KR20250007816A - Novel Crystalline form of Empagliflozin 2L-proline and methods of preparing thereof - Google Patents

Abstract

The present invention relates to a novel crystalline form of empagliflozin 2L-proline and a method for preparing the same, and more particularly, the present invention relates to a method for preparing a novel crystalline form of empagliflozin 2L-proline, comprising the steps of adding 2 equivalents or more of L-proline to empagliflozin, adding an organic solvent, heating and dissolving, and cooling the same, and to a novel crystalline form of empagliflozin 2L-proline prepared by the method. The novel crystalline form of empagliflozin 2L-proline prepared by the method for preparing a novel crystalline form of empagliflozin 2L-proline according to the present invention has the characteristics of high solubility and excellent stability, improving the problems of low solubility and instability of empagliflozin, which has been conventionally used as an SGLT-2 inhibitor, and thus has the effect of enabling more stable formulation.

Description

{Novel Crystalline form of Empagliflozin 2L-proline and methods of preparing thereof}

The present invention relates to a novel crystalline form of empagliflozin 2L-proline and a method for producing the same.

Type 2 diabetes is a progressive disease in which blood sugar control becomes increasingly difficult and complications cannot be avoided even with a combination of drugs, as the beta cell function of the pancreas that secretes insulin gradually declines over time. SGLT2 (sodium glucose co-transporter 2) inhibitors, developed as anti-diabetic drugs, were developed with a new mechanism of action in the reabsorption of glucose in the kidneys, as the role of the kidneys in diabetes has been highlighted.

Also, one SGLT2 inhibitor, empagliflozin, is a drug used to lower blood sugar levels in people with type 2 diabetes (a condition in which blood sugar is too high because the body does not produce or use insulin normally) by getting the kidneys to remove more glucose from the urine. It is also used to reduce the risk of stroke, heart attack, or death in people with type 2 diabetes who also have heart and blood vessel disease, and in adults with heart failure to reduce the risk of hospitalization and death from heart and blood vessel disease.

Pharmaceutical cocrystals are a new class of pharmaceutical materials that have the potential to develop refined physical properties that provide a stable, solid form. These multicomponent crystal forms influence relevant physicochemical parameters such as solubility, chemical stability, and physical stability. The result is a material with properties superior to those of the free drug. Cocrystallization is a process that can alter molecular interactions to optimize drug properties. Cocrystals contain a multicomponent system of an active pharmaceutical ingredient (API) with stoichiometric amounts of pharmaceutically acceptable coformers incorporated within the crystal lattice. The physicochemical properties of a drug can be improved by preparing pharmaceutical cocrystals.

Meanwhile, empagliflozin disclosed in the previous international patent publication WO 2005/092877 is in an amorphous form that does not provide a crystalline form, has poor stability, and has a low melting point and high hygroscopicity, making it difficult to maintain a consistent quality as a raw pharmaceutical material, making it not useful in pharmaceutical terms, and has the disadvantage of low solubility.

In addition, International Patent Publication No. WO 2006/117359 discloses a crystalline form of empagliflozin. However, this crystalline form requires a long-term crystalline manufacturing process during manufacturing, including an additional process for crystallizing amorphous empagliflozin in order to solve the problem of empagliflozin as a raw material drug, or requires a long-term drying process of the produced crystals, and has a low economic efficiency of about 67% in yield. In addition, although it is said to be an improvement over the amorphous form, it still has the disadvantage of low water solubility and stability.

Therefore, there is a need to develop an improved method for manufacturing empagliflozin crystals to solve the problems of low water solubility and instability that prevents maintaining a certain quality, which are problems of conventional empagliflozin.

International Patent Publication No. WO 2005/092877 International Patent Publication No. WO 2006/117359 International Patent Publication No. WO 2016/131431

Accordingly, the inventors of the present invention have completed the present invention by developing a novel 2L-proline crystal form of empagliflozin that can solve the low water solubility and poor stability of conventional empagliflozin that cannot maintain a constant quality and is easy to produce.

Therefore, the purpose of the present invention is to provide a method for producing a novel crystalline form of empagliflozin 2L-proline.

Another object of the present invention is to provide a novel crystalline form of empagliflozin 2L-proline, characterized in that the X-ray powder diffraction spectrum peaks have characteristic peaks at positions of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2° in 2θ diffraction angles, the onset temperature of endotherm by differential scanning calorimetry (DSC) is 162.70±3°C, and the endothermic temperature is 164.53±3°C.

Another object of the present invention is to provide a pharmaceutical composition comprising a novel crystalline form of empagliflozin 2L-proline as an active ingredient, wherein the novel crystalline form has characteristic peaks at positions of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2° in 2θ diffraction angles in an X-ray powder diffraction spectrum, an endothermic onset temperature of 162.70±3°C by differential scanning calorimetry (DSC), and an endothermic temperature of 164.53±3°C.

In order to achieve the above purpose, the present invention relates to a method for preparing a novel crystalline form of empagliflozin 2L-proline of the following chemical formula 1, which comprises the steps of adding 2 equivalents or more of L-proline to empagliflozin of the following chemical formula 2, adding an organic solvent, then heating and dissolving and cooling.

<Chemical Formula 1>

<Chemical Formula 2>

In one embodiment of the present invention, the organic solvent may be at least one organic solvent selected from the group consisting of C1 to C4 alcohol, tetrahydrofuran, acetone, and acetonitrile.

In one embodiment of the present invention, the heating may be performed at a temperature of 40 to 80°C.

In one embodiment of the present invention, after performing the cooling step, a step of adding, stirring, and filtering at least one solvent selected from the group consisting of n-heptane, n-hexane, cyclohexane, water, ethyl acetate, and dichloromethane may be further included.

In one embodiment of the present invention, the stirring may be performed at a temperature of 20 to 30°C for 1 to 3 hours.

In one embodiment of the present invention, the novel crystalline form of empagliflozin 2L-proline of the chemical formula 1 may have characteristic peaks at positions of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2° in 2θ diffraction angles of an X-ray powder diffraction spectrum peak, and may have an endothermic onset temperature of 162.70±3°C and an endothermic temperature of 164.53±3°C by differential scanning calorimetry (DSC).

In addition, the present invention provides a novel crystalline form of empagliflozin 2L-proline, characterized in that the X-ray powder diffraction spectrum peaks have characteristic peaks at positions of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2° in 2θ diffraction angles, the onset temperature of endotherm by differential scanning calorimetry (DSC) is 162.70±3°C, and the endothermic temperature is 164.53±3°C.

In addition, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a novel crystalline form of empagliflozin 2L-proline, which has characteristic peaks in an X-ray powder diffraction spectrum at positions of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2° in 2θ diffraction angles, has an endothermic onset temperature of 162.70±3°C and an endothermic temperature of 164.53±3°C by differential scanning calorimetry (DSC).

In one embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier or excipient.

In one embodiment of the present invention, the pharmaceutical composition may be used for preventing or treating diabetes, diabetic complications, or chronic heart failure.

The method for manufacturing a novel crystalline form of empagliflozin 2L-proline according to the present invention and the novel crystalline form of empagliflozin 2L-proline manufactured by the method have the characteristics of high solubility and excellent stability, improving the problems of low solubility and instability of empagliflozin, which is conventionally used as an SGLT-2 inhibitor, and thus have the effect of enabling more stable formulation.

Figure 1 is an XRD pattern for the novel 2L-proline crystalline form of empagliflozin of the present invention.
Figure 2 is a DSC pattern for the novel 2L-proline crystalline form of empagliflozin of the present invention.
Figure 3 is an XRD pattern for the crystal form of empagliflozin.
Figure 4 is a DSC pattern for the crystalline form of empagliflozin.
Figure 5 is an XRD pattern for the L-proline crystal form of empagliflozin.
Figure 6 is a DSC pattern for the L-proline crystalline form of empagliflozin.

The present invention is characterized by the discovery of a novel empagliflozin 2L-proline crystalline form having high solubility and excellent stability, which improves the problems of low solubility and instability of conventional empagliflozin compounds used as SGLT-2 inhibitors, and a method for producing the same.

The novel crystalline form of empagliflozin 2L-proline according to the present invention has characteristic peaks in an X-ray powder diffraction spectrum at 2θ diffraction angles of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2°, and has an endothermic onset temperature of 162.70±3°C and an endothermic temperature of 164.53±3°C by differential scanning calorimetry (DSC).

In addition, in one embodiment of the present invention, the solubility and stability of the novel crystalline form of empagliflozin 2L-proline according to the present invention were analyzed, and as a result of comparing it with the crystalline form of empagliflozin and empagliflozin L-proline, it was found to have significantly improved solubility compared to the crystalline form of empagliflozin and empagliflozin L-proline, and specifically, it was confirmed to have an aqueous solubility about 20 times higher than that of the crystalline form of empagliflozin (see Table 2).

In addition, the stability analysis results showed that the stability of empagliflozin crystalline form and empagliflozin L-proline decreased over time, whereas the novel crystalline form of empagliflozin 2L-proline of the present invention maintained a high level of stability (see Table 3).

Through this, the inventors of the present invention were able to find out that the novel crystalline form of empagliflozin 2L-proline according to the present invention has superior solubility and stability compared to the crystalline form of empagliflozin and empagliflozin L-proline, and thus can be very easily formulated as a pharmaceutical product.

In addition, the present invention can provide a method for producing a novel crystalline form of empagliflozin 2L-proline according to the present invention.

As shown in the schematic diagram below, the novel crystalline form of empagliflozin 2L-proline according to the present invention is prepared by synthesizing 2 equivalents or more of L-proline into empagliflozin.

Specifically, the method for manufacturing a novel crystalline form of empagliflozin 2L-proline includes the steps of adding 2 equivalents or more of L-proline to empagliflozin of the following chemical formula 2, adding an organic solvent, heating to dissolve, and cooling.

<Chemical Formula 1>

<Chemical Formula 2>

Any organic solvent used for compound synthesis may be used as the above organic solvent, and preferably, at least one organic solvent selected from the group consisting of C1 to C4 alcohol, tetrahydrofuran, acetone, and acetonitrile may be used. That is, any single solvent or mixed solvent selected from the group consisting of C1 to C4 alcohol, tetrahydrofuran, acetone, and acetonitrile may be used.

In one embodiment of the present invention, ethanol, isopropyl alcohol and methanol were used alone or as a mixed solvent selected from among them.

In addition, the heating can be performed at a temperature of 40 to 80°C to dissolve empagliflozin, 2 equivalents or more of L-proline, and an organic solvent all mixed together, and is preferably performed at a temperature of 60 to 70°C to dissolve.

The above cooling is performed by heating the solution to a temperature of 40 to 80°C and then cooling it to 0 to 20°C.

In the above process, the heating, dissolving, and cooling step is a step of generating a new empagliflozin 2L-proline crystal using empagliflozin and 2 equivalents or more of L-proline, and the crystal can be generated by heating, dissolving, and cooling the reaction solution.

After the above cooling step is completed, a step of adding one or more solvents (antisolvents) selected from the group consisting of n-heptane, n-hexane, cyclohexane, water, ethyl acetate, and dichloromethane and stirring and filtering may be further performed. After the cooling step, the yield of the crystalline form can be further increased due to the addition of the antisolvent.

In one embodiment of the present invention, after the cooling step, n-heptane solvent was injected, stirred at a temperature of 20 to 30°C for 1 to 3 hours, and then filtered to obtain a novel crystalline form of empagliflozin 2L-proline according to the present invention.

The yield of the novel crystalline form of empagliflozin 2L-proline manufactured by the method of the present invention is at least 80%.

In addition, the novel crystalline form of empagliflozin 2L-proline manufactured by the method of the present invention has characteristic peaks in the X-ray powder diffraction spectrum at positions of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2° in 2θ diffraction angles, and has an endothermic onset temperature of 162.70±3°C and an endothermic temperature of 164.53±3°C by differential scanning calorimetry (DSC).

Furthermore, the present invention can provide a pharmaceutical composition comprising the novel 2L-proline crystalline form of empagliflozin according to the present invention as an active ingredient.

In the pharmaceutical composition of the present invention, the novel crystalline form of empagliflozin 2L-proline may be included in an amount of 0.1 to 40 wt% relative to the total composition.

The above pharmaceutical composition may further comprise one or more additives selected from the group consisting of diluents, binders, disintegrants and lubricants.

In the pharmaceutical composition of the present invention, i.e., the pharmaceutical composition, the diluent may not include lactose. In addition, the diluent may include a sugar alcohol. For example, the sugar alcohol may be at least one selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol, and preferably mannitol may be used. When the sugar alcohol is used instead of lactose as the diluent, the browning phenomenon observed when formulating the composition including lactose can be prevented. Meanwhile, the sugar alcohol may be included in an amount of 30 to 70 wt% relative to the entire composition, and specifically, may be included in an amount of 40 to 60 wt%.

In addition, the diluent may further include at least one selected from the group consisting of microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, silicified microcrystalline cellulose, dextrates, dextrose, fructose, and sucrose, but is not limited thereto. Meanwhile, other diluents added in addition to the sugar alcohol may be included in an amount of 10 to 40 wt% based on the total composition, and specifically, may be included in an amount of 15 to 30 wt%.

In addition, the binder may be at least one selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, starch, pregelatinized starch, carbomer, xanthan gum, polyvinyl alcohol, vinylpyrrolidone, and povidone, but is not limited thereto. Meanwhile, the binder may be included in an amount of 0.5 to 10 wt% relative to the entire composition, and specifically, may be included in an amount of 1 to 4 wt%.

In addition, the disintegrant may be at least one selected from the group consisting of crospovidone, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, sodium croscarmellose, and low-substituted hydroxypropyl cellulose, but is not limited thereto.

Meanwhile, the disintegrant may be included in an amount of 2 to 20 wt% relative to the entire composition, and specifically, may be included in an amount of 4 to 12 wt%.

Additionally, the above-described lubricant may be at least one selected from the group consisting of talc, colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, sodium lauryl sulfate, and glyceryl behenate, but is not limited thereto.

Meanwhile, the above-mentioned active agent may be included in an amount of 0.1 to 10 wt% relative to the entire composition, and specifically, may be included in an amount of 0.5 to 4 wt%.

In addition, the present invention can provide a pharmaceutical preparation comprising the pharmaceutical composition of the present invention, and in the pharmaceutical preparation of the present invention, the preparation can be a tablet, a capsule, a pellet, a granule, or a powder.

In addition, the pharmaceutical composition of the present invention and the pharmaceutical preparation thereof can be used for the treatment of diabetes, diabetic complications or chronic heart failure.

The diabetes may be type 1 diabetes or type 2 diabetes, and preferably type 2 diabetes. In addition, the diabetic complication may be retinopathy, nephropathy or neuropathy, diabetic foot ulcer, tumor or macroangiopathy. In addition, the chronic heart failure may be heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).

Hereinafter, the present invention will be described in more detail through examples. These examples are intended to explain the present invention more specifically, and the scope of the present invention is not limited to these examples.

<Example 1>

Synthesis of a novel crystal form of empagliflozin 2L-proline

The present inventors synthesized a novel crystalline form of empagliflozin 2L-proline through the following process. 10 kg of empagliflozin was introduced into this reaction unit and 102.57 kg of ethanol was injected. Thereafter, 78.60 kg of isopropyl alcohol was injected, and the internal temperature was raised to 65°C to dissolve it. 15.78 kg of ethanol was injected into another reaction unit and 6.38 kg of L-proline was injected, mixed, and added to the main reaction unit. Then, 15.78 kg of ethanol was washed and injected. Thereafter, it was dissolved by heating at a temperature of 70°C. Then, initial precipitation was performed at 55°C for 1 hour. Thereafter, it was cooled to 20°C and stirred for 2 hours, 136.80 kg of n-heptane was injected, stirred at 20°C for 2 hours, and filtered to synthesize a novel crystalline form of empagliflozin 2L-proline in a yield of 90%.

<Example 2>

Synthesis of a novel crystal form of empagliflozin 2L-proline

The present inventors synthesized a novel crystalline form of empagliflozin 2L-proline by another method.

5 kg of empagliflozin was added to the reaction chamber and 3.2 kg of L-proline was added. Then, 25 L of methanol was injected, and the internal temperature was raised to 60°C to dissolve it. Then, 150 L of n-heptane was injected, stirred at 20°C for 2 hours, cooled to 0°C, stirred for 2 hours, and filtered to synthesize a novel crystalline form of empagliflozin 2L-proline with a yield of 82%.

<Example 3>

Synthesis of a novel crystal form of empagliflozin 2L-proline

The present inventors synthesized a novel crystalline form of empagliflozin 2L-proline by another method.

5 kg of empagliflozin was added to the reaction chamber and 3.2 kg of L-proline was added. Afterwards, 125 L of ethanol was injected and the internal temperature was raised to 60°C to dissolve it. Afterwards, initial precipitation was performed at 55°C for 1 hour, followed by stirring at 20°C for 2 hours and filtration to synthesize a novel crystalline form of empagliflozin 2L-proline with a yield of 85%.

<Comparative Example 1>

Empagliflozin crystal form synthesis

100 g of the compound of the following <Chemical Formula 3> was dissolved in a mixed solution of 1 L of dichloromethane and 1 L of acetonitrile, and then cooled to -40°C. Then, 85 g of triethylsilane was injected, and 60 g of boron trifluoride etherate was injected, and then the temperature was raised to 20°C and reacted for 3 hours. After the reaction, 500 ml of ethyl acetate and 500 ml of a saturated sodium bicarbonate solution were injected, stirred, and the layers were separated. The ethyl acetate layer was concentrated and crystallized with 1 L of isopropyl acetate to synthesize empagliflozin crystals in a yield of 65%.

<Chemical Formula 3>

<Comparative Example 2>

Empagliflozin L-proline synthesis

4.18 kg of methanol, 1.13 kg of empagliflozin, and 0.29 kg of L-proline were added, and 8.37 kg of anhydrous ethanol was washed and injected. Then, the temperature was increased to 60°C and dissolved. Initial precipitation was performed at 50°C for 1 hour, and 23.26 kg of n-heptane was injected at 20°C and stirred for 2 hours to synthesize empagliflozin L-proline with a yield of 87%.

<Experimental Example 1>

XRD and DSC analysis of the novel crystal form of empagliflozin 2L-proline synthesized in the present invention

The present inventors performed XRD (X-ray diffractometer) and DSC (differential scanning calorimetry) analyses on the novel crystalline form of empagliflozin 2L-proline of the present invention synthesized by the method of Example 1. D8 AD-VANCE (Cu/40 kV/40 mA) was used as an instrument for XRD analysis, and the crystallinity was confirmed under the following analysis conditions.

X-ray: Cu / 40 kV / 40 mA

Scan speed: 3.0 / 40.0 / 0.05 / 45.9 (sec)

Scan axis: 2 Theta (deg)

Scan range: 3~40 deg

In addition, DSC analysis was tested using differential scanning calorimetry among thermal analysis methods, and the equipment used was METTLER Toledo Korea. The temperature range was 25.0 → 250.0℃, and the scan speed was 5.00 K/min.

The PXRD intensities and peak positions for the novel crystalline form of empagliflozin 2L-proline synthesized in the present invention are shown in Table 1, and the XRD analysis pattern is shown in FIG. 1, and the DSC analysis pattern is shown in FIG. 2. In addition, for comparison with the novel crystalline form of the present invention, the analysis results of XRD and DSC for empagliflozin synthesized in Comparative Example 1 are shown in FIGS. 3 and 4, and the analysis results of XRD and DSC for empagliflozin L-proline synthesized in Comparative Example 2 are shown in FIGS. 5 and 6.

<Experimental Example 2>

Solubility analysis

The present inventors performed solubility analysis on the crystal forms synthesized in Example 1, Comparative Example 2, and Comparative Example 3, and the results are shown in Table 2 below. For solubility analysis, a solvent was added to 1 g of the crystal form sample synthesized in Example 1 and Comparative Examples, and the amount of solvent that completely dissolved when shaken vigorously at 20±5 ^o C for 30 seconds was measured.

As a result of the analysis, as shown in Table 2 above, the novel crystalline form of empagliflozin 2L-proline of the present invention was found to have significantly superior solubility compared to the crystalline form of empagliflozin of Comparative Example 1 and the crystalline form of empagliflozin L-proline of Comparative Example 2.

Therefore, it was found that the novel 2L-proline crystalline form of empagliflozin synthesized in the present invention can improve the problem of low solubility of the conventional empagliflozin crystalline form.

<Experimental Example 3>

Stability Analysis

Furthermore, the inventors of the present invention performed stability analysis on the crystal forms synthesized in Example 1, Comparative Example 2, and Comparative Example 3, and the results are shown in Table 4 below. In addition, the stability analysis was performed under the following conditions.

- Mobile phase A: Add 1 mL of phosphoric acid to 1 L of water.

- Mobile phase B: Acetonitrile: Methanol: Phosphoric acid = 800: 200: 1 (v/v/v)

-Solution: Water: Acetonitrile = (1:1) (v/v)

As a result of the analysis, as shown in Table 4 above, the novel crystalline form of empagliflozin 2L-proline of the present invention was found to have better stability than the crystalline form of empagliflozin of Comparative Example 1 and the crystalline form of empagliflozin L-proline of Comparative Example 2.

Through the above results, the inventors of the present invention were able to find that the novel crystalline form of empagliflozin 2L-proline synthesized by the method of the present invention has improved solubility and stability compared to the conventional crystalline form of empagliflozin and the crystalline form of empagliflozin L-proline, and thus can further increase its commercial utility.

The present invention has been described with reference to preferred embodiments thereof. Those skilled in the art will appreciate that the present invention may be implemented in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is not set forth in the foregoing description, but in the claims, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (10)

A method comprising adding 2 equivalents or more of L-proline to empagliflozin of the following chemical formula 2, adding an organic solvent, and then heating to dissolve and cooling.
A method for producing a novel crystalline form of empagliflozin 2L-proline of the following chemical formula 1.
<Chemical formula 1>

<Chemical Formula 2>
In the first paragraph,
A method characterized in that the organic solvent is at least one organic solvent selected from the group consisting of C1 to C4 alcohol, tetrahydrofuran, acetone, and acetonitrile. In the first paragraph,
A method characterized in that the above heating is performed at a temperature of 40 to 80°C. In the first paragraph,
A method characterized by further comprising the step of adding, stirring and filtering, at least one solvent selected from the group consisting of n-heptane, n-hexane, cyclohexane, water, ethyl acetate and dichloromethane after performing the above cooling step. In paragraph 4,
A method characterized in that the above stirring is performed at a temperature of 20 to 30°C for 1 to 3 hours. In the first paragraph,
A method characterized in that the novel crystalline form of empagliflozin 2L-proline of the above chemical formula 1 has characteristic peaks in an X-ray powder diffraction spectrum at 2θ diffraction angles of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2°, and has an endothermic onset temperature of 162.70±3°C and an endothermic temperature of 164.53±3°C by differential scanning calorimetry (DSC). A novel crystalline form of empagliflozin 2L-proline, characterized in that the X-ray powder diffraction spectrum has characteristic peaks at 2θ diffraction angles of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2°, and the endothermic onset temperature by differential scanning calorimetry (DSC) is 162.70±3°C and the endothermic temperature is 164.53±3°C. A pharmaceutical composition comprising a novel crystalline form of empagliflozin 2L-proline as an active ingredient, wherein the novel crystalline form has characteristic peaks at 2θ diffraction angles of 4.27±0.2, 12.88±0.2, 15.60±0.2, and 18.75±0.2° in an X-ray powder diffraction spectrum, an endothermic onset temperature of 162.70±3°C and an endothermic temperature of 164.53±3°C by differential scanning calorimetry (DSC). In Article 8,
A pharmaceutical composition, characterized in that the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. In Article 8,
A pharmaceutical composition characterized in that the above pharmaceutical composition is for the prevention or treatment of diabetes, diabetic complications or chronic heart failure.