KR102150825B1 - Novel sglt-2 inhibitors cocrystal - Google Patents

Abstract

As a result of efforts to improve the low stability and water solubility, which are problems of empagliflozin, an empagliflozin/citric acid cocrystal with increased stability and water solubility by more than 60 times is developed. The empagliflozin/citric acid cocrystal is a novel solid form which overcomes the stability and water solubility of the known empagliflozin crystalline form, and is very useful as an optimal SGLT-2 inhibitory drug which can maximize its use as a drug.

Description

Novel co-crystal of new SGLT-2 inhibitor {NOVEL SGLT-2 INHIBITORS COCRYSTAL}

The present invention provides a novel empagliflozin/citric acid co-crystal with improved stability and water solubility, which are problems of empagliflozin as an SGLT-2 inhibitor.

Cocrystals are rich in functional groups that can form hydrogen bonds such as O, OH, and N, or coformers with a difference in pKa of 3 or less and bonded at regular rates through hydrogen bonding to form a new crystal structure. It means having a crystalline solid. Since these co-crystals contain two or more molecules of a compound, they can be expressed in a complex form. Formation of this co-crystal can increase the solubility and dissolution rate of the drug because the crystal structure is formed through new hydrogen bonds of two or more molecules. As a result, the bioavailability can be changed by changing the absorption rate of the drug in the human body. In order to overcome poor solubility, the selection of co-molecules for co-crystal should be water-friendly molecules that are well soluble in water. If the co-molecule is not water-friendly and has poor solubility, the poor solubility of the drug cannot be overcome and the solubility decreases. Therefore, the selection of co-molecules becomes a very important requirement. And co-crystals include amorphous, polymorphic, hydrate, and solvate.

Crystals generally have properties of maintaining thermodynamic stability by preferentially precipitating metastable crystals in the crystallization process and then transitioning from a solvent medium and solid state to a more stable crystal structure to maintain thermodynamic stability. Molecules are rearranged through transformation to form a more stable crystal structure. This creates polymorphism, which is called ostwald's rule of stage. Therefore, the physicochemical properties of metastable crystals and stable crystals are changed. Therefore, it causes a change in solubility, which represents the thermodynamic energy of the crystal, which is most important as a drug. In addition, the co-crystal co-molecules can change their crystal structure or confirm the existence of a polymorph of the co-crystal itself through a phase transition phenomenon that is replaced with the solvent molecules in the solvent. Therefore, in water, the co-crystal can be phase-transformed as a hydrate, and this can cause a phenomenon in which the solubility of the co-crystal changes to the solubility of the hydrate. The reason why the solubility is not improved even when a co-crystal is prepared from a poorly soluble hydrate crystal form is because the co-crystal has been converted into a hydrate. Therefore, the selection of co-molecules is very important. Depending on which comolecule is used, 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 formation of cocrystals is achieved through cocrystallization. Co-crystallization methods include solvent evaporation technique, anti-solvent method, solvent drop grinding, slurry technique, solid state grinfing, etc. (Recrystallization in Materials Processing Intech: Vienna, Austria, 2015; pp. 173-74).

Amorphous refers to a solid state in which molecular interactions exist, but crystal arrangements are not formed. Therefore, it has a higher energy level than that of the crystalline form and has a higher solubility than the crystalline form. However, due to the high energy level, the thermodynamic stability is low, so it has a problem that the phase transition is very fast to the crystalline form. The amorphous co-crystal can form an amorphous solid through new hydrogen bonds between two or more molecules, thereby suppressing the phase transition to the crystalline form, and overcome poor solubility through high solubility. It is in a solid state. The reason why the phase transition to the crystalline form can be suppressed is that the glass transition temperature of the amorphous form is higher than that of the drug itself (Advanced Drug Delivery Reviews (2016) 100, 116-125). In addition, for the formation of amorphous co-crystal, it is necessary to use a crystallization method in which a high degree of supersaturation is rapidly reached by controlling the crystallization rate very quickly. Typically, it uses a method that induces the crystallization rate very rapidly, such as vacuum evaporation crystallization, supercritical crystallization, liquid nitrogen crystallization, freeze evaporation crystallization, etc. However, it is very difficult to design and control an amorphous form even if this extreme crystallization method is used, because hydrogen bonds due to the interaction between drug molecules and co-molecules in the formation of co-crystals are very diverse (From Molecules to Crystallizers An Introduction to Crystallization 2000; pp. 2-14).

SGLT-2 (sodium/glucose cotransporter 2), along with SGLT-1 (sodium/glucose cotransporter 1), is a transporter responsible for reabsorption of excessive blood sugar in the kidney, and SGLT-2 plays most of the role. Therefore, when the SGLT-2 inhibitor inhibits the SGLT-2 transport agent, the blood sugar discharged into the urine increases, and eventually the blood sugar decreases and furthermore, the calories contained in the blood sugar are discharged, resulting in the effect of weight loss.

With this effect, one of the drugs developed as an SGLT-2 inhibitor that can be useful as a treatment for type 2 diabetes is Empagliflozin, which was developed by Boehringer Ingelheim and is currently under the brand name Zadian Tablet. Are sold on.

Empagliflozin is represented by the following structural formula (Chemical Formula 1) and is disclosed in International Publication No. WO 2005/092877.

[Formula 1]

For empagliflozin, an empagliflozin crystalline form is disclosed in WO 2006/117359, and a crystallization method for preparing an empagliflozin crystalline form is disclosed in International Published Patent Publication WO 2011/039107. .

However, it is reported that the crystal form of empagliflozin disclosed in WO 2006/117359 has an aqueous solubility of only 0.11 mg/mL and also has poor stability.

In addition, empagliflozin has a disadvantage that it is not useful as a pharmaceutical ingredient because it is difficult to maintain a certain quality due to poor stability as a drug substance.

International Publication No. WO 2011/039107 discloses a method for preparing a crystal form of empagliflozin, but the complexity of a crystallization method using a centrifugal separation and cooling lamp is problematic.

Therefore, in the present invention, empagliflozin/citric acid 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 low water solubility and constant quality. I did.

Throughout this specification, a number of papers and patent documents are referenced and citations are indicated. The disclosure contents of the cited papers and patent documents are incorporated by reference in this specification as a whole, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly described.

WO 2005/092877 WO 2006/117359 WO 2011/039107

As an SGLT-2 inhibitor, the present inventors have developed an empagliflozin/citric acid co-crystal as a result of making efforts to improve the low water solubility and stability, which is a problem of empagliflozin.

Accordingly, an object of the present invention is to provide a novel empagliflozin/citric acid co-crystal.

Other objects and advantages of the present invention will become more apparent by the following detailed description, claims and drawings.

According to an aspect of the present invention, the present invention provides a co-crystal in which one molecule of empagliflozin and one molecule of citric acid are bonded.

The present inventors prepared empagliflozin/citric acid co-crystal using citric acid, which is an organic acid, not a basic inorganic salt.

Therefore, the present inventors have a very high water solubility to overcome the low stability and water solubility of empagliflozin, rich in NH, N, O, OH L-proline, L-arginine, L-lysine, fumaric acid, oxalic acid, L -Pyroglutamic acid and citric acid were selected to design and manufacture co-crystals. As a result, empagliflozin/citric acid co-crystal was developed.

Since empagliflozin/citric acid co-crystal has increased water solubility and solubility of small intestine pH by about 60 times more than that of the existing empagliflozin crystalline form, and can be sufficiently dissolved in the amount of water injected when taking an oral drug, Oral absorption can be improved, and hygroscopicity and stability are also improved. Therefore, the use of the empagliflozin/citric acid co-crystal of the present invention is suitable for use as an improved drug that improves the stability and water solubility of empagliflozin.

According to an embodiment of the present invention, the empagliflozin/citric acid co-crystal is a compound represented by the following Formula 2:

[Formula 2]

In the empagliflozin/citric acid co-crystal of Formula 2, one molecule of empagliflozin and one molecule of citric acid form a co-crystal in a 1:1 ratio by hydrogen bonding. Since citric acid having such a high water solubility forms co-crystals due to hydrogen bonds with empagliflozin, when citric acid is dissolved due to the interaction with citric acid, empagliflozin is also dissolved in water. Water solubility and solubility in small intestine pH 6.8 are increased.

The empagliflozin/citric acid co-crystal of the present invention is a novel solid form that has not been reported anywhere.

According to an embodiment of the present invention, the empagliflozin/citric acid cocrystal has 2θ diffraction angles of 13.458±0.2, 14.791±0.2, 18.056±0.2, 18.423±0.2, 18.923 in X-ray diffraction (PXRD) analysis. It provides an empagliflozin/citric acid co-crystal represented by Chemical Formula 2, characterized by having a powder X-ray diffraction pattern having characteristic peaks at ±0.2, 20.456±0.2, 23.547±0.2, and 23.930±0.2.

For example, the intensity and peak position of powder X-ray diffraction of an embodiment of the empagliflozin/citric acid cocrystal according to the present invention may be as shown in Table 1 below.

(Intensity and peak position of PXRD of empagliflozin/citric acid co-crystal)

In addition, the present invention appears at an endothermic initiation temperature of 122.88°C±3°C and an endothermic temperature of 129.87°C±3°C when the temperature increase rate is 10°C/min in the temperature differential scanning calorie (DSC) analysis using a sealed fan. Empagliflozin/citric acid co-crystal formed in a 1:1 ratio of molecules is provided.

In addition, in nuclear magnetic resonance spectroscopy (NMR) analysis, the ¹ H-NMR spectrum shows empagliflozin/citric acid cocrystals in which the ratio of one molecule of empagliflozin and one molecule of those molecules with clear citric acid is 1:1. to provide.

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) mixing empagliflozin and an organic solvent and adding an organic acid thereto; (b) heating the product of step (a) and stirring under reflux; (c) cooling and stirring the product of step (b); (d) evaporating 1/2 of the solvent of step (c); And (e) vacuum-drying the product of step (d) to obtain empagliflozin co-crystal.

The present inventors have established a method for preparing a new pharmaceutically useful co-crystal of empagliflozin, and producing a very pure new co-crystal with high yield without applying a separate salt and removing process during the manufacturing process. . This method is called solvent evaporation during co-crystallization.

Since the method of the present invention is to prepare the empagliflozin/citric acid co-crystal of the present invention described above, the description in common between the two is omitted in order to avoid excessive complexity of the specification due to repeated description. .

Hereinafter, the method of the present invention for preparing empagliflozin/citric acid co-crystal will be described in detail step by step as follows:

(a) Mixing empagliflozin and organic solvent and adding organic acid

First, the method of the present invention includes the steps of mixing empagliflozin and an organic solvent in a solid powder and adding an organic acid thereto.

According to an 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)%, and even more preferably 10-20 (w/v)%.

When preparing the empagliflozin co-crystal, an organic solvent that has been proven to be an effective solvent for producing an empagliflozin co-crystal in a high yield and removing excess organic acid is 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, i.e. a single solvent or A mixed solvent thereof is selected, more preferably methanol, ethanol, isopropyl alcohol, or acetone, and most preferably methanol.

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.

The organic acid is preferably added in a molar ratio of 1 to 1.5 equivalents with respect to each empagliflozin. The thus obtained amorphous empagliflozin new co-crystal or complex is an amorphous empagliflozin/organic acid co-crystal or complex in which empagliflozin is bound.

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 the organic solvent.

This is because when the empagliflozin/organic acid co-crystal or the composite agent is prepared, when the solid powder empagliflozin and the organic acid are mixed, the mixing ratio of the organic acid is important in the formation of the empagliflozin in a 1:1 ratio.

Accordingly, it can be most effectively formed by dividing and mixing 1/3 of the total mixing equivalent of the organic acid rather than adding the organic acid to be mixed with the solid empagliflozin at once.

More preferably, the organic acid of step (a) is added to the mixed empagliflozin and the organic solvent in an amount of 1/3 and added at intervals of 20 minutes.

(b) heating and reflux stirring of the resultant

Then, the method of the present invention goes through a step of heating the resultant of step (a) and stirring under reflux.

The heating time of the resultant product of step (a) needs to be adjusted 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.

According to another embodiment of the present invention, the temperature increase in step (b) is carried out for 1 hour to 3 hours.

According to another embodiment of the present invention, the reflux stirring in step (b) is carried out for 1 hour to 3 hours, more preferably for 30 minutes to 2 hours, even more preferably 30 minutes to 1 hour Conduct during.

(c) cooling and stirring the resultant

Then, the method of the present invention includes the step of cooling and stirring the resultant of step (b), that is, the refluxed reaction liquid.

According to another embodiment of the present invention, the cooling in step (c) is performed at 15-40°C, more preferably at 15-30°C, and most preferably at 15-20°C. .

According to another embodiment of the present invention, the stirring in step (c) is carried out for 1-12 hours, more preferably for 1 to 8 hours, and even more preferably for 3 to 5 hours. do.

(d) evaporating and stirring the resultant product

Then, the method of the present invention includes a step of stirring while evaporating 1/2 of the solvent of the resultant of step (c), that is, the cooled reaction liquid.

According to another embodiment of the present invention, the evaporation in step (d) is performed at 30-60°C, more preferably at 30-50°C, and most preferably at 30-40°C. .

According to another embodiment of the present invention, the stirring in step (d) is carried out for 1-12 hours, more preferably for 1 to 8 hours, and even more preferably for 3 to 5 hours. do.

According to another embodiment of the present invention, after step (d), (d-1) the resultant of step (d) is filtered under reduced pressure and then washed with an organic solvent.

According to another embodiment of the present invention, the organic solvent in step (d-1) is methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, chloroform, methyl ethyl. At least one is selected from an organic solvent 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.

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) obtaining vacuum-dried empagliflozin co-crystal of the resultant product

Finally, the method of the present invention undergoes a step of vacuum drying the resultant of step (e) and obtaining empagliflozin cocrystals.

According to another embodiment of the present invention, the vacuum drying in step (e) is performed at a temperature of 30-65° C. for 8 to 12 hours.

More preferably, the vacuum drying is performed at a temperature of 40-55°C, and even more preferably, the vacuum drying is performed at a temperature of 45-50°C.

The empagliflozin citric acid co-crystal obtained by vacuum drying for the above temperature and time is 1% or less and the purity is 99.5% or more by HPLC.

In this way, as an SGLT-2 inhibitor, 1 equivalent of empagliflozin can be used as a therapeutic agent for type 2 diabetes that controls blood sugar by inhibiting the reabsorption of blood sugar from the kidneys and releasing blood sugar into the urine. It is an acid-bound empagliflozin/citric acid co-crystal.

The features and advantages of the present invention are summarized as follows;

(a) The present invention provides an empagliflozin/citric acid co-crystal in which one molecule of empagliflozin and one molecule of organic acid are bound, and a method for preparing the same.

(b) The empagliflozin/citric acid co-crystal of the present invention is prepared by controlling the equivalent amount of organic acid, the evaporation amount of the stirring solvent, the evaporation temperature and time of the solvent in a special solvent environment through co-crystallization. Optimal proportions of novel co-crystals can be obtained in good purity and yield.

(c) The empagliflozin/citric acid co-crystal of the present invention has very low stability and water solubility of empagliflozin, and the water solubility of empagliflozin and the solubility of small intestine pH 6.8 are 60 due to the co-crystal of the present invention. It has been doubled, and its stability is also improved, making it very useful as a drug substance for empagliflozin.

1 shows a powder X-ray diffraction (PXRD) pattern result of empagliflozin/citric acid co-crystal prepared according to an embodiment of the present invention.
Figure 2 is a powder X-ray diffraction of empagliflozin/citric acid co-crystal, known empagliflozin, citric acid, and empagliflozin/citric acid mixture prepared according to an embodiment of the present invention ( PXRD) pattern results are shown. In this pattern, blue shows empagliflozin/citric acid co-crystal, black shows empagliflozin, red shows citric acid, and light green shows empagliflozin/citric acid mixture, showing that the peaks are different. .
FIG. 3 shows a calorific value curve result of differential temperature scanning calorimetry (DSC) of empagliflozin/citric acid co-crystal prepared according to an embodiment of the present invention.
4 is a temperature differential scanning calorific value of empagliflozin/citric acid cocrystal, known empagliflozin, citric acid, and empagliflozin/citric acid mixture prepared according to an embodiment of the present invention ( DSC) shows the results of the calorie curve. From these results, it is confirmed that the empagliflozin/citric acid co-crystal has a new endothermic peak.
5 shows nuclear magnetic resonance spectroscopy (NMR) ¹ H-NMR spectrum results of empagliflozin/citric acid cocrystals prepared according to an embodiment of the present invention, from which empagliflozin/citric acid The stoichiometric ratio of is 1:1, and the peak is accurately integrated.
6 is a result of a comparison test of the water solubility of the empagliflozin/citric acid co-crystal and the empagliflozin crystalline form at a concentration of 1 mg/mL prepared according to an embodiment of the present invention. At this time, all of the empagliflozin/citric acid cocrystals of the present invention are dissolved, but the empagliflozin crystalline form is not dissolved due to low solubility.

The present invention will be described in more detail through the following examples. These examples are only for describing the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

[Example 1] Preparation of empagliflozin/citric acid co-crystal

After adding 10 g of empagliflozin and 100 ml of ethanol, the mixture is stirred at room temperature for 20 minutes. Then, 1.2 equivalents of citric acid were added by 1/3, and the temperature was gradually raised for 1 hour to reach reflux temperature, followed by stirring for 30 minutes. After slowly cooling to 15 ℃-20 ℃ and stirred for 3 hours. Thereafter, while stirring the temperature at 30° C.-40° C. for 3 hours, 70 ml of ethanol 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 longer to obtain a novel empagliflozin/citric acid co-crystal in 89% yield.

[Example 2] Preparation of empagliflozin/citric acid co-crystal

After adding 10 g of empagliflozin and 100 mL of acetone, the mixture is stirred at room temperature for 20 minutes. Then, after adding 1.2 equivalents of citric acid, the mixture was stirred for 1 hour. Thereafter, the temperature was stirred at 30° C.-40° C. for 3 hours to evaporate 80 mL of acetone to precipitate crystals. Thereafter, 50 mL of ethyl acetate was added, followed by stirring 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 longer to obtain a novel empagliflozin/citric acid co-crystal in 82% yield.

[Experimental Example 1] Powder X-ray diffraction (PXRD)

PXRD analysis (see Fig. 1 to Fig. 2) was performed on an X-ray powder diffractometer (D8 Advance) using Cu Kα radiation. The instrument was equipped with tube power, and the amount of current was set at 45 kV and 40 mA. The divergence and scattering slits were set to 1°, and the light receiving slits were set to 0.2 mm. A θ-2θ continuous scan of 3°/min (0.4 sec/0.02° interval) from 5 to 35° 2θ was used.

[Experimental Example 2] Temperature Differential Scanning Calorimetry (DSC)

DSC Q20 obtained from TA company was used to perform DSC measurements (see FIG. 3 to FIG. 4) in a closed pan at a scan rate of 10°C/min from 20°C to 300°C under nitrogen purification.

[Experimental Example 3] Evaluation of the solubility of empagliflozin/citric acid co-crystal

Since empagliflozin is poorly soluble with a water solubility of 0.111 mg/ml, it is combined with citric acid with high water solubility to prepare a new co-crystal to improve water solubility and gastrointestinal pH solubility of empagliflozin. I did. The results are summarized in Table 2 below.

H ₂ O pH6.8 Empagliflozin crystalline form 0.101 mg/mL 0.108 mg/mL Empagliflozin/Citric Acid 6.06 mg/mL 6.48 mg/mL

(Solubility of Empagliflozin/Citric Acid Cocrystal)

As shown in Table 2, it was confirmed that the water solubility of the empagliflozin/citric acid co-crystal of the present invention and the solubility in the small intestine pH 6.8 were increased by about 60 times compared to the known empagliflozin crystalline form. Therefore, it was confirmed that the empagliflozin/citric acid co-crystal of the present invention can increase the water solubility up to about 60 times compared to the known empagliflozin crystalline form. Therefore, the empagliflozin/citric acid co-crystal of the present invention is a novel crystalline form capable of overcoming the low water solubility, which is a problem of the empagliflozin crystalline form, which can maximize the medicinal effect of empagliflozin. Was predicted.

[Experimental Example 4] Acceleration and severe stability comparison evaluation of empagliflozin/citric acid co-crystal and empagliflozin crystalline form

The stability test of a drug is to set the storage method and period of use of the drug, after setting an appropriate standard, and then determining a significant change based on the determined test method and setting the expiration date. Is one of the very important factors in the commercialization of drugs.

Therefore, in order to confirm the commercialization possibility of the empagliflozin/citric acid co-crystal of the present invention, the empagliflozin crystalline form known in International Publication No. WO 2006/117359 was used as a control and accelerated according to the ICH guidelines. After performing severe stability and analyzing using a liquid chromatography (HPLC) analysis method described in the United States Pharmacopeia (USP), the results are shown in Tables 3 and 4.

Early 3 days 7 days Empagliflozin/
Fumaric acid 99.84% 99.85% 99.84% Empagliflozin crystalline form 99.84% 99.31% 99.01%

{Accelerated stability results of empagliflozin/citric acid co-crystal and empagliflozin crystalline form (40℃± 2℃, RH 75%)}

Early 3 days 7 days Empagliflozin/
Citric acid 99.84% 99.83% 99.81% Empagliflozin crystalline form 99.84% 99.02% 98.07%

{Severe stability evaluation result of empagliflozin/citric acid co-crystal and empagliflozin (60℃± 2℃, RH 75%)}

Acceleration of the empagliflozin/citric acid co-crystal and the empagliflozin crystalline form prepared according to Examples, and stability tests under severe conditions were performed. As a result, as shown in Tables 3 and 4, the empagliflozin/citric acid co-crystal remained stable without the influence of the purity, but it was confirmed that the empagliflozin crystal form was poor in stability as the purity decreased.

Therefore, it was confirmed that the stability of the empagliflozin/citric acid co-crystal was improved compared to that of the empagliflozin crystalline form.

[Experimental Example 5] Comparative test of water solubility of empagliflozin/citric acid co-crystal and empagliflozin crystalline form

To increase the absorption rate in the body, water solubility must be increased to some extent. Therefore, the water solubility of the empagliflozin/citric acid co-crystal of the present invention and the known empagliflozin crystalline form was compared and evaluated at a concentration of 1 mg/mL. As a result, it was confirmed that the empagliflozin crystal form did not dissolve and existed in a suspension state, whereas the empagliflozin co-crystal of the present invention was all dissolved to increase water solubility. Therefore, the co-crystal of the present invention has proven its value as a new drug substance capable of overcoming the poor solubility of empagliflozin by improving water solubility [Fig. 6].

Therefore, the present invention empagliflozin/citric acid co-crystal is expected as a new drug substance that overcomes the problems of empagliflozin, such as low stability and water solubility.

As described above, specific parts of the present invention have been described in detail, and it is obvious that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto for those of ordinary skill in the art. Accordingly, it will be said that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (5)

As an empagliflozin/citric acid co-crystal combined with one molecule of empagliflozin and one molecule of citric acid, the empagliflozin/citric acid co-crystal is a compound represented by Formula 1, and X-ray diffraction In (PXRD) analysis, the 2θ diffraction angle was 13.458±0.2, 14.791±0.2, 18.056±0.2, 18.423±0.2, 18.923±0.2, 20.456±0.2, 23.547±0.2, and 23.930±0.2. Empagliflozin/citric acid co-crystal, characterized in that it has a diffraction pattern and appears at an endothermic initiation temperature of 122.88℃±3℃ in temperature differential scanning calorimetry (DSC) analysis, and appears at an endothermic temperature of 129.87℃±3℃:
[Formula 1]

delete delete delete A pharmaceutical composition for the treatment or prevention of diabetes, including the empagliflozin/citric acid co-crystal of claim 1, to control blood sugar by inhibiting SGLT-2.

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