KR102111247B1 - Amorphous state of New dapagliflozin cocrystal or complex - Google Patents

Abstract

As a result of efforts to improve the low stability and water solubility, which is a problem of dapagliflozin, the inventors of the present invention developed an amorphous form of dapagliflozin/L-arginine co-crystal or a composite with an increase in stability and water solubility of 12 times or more. The amorphous form of dapagliflozin/L-arginine co-crystal or the composite is a new solid form with improved stability and water solubility of dapagliflozin, which is very useful as an optimal raw material drug that can maximize the utilization as a drug.

Description

Amorphous state of New dapagliflozin cocrystal or complex

The present invention provides an amorphous form of a dapagliflozin co-crystal or composite agent having improved stability and water solubility, which is a problem of dapagliflozin.

Cocrystals have new functional crystal structures, such as O, OH, N, etc., which are rich in functional groups that can form hydrogen bonds, or have a pKa difference of 3 or less, and combine them at regular rates through hydrogen bonding with coformers. Means a crystalline solid. Since these co-crystals contain two or more molecules, they can be expressed in a complex form. Since the formation of such a co-crystal forms a crystal structure through new hydrogen bonding of two or more molecules, the solubility and dissolution rate of the drug can be increased. Due to this, it is possible to change the bioavailability by changing the absorption rate of the drug in the human body. The co-molecule selection of co-crystals to overcome poor solubility should be water-friendly molecules that are soluble in water. If such a co-molecule is not water-friendly and has poor solubility, it does not overcome the drug's poor solubility, but rather causes a low solubility. Therefore, the selection of co-molecules is a very important requirement. And co-crystals include amorphous polymorphs, hydrates, solvates, and the like.

Crystals generally have the property of maintaining the thermodynamic stability by preferentially depositing metastable crystals in the crystallization process and then transitioning to a more stable crystal structure in a solvent-borne and solid state, and thus, phase transitions in the solvent are generally used. transformation) to rearrange the molecules to form a more stable crystal structure. This creates a crystalline polymorph, called ostwald's rule of stage. Therefore, the physicochemical properties of metastable and stable crystals are changed. Therefore, it is the drug that causes the change in solubility, which represents the thermodynamic energy of the most important crystal. In addition, co-molecules of co-crystals can generally confirm the presence of crystal polymorphs in the crystal structure or the crystal structure is changed through a phase transition phenomenon that is replaced with solvent molecules in a solvent. Therefore, co-crystals in water can be phase-shifted as hydrates, which can cause the solubility of co-crystals to change to the solubility of hydrates. The reason why the solubility is not improved even when the co-crystal is prepared in the poorly soluble hydrate crystal form is that the co-crystal has been converted into a hydrate. Therefore, the selection of co-molecules is very important. Depending on which co-molecule 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 co-crystals is achieved through cocrystallization. Co-crystallization methods include solvent evaporation technique, anti-solvent method, solvent drop grinding, slurry technique, solid state grinfing, etc. There is (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 an energy level higher than that of the crystalline form, and thus higher solubility than the crystalline form. However, due to the high energy level, the thermodynamic stability is low, and thus it has a problem of rapidly reversing to a crystalline form. Amorphous co-amorphous (co-amorphous) forms an amorphous solid through a new hydrogen bond between two or more molecules, and can show the effect of suppressing the phase transformation into a crystalline form, and can overcome poor solubility through high solubility. It is in a solid state. The reason for suppressing the phenomenon of phase change to the crystalline form 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, the formation of the co-crystal in the amorphous form should use a crystallization method in which the crystallization rate is controlled very rapidly and a high degree of supersaturation is rapidly reached. Typically, a method for rapidly inducing crystallization rates such as vacuum evaporation crystallization, supercritical crystallization, liquid nitrogen crystallization, and freeze-evaporation crystallization is used. However, in the formation of co-crystals, hydrogen bonds due to interactions between drug molecules and co-molecules are very diverse, so even with this extreme crystallization method, it is very difficult to design and control amorphous (From Molecules to Crystallizers An Introduction to Crystallization 2000; pp. 2-14).

In addition, in order to confirm the improvement of stability in the amorphous form of the crystal, it is to confirm whether the glass transition temperature (Tg) appears at a temperature higher than that 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 may exist (Advanced Drug Delivery Reviews 100 (2016) 116 -125).

SGLT-2 (sodium / glucose cotransporter 2), along with SGLT-1 (sodium / glucose cotransporter 1), is a transporter responsible for excessive resorption of blood glucose from the kidneys, and SGLT-2 plays the most role. Therefore, when the SGLT-2 inhibitor inhibits the SGLT-2 transporter, the blood sugar discharged to the urine increases, and eventually the blood sugar is lowered, and furthermore, the calories of the blood sugar are discharged, resulting in the effect of weight loss.

One of the drugs developed as an SGLT-2 inhibitor that can be usefully used as a treatment for type 2 diabetes due to this effect is Dapagliflozin, which is currently sold worldwide under the trade name Forxiga. .

Dapagliflozin is represented by the following structural formula (Chemical Formula 1) and was first disclosed in WO 2001/027128.

[Formula 1]

However, dapagliflozin is an amorphous solid and has a low glass transition temperature at 44 ° C, so it has poor stability and hygroscopicity, and its water solubility is only 0.173 mg / mL, so it has a low water solubility even in an amorphous form. Have

In addition, dapagliflozin is a drug substance, and it is difficult to maintain a certain quality, and thus has a disadvantage that it is not useful as a formulation.

WO 2008/002824 discloses a propylene glycol solvate hydrate of dapagliflozin. However, this propylene glycol is an expensive solvent and has low economic efficiency, and when crystallizing a solvate, the complexity of the crystallization method is problematic.

And in Korean Patent Publication No. 10-2004488, dapagliflozin 1,2-hexanediol solvate is disclosed, but data on its water solubility and stability are not disclosed.

Throughout this specification, a number of papers and patent documents are referenced and their citations are indicated. The disclosures of cited papers and patent documents are incorporated by reference into this specification as a whole, and the level of the technical field to which the present invention pertains and the content of the present invention are more clearly described.

As a result of efforts to improve the high hygroscopicity, low stability, and water solubility, which are problems of dapagliflozin, the present inventors have developed a co-crystal or composite agent of the dapagliflozin / L-arginine amorphous form.

Accordingly, an object of the present invention is to provide a novel amorphous form of dapagliflozin / L-arginine co-crystal or complex agent.

 Another object of the present invention is to provide a method for preparing a co-crystal or composite of dapagliflozin / L-arginine in the amorphous form of the present invention described above.

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

According to an aspect of the present invention, the present invention provides an amorphous form of a co-crystal or a complex agent in which one molecule of dapagliflozin and one molecule of L-arginine are combined.

The present inventors prepared an amorphous form of dapagliflozin / L-arginine co-crystal or a complex agent using L-arginine, which is an amino acid other than a basic inorganic salt.

The present inventors have very high water solubility to overcome the low hygroscopicity, stability, and water solubility of dapagliflozin, and are rich in NH, N, O, and OH-rich arginine, L-lysine, fumaric acid, L-pyroglutamic acid, and citric acid. Was selected and attempted to design and manufacture an amorphous co-crystal. As a result, dapagliflozin / L-arginine was developed. Through the experiment, a method for reproducibly manufacturing an amorphous form of dapagliflozin / L-arginine co-crystal or a complex agent was established, and the thus prepared amorphous form of dapagliflozin / L-arginine co-crystal or complex agent was The water solubility and solubility of small intestine pH increased more than 12 times more than the dapagliflozin amorphous form, and can be sufficiently dissolved in 250 ml, which is the amount of water input when ingesting oral drugs, thereby improving oral absorption, hygroscopicity, and Stability is also improved. Therefore, when the co-crystal or composite agent of the dapagliflozin / L-arginine amorphous form of the present invention is used, it is suitable to be used as an improved new drug that improves the stability and water solubility of dapagliflozin.

According to an embodiment of the present invention, the amorphous form of dapagliflozin / L-arginine co-crystal or complex agent is a compound represented by the following Chemical Formula 2:

The amorphous form of dapagliflozin / L-arginine co-crystal or a complex agent of Formula 2 forms a co-crystal in a 1: 1 ratio of a molecule of dapagliflozin and a molecule of L-arginine by hydrogen bonding. When L-arginine dissolves due to the interaction with L-arginine, L-arginine having such high water solubility forms an amorphous form due to hydrogen bonding with dapagliflozin, so that dapagliflozin also dissolves in water. Therefore, the water solubility and solubility of the small intestine pH 6.8 are increased.

Therefore, it was confirmed that water solubility and small intestine pH 6.8 solubility increased 12-fold compared to dapagliflozin amorphous, dissolved in 250 ml of water, and improved stability.

 The amorphous form of the dapagliflozin / L-arginine co-crystal or complex of the present invention is a novel solid form that has not been reported anywhere.

According to an embodiment of the present invention, the amorphous form of dapagliflozin / L-arginine co-crystal or composite agent has an amorphous form with a 2θ diffraction angle in X-ray diffraction (PXRD) analysis, and a temperature differential scanning calorimetry (DSC). In the analysis, the glass transition temperature is 55.82 ° C ± 3 ° C, 59.43 ° C ± 3 ° C, and 62.60 ° C ± 3 ° C, which is an amorphous form of a co-crystal or complex formed with 1: 1 ratio of the molecules.

According to another aspect of the present invention, the present invention provides a method for preparing an amorphous form of dapagliflozin / L-arginine co-crystal or complex comprising the following steps.

(a) mixing dapagliflozin and an organic solvent and adding L-arginine to each; (b) heating the resultant of step (a) and refluxing; (c) cooling and stirring the result of step (b); (d) evaporating 1/2 of the solvent of step (c); And (e) vacuum drying the resultant of step (d) to obtain an amorphous form of dapagliflozin / L-arginine co-crystal or a complex crystal.

The present inventors have prepared a new co-crystal or a complex of a very pure amorphous form without adding a separate salt to the peeling process in addition to preparing a new co-crystal and a complex agent of a pharmaceutically useful amorphous form of dapagliflozin. A method that can be produced with high yield was established. This method is called solvent evaporation during co-crystallization.

Since the method of the present invention is to prepare the above-described amorphous form of the present invention, the dapagliflozin / L-arginine co-crystal or complex agent, the common content between the two is to avoid excessive complexity of the specification according to the repeated description. , The description is omitted.

Hereinafter, the method of the present invention for preparing a co-crystal or composite of dapagliflozin / L-arginine in an amorphous form will be described in detail step by step as follows;

(a) Mixing dapagliflozin and organic solvent and adding L-arginine

First, the method of the present invention includes the step of mixing the dapagliflozin and the organic solvent of the solid powder and adding L-arginine to each.

According to one embodiment of the present invention, the dapagliflozin of step (a) is added at 1-30 (w / v)% relative to the volume of the organic solvent, more preferably 6-25 (w / v)%, even more preferably 10-20 (w / v)%.

In the production of the amorphous form of dapagliflozin / L-arginine co-crystal or complex, an amorphous form of dapagliflozin / L-arginine co-crystal or complex is produced with high yield, and L-arginine used in excess is Organic solvents proven to be effective solvents for removal are preferably methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, chloroform, methyl ethyl ketone, ethyl acetate, methylene chloride And at least one organic solvent composed of 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.

 According to another embodiment of the present invention, L-arginine of step (a) is added in a molar ratio of 1 to 1.5 equivalents relative to dapagliflozin.

 It is preferable that L-arginine is added in a molar ratio of 1 to 1.5 equivalents with respect to dapagliflozin, respectively. The novel co-crystal or co-crystal of the amorphous form of dapagliflozin thus obtained is a co-crystal or co-crystal of the dapagliflozin / L-arginine in the amorphous form to which dapagliflozin is bound.

 According to another embodiment of the present invention, the L-arginine of step (a) is added in the amount of 1/3 to the mixed dapagliflozin and organic solvent.

 This is in the case of mixing the dapagliflozin / L-arginine co-crystal or the complex powder of dapagliflozin and L-arginine in the mixing ratio of L-arginine to form a 1: 1 ratio with dapagliflozin. Because it is important.

 Thus, it can be formed most effectively when dividing and mixing L-arginine by 1/3 of the total mixing equivalent weight than adding L-arginine mixed with solid powder dapagliflozin at one time.

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

(b) heating and reflux stirring of the result

  Then, the method of the present invention is subjected to the step of raising the resultant of step (a) and stirring under reflux.

 The temperature rise time of the result of the step (a) requires adjustment of the temperature so that it takes more than 1 hour to reach the reflux temperature, and the stirring time at the reflux temperature should not exceed 3 hours.

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

 According to another embodiment of the present invention, the reflux stirring in step (b) is performed for 1 hour to 3 hours, more preferably 30 minutes to 2 hours, and even more preferably 30 minutes to 1 hour While conducting.

(c) Cooling and stirring of the result

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

 According to another embodiment of the invention, the cooling of step (c) is carried out at 15-40 ℃, more preferably at a temperature of 15-30 ℃, most preferably at 15-20 ℃ .

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

(d) Evaporating and stirring the resulting product

  The method of the present invention then comprises stirring the product of step (c) above, ie half evaporating the solvent of the cooled reaction solution.

  According to another embodiment of the invention, the evaporation of step (d) is carried out at 30-60 ℃, more preferably at a temperature of 30-50 ℃, most preferably at 30-40 ℃ .

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

   According to another embodiment of the present invention, after the step (d) (d-1) further comprises the step of washing the resultant of the step (d) with an organic solvent after filtering under reduced pressure.

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 is selected from organic solvents composed 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 preferred It is acetone.

According to another embodiment of the present invention, the organic solvent of step (c-1) is added at 1-30 (v / v)% relative to the volume of the organic solvent of step (a), more preferably 1-10 (v / v)%, even more preferably 2-5 (v / v)%.

(e) vacuum drying of the resultant product and obtaining amorphous form of dapagliflozin / L- arginine co-crystal and complex agent crystal

Finally, the method of the present invention is subjected to a step of vacuum drying the result of step (e) and obtaining dapagliflozin / L-arginine co-crystal and co-crystal.

According to another embodiment of the invention, the vacuum drying in step (e) is carried out for 8 to 12 hours at a temperature of 30-65 ℃.

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

Amorphous form of dapagliflozin / L-arginine co-crystal or composite 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.

In this way, as an SGLT-2 inhibitor, 1 equivalent of L- to 1 equivalent of dadapagliflozin, which can be used as a therapeutic agent for type 2 diabetes, regulates blood sugar by suppressing resorption of blood sugar from the kidneys to discharge blood sugar to urine It is an amorphous form of arginine-linked dapagliflozin / L-arginine co-crystal or complex agent.

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

(a) The present invention provides an amorphous form of dapagliflozin / L-arginine co-crystals or complexes in which one molecule of dapagliflozin and one molecule of L-arginine are combined, and a preparation method thereof.

(b) Dapagliflozin / L-arginine co-crystal or composite agent of the amorphous form of the present invention is equivalent to L-arginine, evaporation of stirred solvent, evaporation temperature of solvent in a special solvent environment through co-crystallization in its preparation And by adjusting the time. An optimum ratio of new co-crystals can be obtained with excellent purity and yield.

(c) Dapagliflozin / L-arginine co-crystal or complex agent of the amorphous form of the present invention exhibits very low stability and water solubility of Dapagliflozin due to the amorphous form of the present invention. The water solubility of rosin and the solubility of small intestine pH 6.8 have been increased 12-fold, and the stability has also been improved, making it very useful as a drug substance for the combination of dapagliflozin. That is, the amorphous form of the present invention, a dapagliflozin / L-arginine co-crystal or a complex agent is very useful as a main component of a pharmaceutical composition for treating or preventing diabetes by inhibiting SGLT-2 to control blood sugar.

1 shows the powder X-ray diffraction (PXRD) pattern results of an amorphous form of dapagliflozin / L-arginine co-crystal or composite prepared according to an embodiment of the present invention.
Figure 2 shows the calorific curve results of the temperature differential scanning calorimetry (DSC) of the amorphous form of dapagliflozin / L-arginine co-crystal or composite prepared according to an embodiment of the present invention.
Figure 3 shows the glass transition temperature (Tg) comparison results in the temperature differential scanning calorimetry (DSC) analysis of the amorphous form of dapagliflozin / L-arginine and dapagliflozin amorphous prepared according to an embodiment of the present invention Show.

The present invention will be described in more detail through the following examples. These examples are only intended to illustrate the present invention more specifically, 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. .

[ Example  One] Dapagliflozin / L-arginine Decision  Or compound preparation

After adding 10 g of dapagliflozin and 100 ml of methanol, stir at room temperature for 20 minutes. Subsequently, L-arginine 1.2 equivalent was added in 1/3 increments and the temperature was gradually raised for 1 hour to reach reflux temperature, followed by stirring for 30 minutes. Slowly cooled to 15 ° C-20 ° C and stirred for 3 hours. Thereafter, while stirring the temperature at 30 ° C-40 ° C for 3 hours, 50 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 novel amorphous form of dapagliflozin / L-arginine or a complex agent (purity 99.2%, HPLC) in 90% yield. .

[ Example  2] Dapagliflozin / L-arginine Decision  Or compound preparation

After adding 10 g of dapagliflozin and 200 ml of ethanol, stir for 20 minutes at room temperature. Subsequently, L-arginine 1.2 equivalent was added in 1/3 increments and the temperature was gradually raised for 1 hour to reach reflux temperature, followed by stirring for 30 minutes. Slowly cooled to 15 ° C-20 ° C and stirred for 3 hours. After that, the mixture was stirred for 3 hours at 30 ° C to 40 ° C, and 100 ml of ethanol 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 novel amorphous form of dapagliflozin / L-arginine or a complex agent (purity 99.2%, HPLC) in 90% yield. .

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

PXRD analysis (see FIG. 1) was performed on an X-ray powder diffractometer using Cu Kα radiation (D8 Advance). The instrument was equipped with tube power, and the amount of current was set to 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. A θ-2θ continuous scan of 3 ° min (0.4 sec / 0.02 ° intervals) from 5 to 35 ° 2θ was used.

[ Experimental Example  2] Temperature differential injection Calorimetry ( DSC )

DSC measurement (see FIG. 3 in FIG. 2) was performed in a closed pan at a scanning rate of 10 ° C./min from 20 ° C. to 300 ° C. under nitrogen purification using DSC Q20 obtained from TA.

[ Experimental Example  3] Dapagliflozin / L-arginine Decision  Or evaluation of the solubility of the complex

Since dapagliflozin is poorly soluble with a water solubility of 0.173 mg / ml, water-soluble and gastrointestinal tracts of dapagliflozin are prepared by combining with L-arginine, which has high water solubility, to prepare a new amorphous co-crystal and complex agent. It was intended to improve the pH solubility. The results are summarized in Table 1 below.

Amorphous Dapagliflozin / L-arginine Decision  or
 Combination drugs Dapagliflozin  Solubility H ₂ O pH6.8 Dapagliflozin amorphous 0.172 mg / ml 0.168 mg / ml Dapagliflozin / L-arginine 2.01 mg / ml 2.08 mg / ml

As shown in Table 1 above, compared to the dapagliflozin of the present invention, the water solubility and solubility in the small intestine pH 6.8 of the amorphous form of the dapagliflozin / L-arginine co-crystal or complex were increased by about 12 times or more. Was confirmed.

[ Experimental Example  4] Amorphous Dapagliflozin / L-arginine Public Crystal Division Dapagliflozin  Amorphous acceleration, Comparison of harsh stability  evaluation

      In order to establish the storage method and period of use of pharmaceuticals, the drug stability test is based on the determined test method, and then the significant change is determined and the expiration date is set. Is one of the most important factors in the commercialization of drugs.

Therefore, in order to confirm the commercialization potential of the amorphous form of the dapagliflozin / L-arginine co-crystal of the present invention, accelerated and severe stability was carried out according to the ICH guidelines using the crystalline dapagliflozin amorphous as a control and the United States. After analyzing using liquid chromatography (HPLC) analysis method described in the Pharmacopoeia (USP), the results are shown in Tables 2 and 3.

Amorphous Dapagliflozin / L-arginine Public Crystal Division
Dapagliflozin  Amorphous acceleration stability result (40 ℃ ± 2 ℃, RH 75%) Early 15th 30 days Dapagliflozin / L-arginine 99.84% 99.82% 99.83% Dapagliflozin amorphous 99.72% 99.34% 98.09%

Amorphous Dapagliflozin / L-arginine Public Crystal Division
Dapagliflozin  Severe stability evaluation result (60 ℃ ± 2 ℃, RH 75%) Early 3 days 7 days Dapagliflozin / L-arginine 99.84% 99.80% 99.81% Dapagliflozin
Amorphous 99.72% 98.24% 97.85%

The stability test of the acceleration and harsh conditions of the dapagliflozin / L-arginine and the dapagliflozin amorphous produced by the Examples was conducted. As a result, as shown in Tables 2 and 3, dapagliflozin / L-arginine remained stable without the effect of purity, but it was confirmed that the dapagliflozin amorphous form had low purity and poor stability. Therefore, it was confirmed that the acceleration of dapagliflozin / L-arginine and stability under severe conditions were improved over the dapagliflozin amorphous form.

Therefore, the amorphous form of the present invention, the dapagliflozin / L-arginine co-crystal or composite agent is expected to be a new drug substance that overcomes the low stability and water solubility of the problem of dapagliflozin.

Since the specific parts of the present invention have been described in detail above, it is clear that for those skilled in the art, this specific technology is only a preferred embodiment, and 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 (6)

delete delete Dapagliflozin / L-arginine co-crystal characterized in that the powder X-ray diffraction (PXRD) pattern shows an amorphous form as shown in FIG. 1:
Fig. 1

The method of claim 3, wherein the dapagliflozin / L-arginine co-crystal is an amorphous form of dapagliflozin / L-arginine in which 1 equivalent of L-arginine is combined with 1 equivalent of dapagliflozin. . According to claim 3, in the temperature differential scanning calorimetry (DSC) analysis, the glass transition temperature shown in Figure 2 is shown at 55.82 ℃ ± 3 ℃, 59.43 ℃ ± 3 ℃, 62.60 ℃ ± 3 ℃, the ratio of the molecules 1: Amorphous form of dapagliflozin / L-arginine co-crystal formed of 1:
Figure 2

A pharmaceutical composition for the treatment or prevention of diabetes mellitus that controls blood sugar by inhibiting SGLT-2 as a main component of the amorphous dapagliflozin / L-arginine co-crystal of any one of claims 3 to 5.

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