin co-crystals and have been proven to be effective solvents also for the removal of excess organic acids are preferably methanol, ethanol, isopropyl At least one selected from organic solvents consisting of alcohol, acetone, tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, chloroform, methyl ethyl ketone, ethyl acetate, methylene chloride and acetonitrile, that is, a single solvent or A mixed solvent thereof is selected, more preferably methanol, ethanol, isopropyl alcohol, or acetone, and most preferably methanol.
  • the organic acid of step (a) is added in a molar ratio of 1 to 1.5 equivalents based on empagliflozin.
  • the organic acid is preferably added in a molar ratio of 1 to 1.5 equivalents based on empagliflozin, respectively.
  • the amorphous empagliflozin novel co-crystal or combination agent obtained in this way becomes an amorphous empagliflozin/organic acid co-crystal or combination agent to which empagliflozin is bound.
  • the organic acid of step (a) is added in an amount of 1/3 to the mixed empagliflozin and organic solvent.
  • the organic acid of step (a) is added to the mixed empagliflozin and organic solvent in an amount of 1/3 at intervals of 20 minutes.
  • step (a) is heated and stirred under reflux.
  • the temperature increase time of the resultant of step (a) requires temperature control so that it takes at least 1 hour to reach the reflux temperature, and the stirring time at the reflux temperature should not exceed three hours.
  • the temperature increase in step (b) is carried out for 1 hour to 3 hours.
  • the reflux stirring of step (b) is carried out for 1 hour to 3 hours, more preferably 30 minutes to 2 hours, and even more preferably 30 minutes to 1 hour. carried out during
  • the method of the present invention includes the step of cooling and stirring the product of step (b), that is, the refluxed reaction solution.
  • the cooling of step (c) is carried out at 15-40 ° C, more preferably at a temperature of 15-30 ° C, and most preferably at 15-20 ° C. .
  • the stirring of step (c) is carried out for 1-12 hours, more preferably for 1 hour to 8 hours, and even more preferably for 3 hours to 5 hours. do.
  • the method of the present invention includes the step of stirring while evaporating 1/2 of the solvent of the result of step (c), that is, the cooled reaction solution.
  • the evaporation of step (d) is carried out at 30-60° C., more preferably at a temperature of 30-50° C., and most preferably at 30-40° C. .
  • the stirring of step (d) is carried out for 1-12 hours, more preferably for 1 hour to 8 hours, and even more preferably for 3 hours to 5 hours. do.
  • step (d-1) further comprising the step of washing the resultant of step (d) with an organic solvent after filtration under reduced pressure.
  • the organic solvent of step (d-1) is methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, chloroform, methyl ethyl
  • organic solvents consisting of ketone, ethyl acetate, methylene chloride and acetonitrile, that is, a single solvent or a mixed solvent thereof is selected, more preferably methanol, ethanol, isopropyl alcohol or acetone, most preferably It is acetone.
  • the organic solvent of step (c-1) is added in an amount of 1-30 (v/v)% based on the volume of the organic solvent of step (a), more preferably 1-10 (v/v)%, even more preferably 2-5 (v/v)%.
  • step (e) is vacuum dried and subjected to a step of obtaining an empagliflozin co-crystal.
  • the vacuum drying in step (e) is carried out at a temperature of 30-65° C. for 8 hours to 12 hours.
  • the vacuum drying is carried out at a temperature of 40-55°C, and still more preferably at a temperature of 45-50°C.
  • the amorphous empagliflozin co-crystal obtained by vacuum drying for the above temperature and time has a moisture content of 1% or less and a purity of 99.5% or more by HPLC.
  • an SGLT-2 inhibitor 1 equivalent of organic acid is added to 1 equivalent of empagliflozin, which is available as a treatment for type 2 diabetes, which controls blood sugar by inhibiting the reabsorption of blood sugar by the kidneys and excreting it into urine.
  • a bound empagliflozin co-crystal can be prepared.
  • the present invention provides empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, empagliflozin/ Provided are L-pyruglutamic acid co-crystals and a method for preparing the same.
  • empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal of the present invention have very low stability of empagliflozin
  • water solubility of empagliflozin due to the co-crystal of the present invention increased 120 times the solubility of empagliflozin and the solubility of pH 6.8 in the small intestine, and stability is also improved, so it is very useful as an empagliflozin raw material.
  • PXRD powder X-ray diffraction
  • Figure 2 shows the powder X-ray diffraction (PXRD) pattern results of the empagliflozin / citric acid co-crystal in an amorphous form prepared according to an embodiment of the present invention.
  • PXRD powder X-ray diffraction
  • PXRD powder X-ray diffraction
  • FIG 5 shows the calorimetric curve results of the temperature differential scanning calorimetry (DSC) of the empagliflozin/fumaric acid co-crystal prepared according to an embodiment of the present invention.
  • DSC temperature differential scanning calorimetry
  • FIG. 7 shows the calorimetric curve results of the temperature differential scanning calorimetry (DSC) of an amorphous empagliflozin/citric acid co-crystal prepared according to an embodiment of the present invention.
  • DSC temperature differential scanning calorimetry
  • FIG 9 shows the calorimetric curve results of the temperature differential scanning calorimetry (DSC) of the empagliflozin/L-pyruglutamic acid co-crystal prepared according to an embodiment of the present invention.
  • DSC temperature differential scanning calorimetry
  • FIG. 10 shows the calorimetric curve results of the temperature differential scanning calorimetry (DSC) of empagliflozin/L-pyruglutamic acid co-crystal, L-pyruglutamic acid, and empagliflozin crystal form prepared according to an embodiment of the present invention.
  • DSC temperature differential scanning calorimetry
  • NMR nuclear magnetic resonance spectroscopy
  • NMR nuclear magnetic resonance
  • NMR nuclear magnetic resonance
  • PXRD analysis (see FIGS. 1 to 4 ) was performed on a (D8 Advance) X-ray powder diffractometer using Cu K ⁇ radiation.
  • the instrument was tube-powered, and the amperage was set at 45 kV and 40 mA.
  • the divergence and scattering slits were set at 1°, and the light receiving slits were set at 0.2 mm.
  • Continuous ⁇ -2 ⁇ scans at 3°/min (0.4 sec/0.02° intervals) from 5 to 35° 2 ⁇ were used.
  • DSC Q20 obtained from TA
  • DSC measurements were performed in a closed pan at a scan rate of 10° C./min from 20° C. to 300° C. under nitrogen purge.
  • empagliflozin Since empagliflozin is poorly soluble with a water solubility of 0.111 mg/ml, it is combined with fumaric acid, citric acid, and L-pyruglutamic acid with high water solubility to prepare a new co-crystal to improve the aqueous solubility of empagliflozin and the gastrointestinal tract. It was intended to improve the pH solubility.
  • Table 3 The results are summarized in Table 3 below.
  • the aqueous solubility of empagliflozin/fumaric acid co-crystal of the present invention and solubility at pH 6.8 in the small intestine increased about 18 times compared to the known empagliflozin crystal form, and the amorphous empa
  • the aqueous solubility of glyflozin/citric acid co-crystal and the solubility in small intestine pH 6.8 were increased by more than 120 times, and the aqueous solubility of empagliflozin/L-pyruglutamic acid co-crystal and the solubility in small intestine pH 6.8 were about A 24-fold increase was confirmed.
  • the empagliflozin co-crystal of the present invention can increase water solubility by about 120 times compared to the known empagliflozin crystal form.
  • the empagliflozin co-crystal of the present invention is a novel crystal form that can overcome the low water solubility, which is a problem of the empagliflozin crystal form, and it was predicted that the drug efficacy of empagliflozin could be maximized. .
  • the stability test of the drug determines the significant change based on the established test method after setting the appropriate specification and sets the expiration date, so that the appropriate stability of the drug is secured. is one of the most important factors in the commercialization of drugs.
  • the aqueous solubility of the empagliflozin co-crystal of the present invention and the known empagliflozin crystal form was comparatively evaluated at a concentration of 1 mg/mL.
  • the empagliflozin crystalline form was not dissolved and existed in a suspension state, whereas the empagliflozin co-crystals of the present invention were all dissolved and the water solubility increased. Therefore, the co-crystals of the present invention have improved water solubility, thereby proving their value as a new drug substance that can overcome the poor solubility of empagliflozin [Fig. 15].
  • the empagliflozin co-crystal of the present invention is expected to have potential as a new drug substance that overcomes the problems of low stability and water solubility of empagliflozin.

Landscapes

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

Abstract

L'objectif de la présente invention est de résoudre des problèmes se rapportant à l'empagliflozine, notamment une faible stabilité et une faible hydrosolubilité. La présente invention porte sur le développement d'un co-cristal d'empagliflozine ayant au moins 120 fois plus de stabilité et d'hydrosolubilité. Le co-cristal d'empagliflozine selon la présente invention est sous une nouvelle forme solide qui surmonte la stabilité et l'hydrosolubilité des formes cristallines connues d'empagliflozine, et est très utile en tant qu'ingrédient pharmaceutique actif optimal qui peut être utilisé au maximum en tant que médicament.
PCT/KR2020/008488 2019-12-30 2020-06-29 Nouveau co-cristal d'empagliflozine WO2021137369A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2021515504A JP2023509242A (ja) 2019-12-30 2020-06-29 新規なエンパグリフロジンの共結晶
CN202080006768.3A CN113544127A (zh) 2019-12-30 2020-06-29 新的恩格列净的共结晶体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2019-0178752 2019-12-30
KR1020190178752A KR102111248B1 (ko) 2019-12-30 2019-12-30 새로운 엠파글리플로진의 공결정

Publications (1)

Publication Number Publication Date
WO2021137369A1 true WO2021137369A1 (fr) 2021-07-08

Family

ID=70736930

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/008488 WO2021137369A1 (fr) 2019-12-30 2020-06-29 Nouveau co-cristal d'empagliflozine

Country Status (4)

Country Link
JP (1) JP2023509242A (fr)
KR (1) KR102111248B1 (fr)
CN (1) CN113544127A (fr)
WO (1) WO2021137369A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102111248B1 (ko) * 2019-12-30 2020-05-14 유니셀랩 주식회사 새로운 엠파글리플로진의 공결정
WO2022065895A1 (fr) * 2020-09-24 2022-03-31 동아에스티 주식회사 Nouveau sel d'un dérivé d'empagliflozine, en tant qu'inhibiteur de sglt-2, et hydrate de sel
KR20220080880A (ko) * 2020-12-08 2022-06-15 주식회사 종근당 엠파글리플로진 공결정을 함유하는 약제학적 조성물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105524033A (zh) * 2014-09-28 2016-04-27 上海阳帆医药科技有限公司 达格列净的富马酸共晶体、其制备方法及药物组合物
US20170158659A1 (en) * 2014-06-23 2017-06-08 Sun Pharmaceutical Industries Limited Co-crystal of dapagliflozin with citric acid
KR101811997B1 (ko) * 2009-09-30 2017-12-26 베링거 인겔하임 인터내셔날 게엠베하 １­클로로­４­（베타­ｄ­글루코피라노스­１­일）­２­（４­（（ｓ）­테트라하이드로푸란­３­일옥시）벤질）벤젠의 결정형의 제조방법
US20180362514A1 (en) * 2015-09-15 2018-12-20 Laurus Labs Ltd. Co-crystals of sglt2 inhibitors, process for their preparation and pharmaceutical compositions thereof
KR102111248B1 (ko) * 2019-12-30 2020-05-14 유니셀랩 주식회사 새로운 엠파글리플로진의 공결정

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1730131B1 (fr) 2004-03-16 2012-05-09 Boehringer Ingelheim International GmbH Derives du benzol substitues par un glucopyranosyle,, medicaments renfermant ces composes, leur utilisation et leur procede de production
UA91546C2 (uk) 2005-05-03 2010-08-10 Бьорінгер Інгельхайм Інтернаціональ Гмбх КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101811997B1 (ko) * 2009-09-30 2017-12-26 베링거 인겔하임 인터내셔날 게엠베하 １­클로로­４­（베타­ｄ­글루코피라노스­１­일）­２­（４­（（ｓ）­테트라하이드로푸란­３­일옥시）벤질）벤젠의 결정형의 제조방법
US20170158659A1 (en) * 2014-06-23 2017-06-08 Sun Pharmaceutical Industries Limited Co-crystal of dapagliflozin with citric acid
CN105524033A (zh) * 2014-09-28 2016-04-27 上海阳帆医药科技有限公司 达格列净的富马酸共晶体、其制备方法及药物组合物
US20180362514A1 (en) * 2015-09-15 2018-12-20 Laurus Labs Ltd. Co-crystals of sglt2 inhibitors, process for their preparation and pharmaceutical compositions thereof
KR102111248B1 (ko) * 2019-12-30 2020-05-14 유니셀랩 주식회사 새로운 엠파글리플로진의 공결정

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MASCITTI VINCENT, THUMA BENJAMIN A., SMITH AARON C., ROBINSON RALPH P., BRANDT THOMAS, KALGUTKAR AMIT S., MAURER TRISTAN S., SAMAS: "On the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozin", MEDCHEMCOMM, ROYAL SOCIETY OF CHEMISTRY, UNITED KINGDOM, vol. 4, no. 1, 1 January 2013 (2013-01-01), United Kingdom, pages 101 - 111, XP055826455, ISSN: 2040-2503, DOI: 10.1039/C2MD20163A *

Also Published As

Publication number Publication date
JP2023509242A (ja) 2023-03-08
KR102111248B1 (ko) 2020-05-14
CN113544127A (zh) 2021-10-22

Similar Documents

Publication Publication Date Title
WO2021137369A1 (fr) Nouveau co-cristal d'empagliflozine
KR20030017569A (ko) 카르베딜올
KR100629825B1 (ko) ＥｔＯ2Ｃ-ＣＨ2-(Ｒ)Ｃｇｌ-Ａｚｅ-Ｐａｂ-ＯＨ의 결정질형태
WO2012138147A2 (fr) Forme cristalline de l'acide 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylique et son procédé de préparation
WO2018056697A1 (fr) Sel d'addition d'acide de dérivé de benzimidazole
US5354760A (en) Crystalline Tiagabine monohydrate, its preparation and use
WO2021157861A1 (fr) Nouveau co-cristal de calcium de sacubitril/valsartan et forme co-amorphe
WO2018194416A1 (fr) Nouveau composé solide cristallin de chlorhydrate de 3-phényl-4-propyl-1-(pyridin-2-yl)-1h-pyrazol-5-ol
WO2014058268A1 (fr) Cristal monohydrate de sel de potassium de fimasartan, son procédé de préparation, et composition pharmaceutique le comprenant
JP2002528436A (ja) アムロジピン合成用中間体、その調製方法および使用方法
WO2021125474A1 (fr) Nouvelle forme cristalline d'édoxaban et procédé de préparation associé
WO2010110622A9 (fr) Nouvelles formes cristallisées de l'adéfovir dipivoxil et leurs procédés de préparation
WO2014003400A1 (fr) Cocristal d'aripiprazole-acide organique, préparation ou composition le contenant et son procédé de préparation
JP2008174551A (ja) ラベプラゾールナトリウムの結晶形態
RU2228931C2 (ru) Кристаллические формы 3-(2,4-дихлорбензил)-2-метил-n-(пентилсульфонил)-3h- бензимидазол-5-карбоксамида
KR102111247B1 (ko) 다파글리플로진 무정형 형태의 공결정 또는 복합제
EP1309554A1 (fr) Derive d'amide d'amlodipine
EP1309557A1 (fr) Amlodipine hemimaleate
WO2023080741A1 (fr) Nouveau sel d'un dérivé d'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant
US7521472B2 (en) Crystal of two-ring heterocyclic sulfonamide compound
WO2018038297A1 (fr) Nouveau sel de (r)- (1-méthylpyrrolidin-3-yl) méthyl (3'-chloro -4'-fluoro- [1,1'-biphényl]-2-yl) carbamate et forme cristalline de celui-ci
KR102150825B1 (ko) 새로운 sglt-2 억제제의 신규한 공결정
WO2023182869A1 (fr) Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant
KR102207319B1 (ko) 새로운 엠파글리플로진의 공결정
FI71736B (fi) Foerfarande foer framstaellning av terapeutiskt anvaendbara erolinderivat och deras syraadditionssalter

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2021515504

Country of ref document: JP

Kind code of ref document: A

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

Ref document number: 20909853

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 13/12/2022)

122 Ep: pct application non-entry in european phase

Ref document number: 20909853

Country of ref document: EP

Kind code of ref document: A1