WO2021137369A1 - Novel cocrystal of empagliflozin - Google Patents

Novel cocrystal of empagliflozin Download PDF

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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
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empagliflozin
crystal
acid
present
pyruglutamic
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PCT/KR2020/008488
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French (fr)
Korean (ko)
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안지훈
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유니셀랩 주식회사
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Priority to JP2021515504A priority Critical patent/JP2023509242A/en
Priority to CN202080006768.3A priority patent/CN113544127A/en
Publication of WO2021137369A1 publication Critical patent/WO2021137369A1/en

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    • 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.

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Abstract

As a result of efforts to improve the problems of empagliflozin, that is, low stability and water solubility, an empagliflozin cocrystal having at least 120-fold increase in stability and water solubility was developed. The empagliflozin cocrystal according to the present invention is in a novel solid form that overcomes the stability and water solubility of known crystalline forms of empagliflozin, and is very useful as an optimal active pharmaceutical ingredient that can be maximally utilized as a drug.

Description

새로운 엠파글리플로진의 공결정A new co-crystal of empagliflozin
본 발명은 엠파글리플로진의 문제점인 안정성 및 수용해도가 개선된 새로운 엠파글리플로진 공결정을 제공하는 것이다.The present invention is to provide a new empagliflozin co-crystal with improved stability and water solubility, which are problems of empagliflozin.
공결정(cocrystals)은 O,OH,N등과 같은 수소결합을 이룰 수 있는 작용기가 풍부하거나 pKa 차이가 3이하 차이가 나는 공동분자(coformer)와 수소결합을 통해 규칙적 비율로 결합하여 새로운 결정구조를 갖는 결정성 고체를 의미한다. 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. means a crystalline solid with
이런 공결정들은 2분자 이상의 화합물을 포함하기 때문에, 복합체 형태로 표현 될 수 있다. Since these co-crystals contain two or more molecules of a compound, they can be expressed in the form of a complex.
이런 공결정의 형성은 2분자 이상의 새로운 수소결합을 통해 결정구조를 이루기 때문에, 약물의 용해도 및 용해속도를 증가시킬 수 있다. 이로 인해 인체 내의 약물의 흡수율을 변화시켜 생체이용률을 변화시킬 수 있다. Since the formation of such a co-crystal forms a crystal structure through new hydrogen bonds of two or more molecules, 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.
난용성을 극복하기 위한 공결정의 공동분자 선정은 우선 물에 잘 용해되는 물과 친화적인 분자들이어야 한다. 만약 물과 친화적이지 않고 용해도가 좋지 않은 그런 공동분자의 선정은 약물의 난용성을 극복하지 못하고 오히려 용해도가 낮아지는 현상을 야기시킨다. 때문에 공동분자의 선정은 매우 중요한 필요조건이 된다. In order to overcome poor solubility, 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.
그리고 공결정들은 무정형 결정다형, 수화물, 용매화물등을 포함한다.And co-crystals include amorphous polymorphs, hydrates, solvates, and the like.
결정(crystals)은 대체적으로 결정화 과정에서 준안정한 결정을 우선적으로 석출 시킨 후 용매 매개 및 고체 상태에서 보다 안정한 결정구조로 전이하여 열역학적 안정성을 유지하려는 특성을 가지고 있기 때문에, 대체적으로 용매 안에서 상전이(phase transformation)를 통해서 분자들을 재배열하여 보다 안정한 결정구조를 이룬다. Since 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.
이로 인해 결정다형이 생성 되며, 이를 ostwald의 rule of stage라 한다. This creates polymorphism, which is called the rule of stage of ostwald.
그러므로 준안정한 결정과 안정한 결정의 물리화학적 특성이 변화 되는 것이다. 따라서 약물로서 가장 중요한 결정의 열역학적 에너지를 나타내는 용해도의 변화를 야기시키는 것이다. Therefore, the physicochemical properties of metastable and stable crystals are changed. Therefore, it causes a change in solubility, which represents the thermodynamic energy of the most important crystal as a drug.
그리고 공결정의 공동분자들은 대체적으로 용매 안에서 용매 분자들과 대체되는 상전이 현상을 통해 결정구조가 변화 되거나 공결정 자체의 결정다형의 존재를 확인 할 수 있다. In addition, 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.
그러므로 물안에서 공결정은 수화물로서 상전이 될 수 있으며, 이로 인해 공결정의 용해도가 수화물의 용해도로 변화되는 현상을 야기 시킬 수 있다. Therefore, 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.
난용성 수화물 결정형에서 공결정을 제조하여도 용해도가 개선되지 않는 이유가 바로 공결정이 수화물로 상전이 되었기 때문이다. The reason that the solubility is not improved even when the co-crystal is prepared from the poorly soluble hydrate crystalline form is because the co-crystal is phase-changed to the hydrate.
그래서 공동분자의 선정이 매우 중요하다. 어떤 공동분자를 사용하느냐에 따라 상전이를 억제하거나 촉진 시킬수 있다(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).Therefore, the selection of co-molecules is very important. Depending on which co-molecule is used, the 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).
공결정의 형성은 공결정화(cocrystallization)을 통해 이루어진다.The formation of co-crystals is achieved through cocrystallization.
공결정화 방법은 용매증발법(solvent evaporation technique), 반용매법(anti-solvent method), 용매 첨가 분쇄법(solvent drop grinding), 슬러리법(slurry technique), 고체상태 분쇄법(solid state grinfing) 등이 있다(Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74).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).
무정형(amorphous)은 분자의 상호작용은 존재하지만 결정배열을 이루지 못하는 고체 상태를 의미한다. 때문에 결정형 보다 높은 에너지 준위를 갖고 있어 결정형 보다 용해도가 높다. 그러나 높은 에너지 준위로 인해 열역학적 안정성이 낮아 결정형으로 매우 빠르게 상전이 되는 문제점을 갖고 있다. 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. However, due to the high energy level, thermodynamic stability is low, so it has a problem of very rapidly changing the phase to the crystalline form.
무정형형태의 공결정(co-amorphous)은 두 분자 이상의 분자간의 새로운 수소결합을 통해 무정형 고체를 이루어 결정형으로 상전이 되는 현상을 억제 하는 효과를 보일 수 있으며, 높은 용해도를 통해 난용성을 극복 할 수 있는 고체 상태이다. Amorphous co-crystals (co-amorphous) 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.
이처럼 결정형으로 상전이 되는 현상을 억제 할 수 있는 이유는 무정형 형태의 유리전이 온도가 약물자체의 무정형보다 높기 때문이다(Advanced Drug Delivery Reviews (2016) 100, 116-125). The reason that the 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).
그리고 무정형형태의 공결정의 형성은 결정화속도를 매우 빠르게 제어하여 빠른 높은 과포화도를 빠르게 도달 시키는 결정화 방법을 사용하여야 한다. 대표적으로 감압증발 결정화, 초임계 결정화, 액체질소 결정화, 동결 증발 결정화 등의 매우 극단적으로 결정화속도를 빠르게 유도시키는 방법을 사용한다. And in the formation of amorphous co-crystals, a crystallization method must be used to quickly reach a high degree of supersaturation by controlling the crystallization rate very quickly. Typically, 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.
하지만 공결정의 형성에서 약물분자와 공동분자와의 상호작용에 의한 수소결합은 매우 다양하기 때문에 이런 극단적인 결정화 방법을 사용하더라도 무정형의 설계 및 제어를 하기는 매우 어렵다(From Molecules to Crystallizers An Introduction to Crystallization 2000; pp. 2-14).However, in the formation of co-crystals, hydrogen bonding due to the interaction between drug molecules and co-molecules is very diverse, so even using this extreme crystallization method, it is very difficult to design and control the amorphous form (From Molecules to Crystallizers An Introduction to Crystallization 2000; pp. 2-14).
또한 무정형 형태의 공결정에서 안정성에 대한 향상을 확인하기 위해서는 온도시차주사 열량(DSC)분석을 통해 유리전이온도(Tg)가 기존 약물의 무정형보다 높은 온도에서 나타나는지 확인하는 것이 필요하다. 그 이유는 무정형 형태가 존재할 수 있는 온도를 나타내는 것이 유리전이온도이기 때문이다(Advanced Drug Delivery Reviews 100 (2016) 116 -125).In addition, in order to confirm the improvement in stability in the co-crystal of the amorphous form, it is necessary to check whether the glass transition temperature (Tg) appears at a higher temperature than that of the amorphous drug of the existing drug through temperature differential scanning calorimetry (DSC) analysis. The reason is that the glass transition temperature indicates the temperature at which an amorphous form can exist (Advanced Drug Delivery Reviews 100 (2016) 116 -125).
SGLT-2(sodium/glucose cotransporter 2)는 SGLT-1(sodium/glucose cotransporter 1)과 함께 신장에서의 과도한 혈당 재흡수를 담당하고 있는 수송체이며, SGLT-2가 대부분의 역할을 담당하고 있다. 따라서, SGLT-2 저해제가 SGLT-2 수송제를 억제시키면 소변으로 배출되는 혈당이 늘어나게 되며, 결국 혈당이 낮아지고 더 나아가 혈당이 갖고 있는 칼로리가 배출되어 체중감소의 효과가 발생된다. SGLT-2 (sodium/glucose cotransporter 2) is a transporter responsible for excessive glucose reabsorption in the kidneys together with SGLT-1 (sodium/glucose cotransporter 1), and 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.
이와 같은 효과로 제2형 당뇨병 치료제로서 유용하게 사용될 수 있는 SGLT-2 억제제로 개발된 약물 중 하나가 엠파글리플로진(Empagliflozin)이며, 베링거인겔하임에서 개발하여 현재 자디앙정이라는 상품명으로 전세계에 판매되고 있다.With this effect, 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
엠파글리플로진은 하기 구조식(화학식 1)로 표시되며 국제공개특허공보 WO 2005/092877호에서 개시되었다.Empagliflozin is represented by the following structural formula (Formula 1) and was disclosed in International Patent Publication No. WO 2005/092877.
[화학식 1][Formula 1]
Figure PCTKR2020008488-appb-I000001
Figure PCTKR2020008488-appb-I000001
엠파글리플로진은 국제공개특허공보 WO 2006/117359호에 엠파글리플로진 결정형과, 국제공개특허공보 WO 2011/039107호에 엠파글리플로진 결정형을 제조하기 위한 결정화 방법이 개시되어 있다.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. .
그러나 국제공개특허공보 WO 2006/117359호에 개시된 엠파글리플로진 결정형은 수용해도가 0.11mg/mL 밖에 되지 않으며, 안정성 또한 저조하다는 사실이 보고되어 있다.However, it has been reported that the empagliflozin crystalline form disclosed in International Patent Application Publication No. WO 2006/117359 has only 0.11 mg/mL of water solubility and poor stability.
또한 엠파글리플로진은 원료의약품으로서 저조한 안정성 때문에 일정한 품질을 유지하기가 어려워 제제학적으로 유용하지 못한 단점이 있다.In addition, 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.
국제공개특허공보 WO 2011/039107호에는 엠파글리플로진 결정형에 대한 제조방법이 개시되어 있는데, 원심분리 및 냉각 램프를 사용하는 결정화방법에 대한 복잡성이 문제되고 있다.International Patent Publication No. WO 2011/039107 discloses a manufacturing method for empagliflozin crystal form, but the complexity of the crystallization method using centrifugation and cooling lamps is a problem.
따라서 본 발명에서는 엠파글리플로진의 낮은 수용해도 및 일정한 품질을 유지 시키지 못하는 좋지 않은 안정성을 극복하기 위해 보다 쉽고 생산성이 용이한 결정화 방법을 이용하여, 엠파글리플로진 공결정을 개발하였다.Therefore, in the present invention, 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.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Numerous papers and patent documents are referenced throughout this specification and their citations are indicated. The disclosure contents of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly describe the level of the technical field to which the present invention pertains and the content of the present invention.
[선행기술문헌][Prior art literature]
[특허문헌][Patent Literature]
(특허문헌 1) 국제공개특허공보 WO 2005/092877호(Patent Document 1) International Patent Publication No. WO 2005/092877
(특허문헌 2) 국제공개특허공보 WO 2006/117359호(Patent Document 2) International Patent Publication No. WO 2006/117359
(특허문헌 3) 국제공개특허공보 WO 2011/039107호(Patent Document 3) International Patent Publication No. WO 2011/039107
엠파글리플로진의 문제점인 낮은 수용해도 및 안정성을 개선하고자 이에 노력한 결과 본 발명자들은 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정을 개발하였다.As a result of efforts to improve the low water solubility and stability, which are the problems of empagliflozin, the present inventors have developed empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, empagliflozin/ An L-pyruglutamic acid co-crystal was developed.
따라서 본 발명의 목적은 신규한 엠파글리플로진/푸마르산, 엠파글리플로진/시트르산, 엠파글리플로진/L-피루글루탐산 공결정을 제공하는데 있다.Accordingly, it is an object of the present invention to provide novel empagliflozin/fumaric acid, empagliflozin/citric acid, and empagliflozin/L-pyruglutamic acid co-crystals.
본 발명의 다른 목적은 상술한 본 발명의 신규한 엠파글리플로진/푸마르산, 엠파글리플로진/시트르산, 엠파글리플로진/L-피루글루탐산 공결정의 제조방법을 제공하는데 있다.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.
본 발명의 다른 목적 및 이점은 하기의 발명의 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent from the following description of the invention, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 한 분자의 엠파글리플로진과 한 분자의 푸마르산이 결합 된 공결정을 제공한다.According to one aspect of the present invention, there is provided a co-crystal in which one molecule of empagliflozin and one molecule of fumaric acid are combined.
본 발명의 일 양태에 따르면, 본 발명은 한 분자의 엠파글리플로진과 한 분자의 시트르산이 결합 된 무정형형태의 공결정을 제공한다.According to one aspect of the present invention, the present invention provides an amorphous co-crystal in which one molecule of empagliflozin and one molecule of citric acid are combined.
본 발명의 일 양태에 따르면, 본 발명은 한 분자의 엠파글리플로진과 한 분자의 L-피루글루탐산이 결합 된 공결정을 제공한다.According to one aspect of the present invention, there is provided a co-crystal in which one molecule of empagliflozin and one molecule of L-pyruglutamic acid are combined.
본 발명자들은 염기성 무기염류가 아닌 아미노산 또는 유기산인 푸마르산, 시트르산, L-피루글루탐산을 사용하여 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정을 제조하였다.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.
따라서 본 발명자들은 엠파글리플로진의 낮은 안정성 그리고 수용해도를 극복하고자 수용해도가 매우 높으며, NH, N, O, OH가 풍부한 L-프롤린, L-아르기닌, L-라이신, 푸마릭산, 옥살산, L-피로글루탐산, 시트르산을 선정하여 공결정 설계 및 제조를 시도하였다.Therefore, 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.
그 결과 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정을 개발하였다. As a result, empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal were developed.
따라서 실험적 최적화를 통해 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정을 재현성 있게 제조하는 방법을 확립하였으며, 이렇게 제조한 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정은 기존 엠파글리플로진 결정형 보다 수용해도 및 소장 pH의 용해도가 약 120배 이상 증가되었으며, 경구제 섭취 시 투입 되는 물의 량 250ml에서 충분히 용해 될 수 있기 때문에, 경구 흡수도를 개선시킬 수 있으며, 흡습성 및 안정성 또한 향상되었다.Therefore, we established a method for reproducibly manufacturing 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.
따라서 본 발명의 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정을 사용하면 엠파글리플로진의 안정성 및 수용해도를 개선 시킨 개량신약으로서의 활용이 적절하다.Therefore, when 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.
본 발명의 일 구현예에 따르면, 상기 엠파글리플로진/푸마르산 공결정은 다음 화학식 2로 표시되는 화합물이다:According to one embodiment of the present invention, the empagliflozin/fumaric acid co-crystal is a compound represented by the following formula 2:
[화학식 2][Formula 2]
Figure PCTKR2020008488-appb-I000002
Figure PCTKR2020008488-appb-I000002
화학식 2의 엠파글리플로진/푸마르산 공결정은 수소결합에 의해 한 분자의 엠파글리플로진과 한 분자의 푸마르산이 1:1 비율로 공결정을 형성한다. In the empagliflozin/fumaric acid co-crystal of Formula 2, one molecule of empagliflozin and one molecule of fumaric acid form a co-crystal in a 1:1 ratio by hydrogen bonding.
이와 같은 높은 수용해도를 갖는 푸마르산이 엠파글리플로진과 수소결합으로 인해 공결정을 형성함으로써, 푸마르산과의 상호작용으로 인해 푸마르산이 용해될 때 엠파글리플로진도 함께 물에서 용해되기 때문에, 수용해도 및 소장 pH 6.8 용해도가 증가되는 것이다.Since fumaric acid having such a high water solubility forms co-crystals due to hydrogen bonding with empagliflozin, empagliflozin is also dissolved in water when fumaric acid is dissolved due to interaction with fumaric acid. and small intestine pH 6.8 solubility is increased.
본 발명의 엠파글리플로진/푸마르산 공결정은 어디에도 보고된 바 없는 신규한 고체형태이다.The empagliflozin/fumaric acid co-crystal of the present invention is a novel solid form that has not been reported anywhere.
본 발명의 구현예에 따르면, 상기의 엠파글리플로진/푸마르산 공결정은 X선 회절(PXRD)분석에서 2θ 회절각이 14.703±0.2, 15.747± 0.2, 17.958± 0.2, 18.859± 0.2, 19.192± 0.2, 19.518± 0.2, 20.367± 0.2, 25.23± 0.2 및 28.794± 0.2에서 특징적인 피크를 갖는 분말 X선 회절 패턴을 갖는 것을 특징으로 하는 하기 화학식 2로 표기되는 엠파글리플로진/푸마르산 공결정을 제공한다.According to an embodiment of the present invention, the empagliflozin/fumaric acid co-crystal has 2θ 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.
예컨대 본 발명에 따른 엠파글리플로진/푸마르산 공결정의 일 구현예의 분말 X선 회절의 강도 및 피크 위치는 하기 [표 1]와 같을 수 있다.For example, 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.
[표 1][Table 1]
Figure PCTKR2020008488-appb-I000003
Figure PCTKR2020008488-appb-I000003
(엠파글리플로진/푸마르산 공결정의 PXRD 강도 및 피크 위치)(PXRD intensity and peak position of empagliflozin/fumaric acid co-crystal)
또한 본 발명은 밀폐 팬을 사용한 온도시차주사 열량(DSC)분석에서 승온속도를 10℃/min으로 하였을 때, 흡열개시온도 145.78℃±3℃에서 나타나고, 흡열온도 148.10℃±3℃에서 나타나는, 그 분자들의 비율이 1:1로 형성된 엠파글리플로진/푸마르산 공결정을 제공한다.In addition, the present invention is shown at the endothermic temperature of 145.78 ℃ ± 3 ℃ when the temperature increase rate is 10 ℃ / min in the temperature differential scanning calorimetry (DSC) analysis using a closed fan, and appears at the endothermic temperature of 148.10 ℃ ± 3 ℃, An empagliflozin/fumaric acid co-crystal formed in a ratio of molecules of 1:1 is provided.
또한 핵자기공명분광(NMR)분석에서 1H-NMR 스펙트럼이 한분자의 엠파글리플로진과 한분자의 푸마르산이 명확한 그 분자들의 비율이 1:1로 형성된 엠파글리플로진/푸마르산 공결정을 제공한다. In addition, 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. .
본 발명의 일 구현예에 따르면, 상기 무정형형태의 엠파글리플로진/시트르산 공결정은 다음 화학식 3로 표시되는 화합물이다:According to one embodiment of the present invention, the empagliflozin/citric acid co-crystal in the amorphous form is a compound represented by the following Chemical Formula 3:
[화학식 3][Formula 3]
Figure PCTKR2020008488-appb-I000004
Figure PCTKR2020008488-appb-I000004
화학식 3의 무정형형태의 엠파글리플로진/시트르산 공결정은 수소결합에 의해 한 분자의 엠파글리플로진과 한 분자의 시트르산이 1:1 비율로 공결정을 형성한다. 이와 같은 높은 수용해도를 갖는 시트르산이 엠파글리플로진과 수소결합으로 인해 무정형형태를 이룸으로써 시트르산과의 상호작용으로 인해 시트르산이 용해될 때 엠파글리플로진도 함께 물에서 용해되기 때문에, 수용해도 및 소장 pH 6.8 용해도가 증가 되는 것이다.In the amorphous empagliflozin/citric acid co-crystal of 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.
본 발명의 무정형형태의 엠파글리플로진/시트르산 공결정은 어디에도 보고된 바 없는 신규한 고체형태이다. The amorphous form of empagliflozin/citric acid co-crystal of the present invention is a novel solid form that has not been reported anywhere.
본 발명의 구현예에 따르면, 상기 무정형형태의 엠파글리플로진/시트르산 공결정 또는 복합제는 X선 회절(PXRD)분석에서 2θ 회절각이 무정형형태를 나타내며, 온도시차주사 열량(DSC)분석에서 열량곡선이 무정형형태를 나타내는, 그 분자들의 비율이 1:1로 형성된 무정형형태의 공결정 또는 복합제이다.According to an embodiment of the present invention, the empagliflozin / citric acid co-crystal or composite agent in the amorphous form exhibits an amorphous 2θ 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.
또한 핵자기공명분광(NMR)분석에서 1H-NMR 스펙트럼이 한분자의 엠파글리플로진과 한분자의 시트르산이 명확한 그 분자들의 비율이 1:1로 형성된 무정형형태의 엠파글리플로진/시트르산 공결정을 제공한다.In addition, in nuclear magnetic resonance spectroscopy (NMR) analysis, 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. provides
본 발명의 일 구현예에 따르면, 상기 엠파글리플로진/L-피루글루탐산 공결정은 다음 화학식 4로 표시되는 화합물이다:According to one embodiment of the present invention, the empagliflozin/L-pyruglutamic acid co-crystal is a compound represented by the following formula (4):
[화학식 4][Formula 4]
Figure PCTKR2020008488-appb-I000005
Figure PCTKR2020008488-appb-I000005
화학식 4의 엠파글리플로진/L-피루글루탐산 공결정은 수소결합에 의해 한 분자의 엠파글리플로진과 한 분자의 L-피루글루탐산이 1:1 비율로 공결정을 형성한다. 이와 같은 높은 수용해도를 갖는 L-피루글루탐산이 엠파글리플로진과 수소결합으로 인해 공결정을 형성함으로써 L-피루글루탐산과의 상호작용으로 인해 L-피루글루탐산이 용해될 때 엠파글리플로진도 함께 물에서 용해되기 때문에, 수용해도 및 소장 pH 6.8 용해도가 증가 되는 것이다.In the 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. When L-pyruglutamic acid with such high water solubility forms a co-crystal due to hydrogen bonding with empagliflozin, when L-pyruglutamic acid is dissolved due to interaction with L-pyruglutamic acid, empagliflozin is also Because it is soluble in water, the solubility in water and small intestine pH 6.8 is increased.
본 발명의 엠파글리플로진/L-피루글루탐산 공결정은 어디에도 보고된 바 없는 신규한 고체형태이다.The empagliflozin/L-pyruglutamic acid co-crystal of the present invention is a novel solid form that has not been reported anywhere.
본 발명의 구현예에 따르면, 상기의 엠파글리플로진/L-피루글루탐산 공결정은 X선 회절(PXRD)분석에서 2θ 회절각이 14.738±0.2, 18.001±0.2, 18.892±0.2, 20.418±0.2, 22.226±0.2, 23.041±0.2, 24.878±0.2, 25.712±0.2 및 27.306±0.2에서 특징적인 피크를 갖는 분말 X선 회절 패턴을 갖는 것을 특징으로 하는 화학식 4로 표기되는 엠파글리플로진/L-피루글루탐산 공결정을 제공한다. According to an embodiment of the present invention, the empagliflozin/L-pyruglutamic acid co-crystal has 2θ 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.
예컨대 본 발명에 따른 엠파글리플로진/L-피루글루탐산 공결정의 일 구현예의 분말 X선 회절의 강도 및 피크 위치는 하기 [표 2]와 같을 수 있다.For example, 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.
[표 2][Table 2]
Figure PCTKR2020008488-appb-I000006
Figure PCTKR2020008488-appb-I000006
(엠파글리플로진/L-피루글루탐산 공결정의 PXRD 강도 및 피크 위치)(PXRD intensity and peak position of empagliflozin/L-pyruglutamic acid co-crystal)
또한 본 발명은 밀폐 팬을 사용한 온도시차주사 열량(DSC)분석에서 승온속도를 10℃/min으로 하였을 때, 흡열개시온도 122.98℃±3℃에서 나타나고, 흡열온도 127.09℃±3℃에서 나타나는, 그 분자들의 비율이 1:1로 형성된 엠파글리플로진/L-피루글루탐산 공결정을 제공한다.In addition, the present invention, when the temperature increase rate is 10 ℃ / min in the temperature differential scanning calorimetry (DSC) analysis using a sealed fan, it appears at the endothermic temperature of 122.98 ℃ ± 3 ℃, the endothermic temperature 127.09 ℃ ± 3 ℃, An empagliflozin/L-pyruglutamic acid co-crystal formed in a ratio of molecules of 1:1 is provided.
또한 핵자기공명분광(NMR)분석에서 1H-NMR 스펙트럼이 한분자의 엠파글리플로진과 한분자의 L-피루글루탐산이 명확한 그 분자들의 비율이 1:1로 형성된 엠파글리플로진/L-피루글루탐산 공결정을 제공한다.In addition, in nuclear magnetic resonance spectroscopy (NMR) analysis, the 1 H-NMR spectrum showed that one molecule of empagliflozin and one molecule of L-pyruglutamic acid was clearly formed, with a ratio of 1:1 empagliflozin/L-pyru glutamic acid co-crystal.
본 발명의 다른 양태에 따르면, 본 발명은 다음 단계를 포함하는 엠파글리플로진의 공결정 제조방법을 제공한다. According to another aspect of the present invention, the present invention provides a method for producing a co-crystal of empagliflozin comprising the following steps.
(a) 엠파글리플로진 및 유기용매를 혼합하고 이에 유기산을 각각 첨가하는 단계; (b) 상기 단계 (a)의 결과물을 승온시키고 환류 고반하는 단계; (c) 상기 단계 (b)의 결과물을 냉각하고 교반하는 단계; (d) 상기 단계 (c)의 용매의 1/2를 증발시키는 단계; 및 (e) 상기 단계 (d)의 결과물을 진공건조하고 엠파글리플로진 공결정을 수득하는 단계.(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.
본 발명자들은 엠파글리플로진의 약제학적으로 유용한 신규 공결정을 제조함과 더불어 제조과정에서 별도의 염류를 붙였다 떼어 내는 공정을 가하지 않아도 매우 순수한 신규 공결정을 높은 수율로 제조할수 있는 방법을 확립하였다. 이 방법은 공결정화 중 용매 증발법이라 한다.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.
본 발명의 방법은 상술한 본 발명의 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정을 제조하는 것이기 때문에, 이들 사이에 공통된 내용은 반복 기재에 따른 명세서의 과도한 복잡성을 피하기 위하여, 그 기재를 생략한다.Since 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.
이하, 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정을 제조하기 위한 본 발명의 방법을 단계별로 상세하게 설명하면 다음과 같다:Hereinafter, the method of the present invention for preparing empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal will be described in detail step by step. To explain:
(a) 엠파글리플로진 및 유기용매 혼합 및 유기산의 첨가 (a) empagliflozin and organic solvent mixing and addition of organic acid
우선, 본 발명의 방법은 고체 분말의 엠파글리플로진 및 유기용매를 혼합하고 이에 유기산을 각각 첨가하는 단계를 포함한다.First, the method of the present invention includes mixing empagliflozin and an organic solvent in a solid powder and adding an organic acid thereto, respectively.
본 발명의 일 구현예에 따르면, 상기 단계 (a)의 엠파글리플로진은 유기용매의 부피에 대하여 1-30 (w/v)%로 첨가 되고, 보다 바람직하게는 6-25 (w/v)%이며, 보다 더 바람직하게는 10-20 (w/v)%이다.According to one embodiment of the present invention, 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)%.
상기 엠파글리플로진 공결정의 제조 시 높은 수율로 엠파글리플로진 공결정을 생성시키고, 과량으로 사용된 유기산의 제거에도 효과적인 용매로 검증된 유기용매는 바람직하게는 메탄올, 에탄올, 이소프로필알콜, 아세톤, 테트라하이드로퓨란, 디메틸 아세트아미드, 디메틸술폭사이드, 디메틸 포름아미드, 클로로포름, 메틸 에틸케톤, 에틸 아세테이트, 메틸렌클로라이드 및 아세토나이트릴로 구성된 유기용매로부터 최소 1종 이상 선택되고, 즉 단일 용매 또는 이의 혼합 용매가 선택되고, 보다 바람직하게는 메탄올, 에탄올, 이소프로필알콜, 또는 아세톤이며, 가장 바람직하게는 메탄올이다.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.
본 발명의 또 다른 구현예에 따르면, 상기 단계 (a)의 유기산은 엠파글리플로진에 대하여 1 내지 1.5 당량의 몰비로 첨가된다.According to another embodiment of the present invention, the organic acid of step (a) is added in a molar ratio of 1 to 1.5 equivalents based on empagliflozin.
유기산은 각각 엠파글리플로진에 대하여 1 내지 1.5 당량의 몰비로 첨가되는 것이 바람직하다. 이렇게 하여 얻어진 무정형형태의 엠파글리플로진 신규 공결정 또는 복합제는 엠파글리플로진이 결합 된 무정형형태의 엠파글리플로진/유기산 공결정 또는 복합제가 된다.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.
본 발명의 다른 구현예에 따르면, 상기 단계 (a)의 유기산은 상기 혼합된 엠파글리플로진 및 유기용매에 1/3의 양으로 나누어 첨가된다.According to another embodiment of the present invention, the organic acid of step (a) is added in an amount of 1/3 to the mixed empagliflozin and organic solvent.
이는 상기 엠파글리플로진/유기산 공결정 또는 복합제의 제조 시 고체분말 엠파글리플로진과 유기산을 혼합 시 유기산의 혼합 비율이 엠파글리플로진과 1:1 비율로 형성됨에 있어 중요하기 때문이다. This is because it is important that the mixing ratio of empagliflozin/organic acid co-crystal or combination agent is formed in a 1:1 ratio with empagliflozin when solid powder empagliflozin and organic acid are mixed.
이에, 고체 분말 엠파글리플로진과 혼합하는 유기산을 한 번에 첨가하는 것보다 전체 혼합 당량의 1/3씩의 유기산을 나누어서 혼합할 때 가장 효과적으로 형성시킬 수 있다.Therefore, it can be formed most effectively when mixing the organic acid by dividing 1/3 of the total mixing equivalent rather than adding the organic acid to be mixed with the solid powder empagliflozin at once.
보다 바람직하게는, 상기 단계 (a)의 유기산을 상기 혼합된 엠파글리플로진 및 유기용매에 1/3의 양으로 나누어 20분 간격으로 첨가한다.More preferably, 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.
(b) 상기 결과물의 승온 및 환류 교반 (b) stirring at elevated temperature and reflux of the resultant
그 다음, 본 발명의 방법은 상기 단계 (a)의 결과물을 승온시키고 환류 교반하는 단계를 거친다.Then, in the method of the present invention, the resultant of step (a) is heated and stirred under reflux.
상기 단계 (a)의 결과물의 승온 시간은 환류 온도에 도달하기 까지 1시간 이상의 시간이 소요되도록 온도의 조절이 팔요하며, 환류 온도에서의 교반시간은 세 시간이 넘지 않도록 하여야 한다.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.
본 발명의 또 다른 구현예에 따르면, 상기 단계 (b)의 승온은 1시간 내지 3시간 동안 실시한다.According to another embodiment of the present invention, the temperature increase in step (b) is carried out for 1 hour to 3 hours.
본 발명의 다른 구현예에 따르면, 상기 단계 (b)의 환류 교반은 1시간 내지 3시간 동안 실시하고, 보다 바람직하게는 30분 내지 2시간 동안 실시하며, 보다 더 바람직하게는 30분 내지 1시간 동안 실시한다.According to another embodiment of the present invention, 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
(c) 상기 결과물의 냉각 및 교반 (c) cooling and stirring of the resultant;
그 다음, 본 발명의 방법은 상기 단계 (b)의 결과물, 즉 환류한 반응액을 냉각하고 교반하는 단계를 포함한다.Then, the method of the present invention includes the step of cooling and stirring the product of step (b), that is, the refluxed reaction solution.
본 발명의 또 다른 구현예에 따르면, 상기 단계 (c)의 냉각은 15-40℃에서 실시하고, 보다 바람직하게는 온도 15-30℃에서 실시하며, 가장 바람직하게는 15-20℃에서 실시한다.According to another embodiment of the present invention, 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. .
본 발명의 다른 구현예에 따르면, 상기 단계 (c)의 교반은 1-12시간 동안 실시하고, 보다 바람직하게는 1시간 내지 8시간 동안 실시하며, 보다 더 바람직하게는 3시간 내지 5시간 동안 실시한다.According to another embodiment of the present invention, 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.
(d) 상기 결과물을 증발 및 교반 (d) evaporating and stirring the resultant
그 다음 본 발명의 방법은 상기 단계 (c)의 결과물, 즉 냉각된 반응액의 용매의 1/2 증발시키면서 교반하는 단계를 포함한다.Then, 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.
본 발명의 또 다른 구현예에 따르면, 상기 단계 (d)의 증발은 30-60℃에서 실시하고, 보다 바람직하게는 온도 30-50℃에서 실시하며, 가장 바람직하게는 30-40℃에서 실시한다. According to another embodiment of the present invention, 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. .
본 발명의 다른 구현예에 따르면, 상기 단계 (d)의 교반은 1-12시간 동안 실시하고, 보다 바람직하게는 1시간 내지 8시간 동안 실시하며, 보다 더 바람직하게는 3시간 내지 5시간 동안 실시한다.According to another embodiment of the present invention, 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.
본 발명의 또 다른 구현예에 따르면, 상기 단계 (d)이후에 (d-1) 상기 단계 (d)의 결과물을 감압 여과 후 유기용매로 세척하는 단계를 추가적으로 포함한다.According to another embodiment of the present invention, after step (d), (d-1) further comprising the step of washing the resultant of step (d) with an organic solvent after filtration under reduced pressure.
본 발명의 다른 구현예에 따르면, 상기 단계 (d-1)의 유기용매는 메탄올, 에탄올, 이소프로필알콜, 아세톤, 테트라하이드로퓨란, 디메틸 아세트아미드, 디메틸술폭사이드, 디메틸 포름아미드, 클로로포름, 메틸 에틸케톤, 에틸 아세테이트, 메틸렌클로라이드 및 아세토나이트릴로 구성된 유기용매로부터 최소 1종 이상 선택되고, 즉 단일 용매 또는 이의 혼합 용매가 선택되고, 보다 바람직하게는 메탄올, 에탄올, 이소프로필알콜 또는 아세톤이며, 가장 바람직하게는 아세톤이다.According to another embodiment of the present invention, the organic solvent of step (d-1) is methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, chloroform, methyl ethyl At least one selected from 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.
본 발명의 또 다른 구현예에 따르면, 상기 단계 (c-1)의 유기용매는 상기 단계 (a)의 유기용매의 부피에 대하여 1-30 (v/v)%로 첨가되고, 보다 바람직하게는 1-10 (v/v)%, 보다 더 바람직하게는 2-5 (v/v)%이다.According to another embodiment of the present invention, 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)%.
(e) 상기 결과물의 진공건조 엠파글리플로진 공결정의 수득 (e) obtaining the vacuum-dried empagliflozin co-crystal of the resultant
마지막으로, 본 발명의 방법은 상기 단계 (e)의 결과물을 진공 건조하고 엠파글리플로진 공결정을 수득 하는 단계를 거친다.Finally, in the method of the present invention, the resultant of step (e) is vacuum dried and subjected to a step of obtaining an empagliflozin co-crystal.
본 발명의 다른 구현예에 따르면, 상기 단계 (e)의 진공 건조는 온도 30-65℃에서 8시간 내지 12시간 동안 실시한다.According to another embodiment of the present invention, the vacuum drying in step (e) is carried out at a temperature of 30-65° C. for 8 hours to 12 hours.
보다 바람직하게는 상기 진공 건조는 온도 40-55℃에서 실시하고, 보다 더 바람직하게는 온도 45-50℃에서 실시한다.More preferably, the vacuum drying is carried out at a temperature of 40-55°C, and still more preferably at a temperature of 45-50°C.
상기 온도 및 시간 동안 진공 건조를 실시하여 수득한 무정형형태의 엠파글리플로진 공결정 수분 함량이 1% 이하이며 순도는 HPLC로써 99.5% 이상이다.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.
이러한 방법으로 SGLT-2 억제제로서 신장에서 혈당의 재흡수를 억제시켜 혈당을 소변으로 배출하도록 하여 혈당을 조절하는 제2형 당뇨병의 치료제로서 이용 가능한 엠파글리플로진 1당량에 1당량의 유기산이 결합된 엠파글리플로진 공결정을 제조할 수 있다.In this way, as 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.
본 발명의 특징 및 이점을 요약하면 다음과 같다;The features and advantages of the present invention are summarized as follows;
(a) 본 발명은 한 분자의 엠파글리플로진과 한 분자의 유기산이 결합된 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정 및 이의 제조 방법을 제공한다.(a) 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.
(b) 본 발명의 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정은 그 제조에 있어 공결정화를 통한 특수한 용매 환경에 유기산의 당량, 교반 용매의 증발량, 용매의 증발 온도 및 시간을 조절함으로써. 최적 비율의 신규한 공결정을 우수한 순도 및 수율로 수득할 수 있다.(b) empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal of the present invention are prepared through co-crystalization By controlling the equivalent of organic acid, the evaporation amount of the stirring solvent, the evaporation temperature and time of the solvent in a special solvent environment. An optimal ratio of novel co-crystals can be obtained with good purity and yield.
(c) 본 발명의 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정은 매우 낮은 엠파글리플로진의 안정성 및 수용해도를 본 발명의 공결정으로 인해 엠파글리플로진의 수용해도 및 소장 pH 6.8의 용해도가 120배 증가시켰으며, 안정성 또한 향상되어 엠파글리플로진 원료의약품으로서 매우 유용하다.(c) 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 And 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.
도 1은 본 발명의 실시예에 따라 제조된 엠파글리플로진/푸마르산 공결정의 분말 X선 회절(PXRD)패턴 결과를 보여준다.1 shows the powder X-ray diffraction (PXRD) pattern results of empagliflozin/fumaric acid co-crystals prepared according to an embodiment of the present invention.
도 2은 본 발명의 실시예에 따라 제조된 무정형형태의 엠파글리플로진/시트르산 공결정의 분말 X선 회절(PXRD)패턴 결과를 보여준다.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.
도 3은 본 발명의 실시예에 따라 제조된 엠파글리플로진/L-피루글루탐산 공결정의 분말 X선 회절(PXRD)패턴 결과를 보여준다.3 shows the powder X-ray diffraction (PXRD) pattern results of empagliflozin/L-pyruglutamic acid co-crystals prepared according to an embodiment of the present invention.
도 4은 국제공개특허공보 WO 2006/117359호의 실시예에 따라 제조된 엠파글리플로진 결정형의 분말 X선 회절(PXRD)패턴 결과를 보여준다.4 shows the powder X-ray diffraction (PXRD) pattern results of empagliflozin crystalline form prepared according to the Example of International Patent Publication No. WO 2006/117359.
도 5는 본 발명의 실시예에 따라 제조된 엠파글리플로진/푸마르산 공결정의 온도시차주사열량(DSC)의 열량곡선 결과를 보여준다.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.
도 6는 국제공개특허공보 WO 2006/117359호의 실시예에 따라 제조된 엠파글리플로진 결정형의 온도시차주사열량(DSC)의 열량곡선 결과를 보여준다.6 shows the calorimetric curve results of the temperature differential scanning calorimetry (DSC) of the empagliflozin crystalline form prepared according to the Example of International Patent Publication No. WO 2006/117359.
도 7는 본 발명의 실시예에 따라 제조된 무정형형태의 엠파글리플로진/시트르산 공결정의 온도시차주사열량(DSC)의 열량곡선 결과를 보여준다.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.
도 8은 본 발명의 실시예에 따라 제조된 무정형형태의 엠파글리플로진/시트르산 공결정, 시트르산, 엠파글리플로진 결정형의 온도시차주사열량(DSC)의 열량곡선 결과를 보여준다.8 shows the calorimetric curve results of the temperature differential scanning calorimetry (DSC) of the amorphous empagliflozin/citric acid co-crystal, citric acid, and empagliflozin crystal form prepared according to an embodiment of the present invention.
도 9는 본 발명의 실시예에 따라 제조된 엠파글리플로진/L-피루글루탐산 공결정의 온도시차주사열량(DSC)의 열량곡선 결과를 보여준다.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.
도 10은 본 발명의 실시예에 따라 제조된 엠파글리플로진/L-피루글루탐산 공결정, L-피루글루탐산, 엠파글리플로진 결정형의 온도시차주사열량(DSC)의 열량곡선 결과를 보여준다.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; .
도 11은 본 발명의 실시예에 따라 제조된 엠파글리플로진/푸마르산 공결정의 핵자기공명분광(NMR) 1H-NMR 스펙트럼 결과를 보여주는데, 이 결과에서 엠파글리플로진/푸마르산의 화학양론적 비율이 1:1로 정확하게 그 피크가 적분 되어 나타난다. 11 shows nuclear magnetic resonance spectroscopy (NMR) 1 H-NMR spectrum results of empagliflozin/fumaric acid co-crystals prepared according to Examples of the present invention, in which the chemistry of empagliflozin/fumaric acid The peak is precisely integrated with a stoichiometric ratio of 1:1.
도 12은 본 발명의 실시예에 따라 제조된 무정형형태의 엠파글리플로진/시트르산 공결정의 핵자기공명분광(NMR) 1H-NMR 스펙트럼 결과를 보여주는데, 이 결과에서 엠파글리플로진/푸마르산의 화학양론적 비율이 1:1로 정확하게 그 피크가 적분 되어 나타난다. 12 shows nuclear magnetic resonance (NMR) 1 H-NMR spectrum results of amorphous empagliflozin/citric acid co-crystals prepared according to an embodiment of the present invention, in which empagliflozin/ The peak is precisely integrated with a stoichiometric ratio of fumaric acid of 1:1.
도 13은 본 발명의 실시예에 따라 제조된 엠파글리플로진/L-피루글루탐산 공결정의 핵자기공명분광(NMR) 1H-NMR 스펙트럼 결과를 보여주는데, 이 결과에서 엠파글리플로진/푸마르산의 화학양론적 비율이 1:1로 정확하게 그 피크가 적분 되어 나타난다. 13 shows nuclear magnetic resonance (NMR) 1 H-NMR spectrum results of empagliflozin/L-pyruglutamic acid co-crystals prepared according to an embodiment of the present invention, in which empagliflozin/ The peak is precisely integrated with a stoichiometric ratio of fumaric acid of 1:1.
도 14는 국제공개특허공보 WO 2006/117359호의 실시예에 따라 제조된 엠파글리플로진 결정형의 핵자기공명분광(NMR) 1H-NMR 스펙트럼 결과를 보여준다. 14 shows nuclear magnetic resonance spectroscopy (NMR) 1 H-NMR spectrum results of empagliflozin crystal form prepared according to an example of International Patent Publication No. WO 2006/117359.
도 15는 본 발명의 실시예에 따라 제조된 엠파글리플로진/푸마르산 공결정, 엠파글리플로진/시트르산 무정형형태의 공결정, 엠파글리플로진/L-피루글루탐산 공결정 그리고 엠파글리플로진 결정형의 1mg/mL의 농도의 수용해성을 비교 시험한 결과이다. 이때 본 발명의 엠파글리플로진 공결정들은 모두 용해가 되었지만 엠파글리플로진 결정형은 용해도가 낮아서 용해되지 않는다.15 is an empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid amorphous co-crystal, empagliflozin/L-pyruglutamic acid co-crystal, and empagle prepared according to an embodiment of the present invention. This is the result of a comparative test for solubility in water at a concentration of 1 mg/mL of the crystalline form of reflozin. At this time, all of the empagliflozin co-crystals of the present invention were dissolved, but the empagliflozin crystal form did not dissolve due to low solubility.
이하 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.The present invention will be described in more detail with reference to the following examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
[실시예 1] 엠파글리플로진/푸마르산 공결정 제조[Example 1] Preparation of empagliflozin/fumaric acid co-crystal
엠파글리플로진 10g과 메탄올 100ml를 넣은 후 상온에서 20분간 교반한다. 그 후 푸마르산 1.2 당량을 1/3씩 투입하고 온도를 1시간 동안 서서히 올려 환류온도까지 도달한 후 30분간 더 교반하였다. 서서히 15℃-20℃까지 냉각한 후 3시간 동안 교반 하였다. 그 후 온도를 30℃-40℃ 3시간 동안 교반 하면서 메탄올을 70ml 증발시켜 결정을 석출시켰다. 석출된 결정을 감압 여과 후 아세톤 10ml로 세척하고 45℃에서 16시간이상 진공 건조하여 신규한 엠파글리플로진/푸마르산 공결정을 90% 수율로 얻었다.After adding 10 g of empagliflozin and 100 ml of methanol, the mixture was stirred at room temperature for 20 minutes. After that, 1.2 equivalents of fumaric acid were added by 1/3, and the temperature was gradually increased for 1 hour to reach the reflux temperature, followed by further stirring for 30 minutes. After cooling to 15°C-20°C slowly, the mixture was stirred for 3 hours. Then, while stirring the temperature at 30°C-40°C for 3 hours, 70 ml of methanol was evaporated to precipitate crystals. The precipitated crystals were filtered under reduced pressure, washed with 10 ml of acetone, and vacuum dried at 45° C. for 16 hours or more to obtain a new empagliflozin/fumaric acid co-crystal in 90% yield.
[실시예 2] 엠파글리플로진/시트르산 공결정 제조[Example 2] Preparation of empagliflozin/citric acid co-crystal
엠파글리플로진 10g과 메탄올 100mL를 넣은 후 상온에서 20분간 교반한다. 그 후 시트르산 1.2 당량을 투입한 후 1시간 동안 교반하였다. 그 후 온도를 30℃-40℃ 3시간 동안 교반 하면서 메탄올을 80mL 증발시켜 결정을 석출시켰다. 그 후 에틸아세테이트 50mL를 투입한 후 20분간 교반하였다. 그리고 석출된 결정을 감압 여과 후 에틸아세테이트 10ml로 세척하고 45℃에서 16시간이상 진공 건조하여 신규한 엠파글리플로진/시트르산 공결정을 85% 수율로 얻었다.10 g of empagliflozin and 100 mL of methanol are added and stirred at room temperature for 20 minutes. Thereafter, 1.2 equivalents of citric acid was added and stirred for 1 hour. Then, while stirring the temperature at 30°C-40°C for 3 hours, 80 mL of methanol was evaporated to precipitate crystals. After that, 50 mL of ethyl acetate was added and stirred for 20 minutes. Then, the precipitated crystals were filtered under reduced pressure, washed with 10 ml of ethyl acetate, and vacuum dried at 45° C. for 16 hours or more to obtain a novel empagliflozin/citric acid co-crystal in 85% yield.
[실시예 3] 엠파글리플로진/L-피루글루탐산 공결정 제조[Example 3] Preparation of empagliflozin/L-pyruglutamic acid co-crystal
엠파글리플로진 10g과 메탄올 100ml를 넣은 후 상온에서 20분간 교반한다. 그 후 L-피루글루탐산 1.2 당량을 1/3씩 투입하고 온도를 1시간 동안 서서히 올려 환류온도까지 도달한 후 30분간 더 교반하였다. 서서히 15℃-20℃까지 냉각한 후 3시간 동안 교반 하였다. 그 후 온도를 30℃-40℃ 3시간 동안 교반 하면서 메탄올을 60ml 증발시켜 결정을 석출시켰다. 석출된 결정을 감압 여과 후 에틸아세테이트 10ml로 세척하고 45℃에서 16시간이상 진공 건조하여 신규한 엠파글리플로진/L-피루글루탐산 공결정을 82% 수율로 얻었다.After adding 10 g of empagliflozin and 100 ml of methanol, the mixture was stirred at room temperature for 20 minutes. After that, 1.2 equivalents of L-pyruglutamic acid were added by 1/3, and the temperature was gradually increased for 1 hour to reach the reflux temperature, followed by further stirring for 30 minutes. After cooling to 15°C-20°C slowly, the mixture was stirred for 3 hours. Thereafter, while stirring the temperature at 30°C-40°C for 3 hours, 60 ml of methanol was evaporated to precipitate crystals. The precipitated crystals were filtered under reduced pressure, washed with 10 ml of ethyl acetate, and vacuum dried at 45° C. for 16 hours or more to obtain a novel empagliflozin/L-pyruglutamic acid co-crystal in 82% yield.
[실시예 4] 엠파글리플로진/푸마르산 공결정 제조[Example 4] Preparation of empagliflozin/fumaric acid co-crystal
엠파글리플로진 10g과 메탄올 300ml를 넣은 후 상온에서 20분간 교반하여 용해 하였다. 그 후 푸마르산 1.2 당량을 투입하여 30분간 교반 하면서 용해하였다. 그 후 농축기를 이용하여 결정이 석출 될 때까지 메탄올을 모두 증발시겼다. 그리고 에틸아세테이트 50mL를 투입하여 20분간 교반한 후 감압 여과 하여 에틸아세테이트 10ml로 세척하고 45℃에서 16시간이상 진공 건조하여 신규한 엠파글리플로진/푸마르산 공결정을 88% 수율로 얻었다.After 10 g of empagliflozin and 300 ml of methanol were added, the mixture was dissolved by stirring at room temperature for 20 minutes. Then, 1.2 equivalents of fumaric acid was added and dissolved while stirring for 30 minutes. Then, all methanol was evaporated using a concentrator until crystals were precipitated. Then, 50 mL of ethyl acetate was added, stirred for 20 minutes, filtered under reduced pressure, washed with 10 ml of ethyl acetate, and vacuum dried at 45° C. for 16 hours or more to obtain a novel empagliflozin/fumaric acid co-crystal in 88% yield.
[실시예 5] 엠파글리플로진/L-피루글루탐산 공결정 제조[Example 5] Preparation of empagliflozin/L-pyruglutamic acid co-crystal
엠파글리플로진 10g과 메탄올 300ml를 넣은 후 상온에서 20분간 교반하여 용해 하였다. 그 후 L-피루글루탐산 1.2 당량을 투입하여 30분간 교반 하면서 용해하였다. 그 후 농축기를 이용하여 결정이 석출 될 때까지 메탄올을 모두 증발시겼다. 그리고 에틸아세테이트 50mL를 투입하여 20분간 교반한 후 감압 여과 하여 에틸아세테이트 10ml로 세척하고 45℃에서 16시간 이상 진공 건조하여 신규한 엠파글리플로진/L-피루글루탐산 공결정을 83% 수율로 얻었다.After 10 g of empagliflozin and 300 ml of methanol were added, the mixture was dissolved by stirring at room temperature for 20 minutes. After that, 1.2 equivalents of L-pyruglutamic acid was added and dissolved while stirring for 30 minutes. Then, all methanol was evaporated using a concentrator until crystals were precipitated. Then, 50 mL of ethyl acetate was added, stirred for 20 minutes, filtered under reduced pressure, washed with 10 mL of ethyl acetate, and vacuum dried at 45° C. for 16 hours or more to obtain a novel empagliflozin/L-pyruglutamic acid co-crystal in 83% yield. .
[실험예 1] 분말 X-선 회절 (PXRD)[Experimental Example 1] Powder X-ray diffraction (PXRD)
PXRD 분석(도 1에서 도 4 참조)을 Cu Kα 방사선을 사용하여 (D8 Advance) X-선 분말 회절계 상에서 수행하였다. 기구에는 관 동력이 장치되어 있고, 전류량은 45 kV 및 40 mA 로 설정하였다. 발산 및 산란 슬릿은 1°로 설정하였고, 수광 슬릿은 0.2 mm 로 설정하였다. 5 에서 35° 2θ까지 3°/분 (0.4 초/0.02°간격) 의 θ-2θ 연속 스캔을 사용하였다. PXRD analysis (see FIGS. 1 to 4 ) was performed on a (D8 Advance) X-ray powder diffractometer using Cu Kα 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 θ-2θ scans at 3°/min (0.4 sec/0.02° intervals) from 5 to 35° 2θ were used.
[실험예 2] 온도 시차주사 열량법(DSC)[Experimental Example 2] Temperature differential scanning calorimetry (DSC)
TA사로부터 입수한 DSC Q20을 사용하여, 질소 정화 하에 20℃ 에서 300℃까지 10℃/min 스캔속도로, 밀폐 팬에서 DSC 측정(도 5에서 도 10 참조)을 수행하였다.Using DSC Q20 obtained from TA, DSC measurements (see FIGS. 5 to 10 ) were performed in a closed pan at a scan rate of 10° C./min from 20° C. to 300° C. under nitrogen purge.
[실험예 3] 엠파글리플로진 공결정의 용해도 평가 [Experimental Example 3] Solubility evaluation of empagliflozin co-crystal
엠파글리플로진은 0.111mg/ml의 수용해도를 갖는 난용성이기 때문에 그에 따라 수용해도가 높은 푸마르산, 시트르산, L-피루글루탐산과 결합시켜 새로운 공결정을 제조하여 엠파글리플로진의 수용해도 및 위장관 pH 용해도를 개선시키고자 하였다. 그 결과를 아래 표 3에 정리하였다Since 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. The results are summarized in Table 3 below.
[표 3][Table 3]
Figure PCTKR2020008488-appb-I000007
Figure PCTKR2020008488-appb-I000007
(엠파글리플로진 공결정과 엠파글리플로진 결정형의 용해도)(solubility of empagliflozin co-crystal and empagliflozin crystal form)
상기 표 3에서 보는 바와 같이 공지된 엠파글리플로진 결정형에 비해 본 발명의 엠파글리플로진/푸마르산 공결정의 수용해도 및 소장 pH 6.8에서의 용해도가 약 18배 증가하였고, 무정형형태의 엠파글리플로진/시트르산 공결정의 수용해도 및 소장 pH 6.8에서의 용해도가 약 120배 이상 증가 되었으며, 엠파글리플로진/L-피루글루탐산 공결정의 수용해도 및 소장 pH 6.8에서의 용해도가 약 24배 증가 되었다는 것이 확인되었다.As shown in Table 3, 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.
따라서 본 발명의 엠파글리플로진 공결정이 공지된 엠파글리플로진 결정형에 비해 수용해도가 약 120배까지 증가 될수 있다는 것이 확인되었다.Therefore, it was confirmed that the empagliflozin co-crystal of the present invention can increase water solubility by about 120 times compared to the known empagliflozin crystal form.
따라서 본 발명의 엠파글리플로진 공결정은 엠파글리플로진 결정형의 문제점인 낮은 수용해도를 극복할 수 있는 신규한 결정형태이며, 이는 엠파글리플로진의 약효를 극대화시킬 수 있음이 예측되었다. Therefore, 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. .
[실험예 4] 엠파글리플로진 공결정과 엠파글리플로진 결정형의 가속, 가혹 안정성비교 평가 [Experimental Example 4] Comparative evaluation of accelerated and severe stability of empagliflozin co-crystal and empagliflozin crystal form
의약품의 안정성 시험이라 함은 의약품등의 저장방법 및 사용기간을 설정하기 위하여, 적절한 규격을 설정한 후 정해진 시험법에 근거하여 유의적인 변화를 판단하여 유효기간을 설정하게 되므로, 약물의 적정한 안정성 확보는 약물의 제품화에 있어 대단히 중요한 요소 중 하나이다.In order to establish the storage method and period of use of the drug, 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.
따라서 본 발명의 엠파글리플로진/푸마르산 공결정, 무정형형태의 엠파글리플로진/시트르산 공결정, 엠파글리플로진/L-피루글루탐산 공결정의 제품화 가능성을 확인하기 위해 국제공개특허공보 WO 2006/117359호에 공지된 엠파글리플로진 결정형을 대조군으로 하여 ICH 가이드라인에 따라 가속 및 가혹 안정성을 실시하고 미국 약전(USP)에 기재되어 있는 액체크로마토그래피(HPLC) 분석법을 이용하여 분석한 후 그 결과를 표 4와 5에 나타내었다.Therefore, in order to confirm the commercialization possibility of empagliflozin/fumaric acid co-crystal, empagliflozin/citric acid co-crystal, and empagliflozin/L-pyruglutamic acid co-crystal of the present invention, International Patent Publication No. Using the empagliflozin crystalline form known in WO 2006/117359 as a control, accelerated and harsh stability were performed according to ICH guidelines, and analyzed using liquid chromatography (HPLC) analysis described in the United States Pharmacopoeia (USP). After that, the results are shown in Tables 4 and 5.
[표 4][Table 4]
Figure PCTKR2020008488-appb-I000008
Figure PCTKR2020008488-appb-I000008
(엠파글리플로진 공결정과 엠파글리플로진 결정형의 가속 안정성 결과, 40℃± 2℃, RH 75%)(Result of accelerated stability of empagliflozin co-crystal and empagliflozin crystal form, 40℃±2℃, RH 75%)
[표 5][Table 5]
Figure PCTKR2020008488-appb-I000009
Figure PCTKR2020008488-appb-I000009
(엠파글리플로진 공결정과 엠파글리플로진의 가혹 안정성 평가 결과, 60℃± 2℃, RH 75%)(Result of severe stability evaluation of empagliflozin co-crystal and empagliflozin, 60℃±2℃, RH 75%)
실시예에 의해 제조된 엠파글리플로진 공결정과 엠파글리플로진 결정형의 가속, 가혹조건의 안정성 시험을 실시하였다. 그 결과 표 4와 5에서 나타난 것 같이 엠파글리플로진 공결정들은 순도의 영향 없이 안정하게 유지 되었지만, 엠파글리플로진 결정형은 순도가 낮아지면서 안정성이 좋지 않다는 것이 확인되었다.Stability tests of the empagliflozin co-crystal and the empagliflozin crystal form prepared in Examples were performed under accelerated and severe conditions. As a result, as shown in Tables 4 and 5, the empagliflozin co-crystals were stably maintained without the effect of purity, but it was confirmed that the empagliflozin crystal form had poor stability as the purity decreased.
따라서 엠파글리플로진 공결정의 가속, 가혹 조건에서의 안정성은 엠파글리플로진 결정형 보다 개선되었다는 것이 확인되었다.Therefore, it was confirmed that the stability of the empagliflozin co-crystal under accelerated and severe conditions was improved compared to the empagliflozin crystal form.
[실험예 5] 엠파글리플로진 공결정과 엠파글리플로진 결정형의 수용해성 비교시험[Experimental Example 5] Comparative test of water solubility of empagliflozin co-crystal and empagliflozin crystal form
체내 흡수율을 증가시키기 위해서는 수용해성이 어느 정도는 증가 되어야 한다. 따라서 본 발명의 엠파글리플로진 공결정과 공지된 엠파글리플로진 결정형의 수용해성을 1mg/mL의 농도로 하여 비교평가 하였다.In order to increase the absorption rate in the body, the water solubility must be increased to some extent. Therefore, 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.
그 결과 엠파글리플로진 결정형은 용해되지 않아 현탁액 상태로 존재하는 반면 본 발명의 엠파글리플로진 공결정들은 모두 용해되어 수용해성이 증가 되었음을 확인하였다. 따라서 본 발명의 공결정들은 수용해도를 개선시켜, 엠파글리플로진의 난용성을 극복할 수 있는 새로운 원료의약품으로서의 가치를 입증하였다[도 15].As a result, it was confirmed that 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].
그러므로 본 발명 엠파글리플로진 공결정은 엠파글리플로진의 문제점인 낮은 안정성 및 수용해도를 극복한 새로운 원료의약품으로서의 가능성을 기대한다.Therefore, 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.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

  1. X선 회절(PXRD)분석에서 2θ회절각이 14.703±0.2, 15.747±0.2, 17.958±0.2, 18.859±0.2, 19.192±0.2, 19.518±0.2, 20.367±0.2, 25.23±0.2 및 28.794±0.2에서 특징적인 피크를 갖는 분말 X선 회절 패턴을 갖고, 온도시차주사 열량(DSC)분석에서 흡열개시온도 145.78℃±3℃에서 나타나고, 흡열온도 148.10℃±3℃에서 나타나는 것을 특징으로 하는 엠파글리플로진/푸마르산 공결정.In X-ray diffraction (PXRD) analysis, 2θ diffraction angles were characteristic at 14.703±0.2, 15.747±0.2, 17.958±0.2, 18.859±0.2, 19.192±0.2, 19.518±0.2, 20.367±0.2, 25.23±0.2 and 28.794±0.2. Empagliflozin / characterized in that it has a powder X-ray diffraction pattern having a peak, and appears at an endothermic onset temperature of 145.78 ° C ± 3 ° C in temperature differential scanning calorimetry (DSC) analysis, and appears at an endothermic temperature of 148.10 ° C ± 3 ° C. Fumaric acid co-crystal.
  2. 제 1 항에 있어서, 상기 엠파글리플로진/푸마르산 공결정은 엠파글리플로진 1당량에 1당량의 푸마르산이 결합된 엠파글리플로진/푸마르산 공결정.According to claim 1, wherein the empagliflozin/fumaric acid co-crystal is empagliflozin/fumaric acid co-crystal in which 1 equivalent of empagliflozin is bound to 1 equivalent of fumaric acid.
  3. 분말 X선 회절(PXRD)패턴이 무정형형태를 나타내는 것을 특징으로 하는 엠파글리플로진/시트르산 공결정.Empagliflozin/citric acid co-crystal, characterized in that the powder X-ray diffraction (PXRD) pattern shows an amorphous form.
  4. 제 3 항에 있어서, 상기 엠파글리플로진/시트르산 공결정은 엠파글리플로진 1당량에 1당량의 시트르산이 결합된 무정형형태의 엠파글리플로진/시트르산 공결정.4. The empagliflozin/citric acid co-crystal according to claim 3, wherein the empagliflozin/citric acid co-crystal is an amorphous empagliflozin/citric acid co-crystal in which 1 equivalent of empagliflozin is bound to 1 equivalent of citric acid.
  5. 분말 X선 회절(PXRD)분석에서 2θ 회절각이 14.738±0.2, 18.001±0.2, 18.892±0.2, 20.418±0.2, 22.226±0.2, 23.041±0.2, 24.878±0.2, 25.712±0.2 및 27.306±0.2에서 특징적인 피크를 갖고, 온도시차주사 열량(DSC)분석에서 흡열개시온도 122.98℃±3℃에서 나타나고, 흡열온도 127.09℃±3℃에서 나타나는 것을 특징으로 하는 엠파글리플로진/L-피루글루탐산 공결정.In powder X-ray diffraction (PXRD) analysis, 2θ diffraction angles were 14.738±0.2, 18.001±0.2, 18.892±0.2, 20.418±0.2, 22.226±0.2, 23.041±0.2, 24.878±0.2, 25.712±0.2 and 27.306±0.2. Empagliflozin/L-pyruglutamic acid co-crystal, characterized in that it has a positive peak and appears at an endothermic onset temperature of 122.98°C±3°C in temperature differential scanning calorimetry (DSC) analysis and an endothermic temperature of 127.09°C±3°C. .
  6. 제 5 항에 있어서, 상기 엠파글리플로진/L-피루글루탐산 공결정은 엠파글리플로진 1당량에 1당량의 L-피루글루탐산이 결합된 엠파글리플로진/L-피루글루탐산 공결정.The empagliflozin/L-pyruglutamic acid co-crystal according to claim 5, wherein the empagliflozin/L-pyruglutamic acid co-crystal is in which 1 equivalent of empagliflozin is bound to 1 equivalent of L-pyruglutamic acid. .
  7. 제 1 항 내지 제 6 항 중 어느 한 항의 공결정을 포함하여 SGLT-2 를 억제하여 혈당을 조절하는 당뇨병 치료 또는 예방용 약제학적 조성물.A pharmaceutical composition for treating or preventing diabetes, comprising the co-crystal of any one of claims 1 to 6 to control blood sugar by inhibiting SGLT-2.
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WO2022065895A1 (en) * 2020-09-24 2022-03-31 동아에스티 주식회사 Novel salt of empagliflozin derivative, which is sglt-2 inhibitor, and hydrate of salt
KR20220080880A (en) * 2020-12-08 2022-06-15 주식회사 종근당 Pharmaceutical composition comprising empagliflozin co-crystal

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