KR20200127480A - Crystalline Forms of Teneligliptin Edisylate and Process of Preparing the Same - Google Patents

Abstract

The present invention provides a novel crystalline form of teneligliptin edisylate and a method for preparing the same. The tenerigliptin edicylate crystalline form according to the present invention has excellent stability against heat and moisture, and thus can be usefully used in the preparation of pharmaceutical preparations.

Description

Teneligliptin Edisylate and Process of Preparing the Same {Crystalline Forms of Teneligliptin Edisylate and Process of Preparing the Same}

The present invention relates to a crystalline form of tenerigliptin edisylate and a method for preparing the same. More specifically, the present invention relates to a novel crystalline form of tenerigliptin edicylate excellent in stability against heat and moisture, and a method for preparing the same.

Diabetes is a disease that causes complications such as kidney dysfunction, cardiovascular disease, and cerebrovascular disease because blood sugar in the body is not regulated normally and is present in a concentration higher than the standard value. Diabetes is classified into type 1 diabetes and type 2 diabetes, and type 2 diabetes is caused by the secretion of insulin, but insufficient amount of insulin or insufficient use of secreted insulin, and 90% to 95% of all diabetes mellitus. Occupies.

Type 2 diabetes patients take oral hypoglycemic drugs as an adjunct to diet and exercise therapy, and the types include biguanide, sulfonylurea, non-sulfonylurea, and thiazoli. Thiazolidinedione (TZD), alpha-glucosidase inhibitor (α-GI), glucagon-like peptide-1 analogues, GLP-1 analogues, dipeptidyl peptida 4th inhibitor (DPP-4 inhibitor), sodium/glucose co-transporter-2 inhibitor (sodium/glucose co-transporter-2 inhibitor, SGLT-2 inhibitor), and the like. Among them, dipeptidyl peptidase-4 inhibitors are drugs that treat diabetes by prolonging the duration of action of GLP-1 by inhibiting the degradation of glucagon-like peptide-1 (GLP-1), which lowers blood sugar in the body.

Tenerigliptin (3-{(2 S ,4 S )-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine-1 of the following formula I -Yl]pyrrolidin-2-ylcarbonyl}thiazolidine) is a dipeptidyl peptidase-4 inhibitor family drug used as an adjunct to diet and exercise therapy for blood sugar control in type 2 diabetes patients. .

(Ⅰ)

Tenerigliptin and salts thereof are disclosed in Korean Patent No. 817,378 and Korean Patent No. 1,352,650. In addition, teneligliptin is marketed under the brand name Tenelia in the form of teneligliptin hydrobromide hydrate of the following formula II.

(Ⅱ)

However, although the crystalline form of a pharmaceutically useful compound can improve the performance of a pharmaceutical composition based on its unique physicochemical properties, studies on the crystalline form of teneligliptin edisylate are insufficient.

Korean Registered Patent No. 817,378 Registered Korean Patent No. 1,352,650

An object of the present invention is to provide a teneligliptin edicylate crystalline form that is stable against heat and has relatively little hygroscopicity.

Another object of the present invention is to provide a method for preparing the teneligliptin edicylate crystalline form.

Another object of the present invention is to provide a pharmaceutical composition comprising the teneligliptin edicylate crystalline form as an active ingredient.

One embodiment of the present invention is a value of the diffraction angle (2θ) in which I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) is 10% or more in X-ray powder diffraction analysis. 9.3±0.2, 11.8±0.2, 12.5±0.2, 13.0±0.2, 13.6±0.2, 14.0±0.2, 14.6±0.2, 15.7±0.2, 17.1±0.2, 17.9±0.2, 18.7±0.2, 19.4±0.2, 20.6 ±0.2, 20.9±0.2, 21.5±0.2, 22.2±0.2, 22.5±0.2, 23.0±0.2, 24.1±0.2, 24.3±0.2, 25.0±0.2, 25.7±0.2, 26.9±0.2, 27.3±0.2 and 28.0±0.2 Phosphorus relates to a crystalline form Ⅲ of teneligliptin edicylate represented by the following formula (1).

[Formula 1]

Tenerigliptin edisylate crystalline form Ⅲ according to an embodiment of the present invention has a weak intensity other than the X-ray powder diffraction peak, and diffraction angles of 10.8±0.2, 28.7±0.2, 32.9±0.2, 35.2±0.2 (2θ) ) May additionally have an X-ray powder diffraction peak. At this time, "weak intensity" refers to a peak in which I/I ₀ (relative intensity) is less than 10%.

Teneligliptin edicylate crystalline form Ⅲ according to an embodiment of the present invention shows a value of 199.40°C for a first endothermic point, 281.16°C for a second endothermic point, and 206.69°C for a differential scanning calorie analysis.

Tenerigliptin edicylate crystalline form Ⅲ according to an embodiment of the present invention is obtained by suspending teneligliptin edicylate amorphous form in acetonitrile, stirring by applying heat or stirring at room temperature, filtration and drying under reduced pressure. Can be manufactured.

Another embodiment of the present invention is the value of the diffraction angle (2θ) in which I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) is 10% or more in X-ray powder diffraction analysis. 10.7±0.2, 11.5±0.2, 12.6±0.2, 13.9±0.2, 14.8±0.2, 15.2±0.2, 16.2±0.2, 17.8±0.2, 18.3±0.2, 19.1±0.2, 19.8±0.2, 20.4±0.2, 21.1 ±0.2, 21.6±0.2, 22.1±0.2, 22.4±0.2, 23.2±0.2, 24.0±0.2, 24.7±0.2, 26.8±0.2, 28.1±0.2, 28.2±0.2, 29.8±0.2, 30.0±0.2, and 32.2± It relates to a crystalline form IV of teneligliptin edisylate represented by Chemical Formula 1, which is 0.2.

Tenerigliptin edicylate crystalline form IV according to an embodiment of the present invention has a weak intensity in addition to the X-ray powder diffraction peak, and is 9.0±0.2, 9.5±0.2, 16.9±0.2, 25.4±0.2, 26.1±0.2, 31.2. It may additionally have an X-ray powder diffraction peak at diffraction angles (2θ) of ±0.2 and 33.9±0.2.

Tenerigliptin edisylate crystalline form IV according to an embodiment of the present invention shows a value of 93.29°C for a first endothermic point and 281.93°C for a second endothermic point in differential scanning calorimetry analysis.

Tenerigliptin edicylate crystalline form IV according to an embodiment of the present invention may be prepared from tenerigliptin edicylate amorphous form.

Specifically, for teneligliptin edicylate crystalline form IV, teneligliptin edicylate amorphous form is suspended in acetonitrile and stirred by heating or stirred at room temperature, followed by filtration in a mixed solvent of water and acetonitrile. It can be prepared by suspending and stirring at room temperature, followed by filtration and drying under reduced pressure or oven drying at 60 to 80°C. Alternatively, teneligliptin edisylate amorphous form is suspended in acetonitrile, stirred by heating or stirred at room temperature, and then filtered and stored at 40° C., 75% RH or 25° C., 60% RH. I can. The storage may be performed for one or more days.

In addition, teneligliptin edisylate crystalline form IV according to an embodiment of the present invention may be prepared from teneligliptin edicylate crystalline form III.

Specifically, for teneligliptin edicylate crystalline form IV, teneligliptin edicylate crystalline form Ⅲ is suspended in a mixed solvent of water and acetonitrile, stirred at room temperature, filtered and dried under reduced pressure or at 60 to 80°C. It can be prepared by drying in the oven. Alternatively, it can be prepared by storing tenerigliptin edicylate crystalline form III at 40°C, 75% RH or 25°C, 60% RH. The storage may be performed for one or more days.

In another embodiment of the present invention, in X-ray powder diffraction analysis, I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) is 10% or more of the diffraction angle (2θ). Values are 11.9±0.2, 14.0±0.2, 14.5±0.2, 15.5±0.2, 16.4±0.2, 17.5±0.2, 20.2±0.2, 20.8±0.2, 21.6±0.2, 21.8±0.2, 22.4±0.2, 23.1±0.2, 25.1±0.2, 25.4±0.2, 26.5±0.2 and 27.2±0.2 of tenerigliptin edicylate crystalline form VI.

Tenerigliptin edisylate crystalline form VI according to an embodiment of the present invention has a weak intensity other than the X-ray powder diffraction peak, 5.9±0.2, 10.2±0.2, 13.3±0.2, 18.9±0.2, 24.0±0.2, 24.6 ±0.2, 25.6±0.2, 28.8±0.2, 28.9±0.2, 30.0±0.2, 31.0±0.2, 31.5±0.2, 31.8±0.2, 32.3±0.2, 32.8±0.2, 34.2±0.2, 35.1±0.2, 38.4±0.2 And an X-ray powder diffraction peak at a diffraction angle (2θ) of 39.1±0.2.

Teneligliptin edisylate crystalline form VI according to an embodiment of the present invention exhibits a value of 285.26°C in an endothermic point in differential scanning calorimetry analysis.

Tenerigliptin edisylate crystalline form VI according to an embodiment of the present invention may be prepared from tenerigliptin edisylate amorphous form.

Specifically, teneligliptin edicylate crystalline form VI can be prepared by suspending tenerigliptin edicylate amorphous in a mixed solvent of water and acetonitrile, stirring by applying heat, filtering and drying under reduced pressure. . Alternatively, teneligliptin edisylate amorphous form is suspended in acetonitrile and stirred by applying heat, followed by adding water dropwise and stirring by applying heat, followed by filtration and drying under reduced pressure or oven drying at 60 to 80°C. Can be manufactured.

Tenerigliptin edisylate crystalline form VI according to an embodiment of the present invention may be prepared from a dimethylformamide solvate of tenerigliptin edisylate.

Specifically, for tenerigliptin edicylate crystalline form VI, a dimethylformamide solvate of tenerigliptin edicylate is suspended in a mixed solvent of water and acetonitrile, and stirred by heating or stirred at room temperature, It can be prepared by filtration and drying under reduced pressure or oven drying at 60 to 80°C.

The dimethylformamide solvate of the teneligliptin edicyl acid salt may be prepared from the teneligliptin free base.

Specifically, the dimethylformamide solvate of teneligliptin edicyl acid salt is added dropwise by dissolving tenerigliptin free base in dimethylformamide and stirring, then dissolving ethane-1,2-disulfonic acid in dimethylformamide. After that, it can be prepared by filtering the resulting solid and drying under reduced pressure.

In addition, the dimethylformamide solvate of teneligliptin edicylate is an amorphous form of teneligliptin edicylate, crystalline form I to V of teneligliptin edicylate, or Tenerie prepared from the free base. It can be prepared from a dimethylformamide solvate of gliptin edicylate.

Specifically, the dimethylformamide solvate of teneligliptin edicylate is an amorphous form of teneligliptin edicylate, crystalline form I to V of teneligliptin edicylate, or te prepared from the free base. It can be prepared by putting the dimethylformamide solvate of nerigliptin edicylate in a mixed solvent of dimethylformamide and water, then completely dissolving it by applying heat, and then slowly lowering the temperature to room temperature and filtering the resulting solid.

In one embodiment of the present invention, the teneligliptin edisylate amorphous form can be prepared by reacting the teneligliptin free base with ethane-1,2-disulfonic acid.

As the reaction solvent, an alcohol-based solvent, a nitrile-based solvent, an ester-based solvent, a ketone-based solvent, a hydrocarbon-based solvent, or a mixed solvent thereof may be used. Examples of the alcohol-based solvent include methanol, ethanol, isopropanol, and t -butyl alcohol, and examples of the nitrile-based solvent include acetonitrile. In addition, ethyl acetate and the like may be exemplified as the ester solvent, acetone and methyl ethyl ketone may be exemplified as the ketone solvent, and hexane may be exemplified as the hydrocarbon solvent. In addition, a mixed solvent of the solvents and water may be used.

The ethane-1,2-disulfonic acid may be used in an amount of 0.5 to 3 equivalents, preferably 0.6 to 1.2 equivalents, based on 1 equivalent of teneligliptin organic base.

Another embodiment of the present invention is one or more crystalline forms selected from the group consisting of the teneligliptin edicylate crystalline form Ⅲ, tenerigliptin edicylate crystalline form IV, and tenerigliptin edicylate crystalline form VI. It relates to a pharmaceutical composition for treating type 2 diabetes comprising, together with a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention may contain another physiologically active substance in addition to the teneligliptin edicylate crystalline form.

The pharmaceutical composition according to the present invention may be administered orally, and may be formulated in various forms such as tablets, capsules, granules, powders, emulsions, suspensions, and syrups. The various types of pharmaceutical compositions include excipients, fillers, bulking agents, binders, disintegrators, lubricants, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweetening agents, solubilizing agents, base agents. ), a dispersing agent, a wetting agent, a suspending agent, a stabilizer, a colorant, a fragrance, etc., and may be prepared by a known technique using a pharmaceutically acceptable carrier commonly used in each formulation.

In the manufacture of the drug, the content of the crystalline form of teneligliptin edisylate of the present invention varies depending on the form of the drug, but is preferably a concentration of 10 to 90% by weight, more preferably 30 to 80% by weight. .

The dosage of the pharmaceutical composition of the present invention varies in a wide range depending on the type of mammal including the person to be treated, the route of administration, weight, sex, age, degree of disease, judgment of a doctor, and the like. In general, in the case of oral administration, the active ingredient may be administered in an amount of about 1 to 240 mg per day, preferably 5 to 180 mg, and more preferably 10 to 120 mg, based on an adult of about 60 kg. The above-described daily dosage may be used at one time or dividedly depending on the degree of disease, judgment of a doctor, and the like.

Tenerigliptin edicylate crystalline forms Ⅲ, Ⅳ, and Ⅵ forms according to the present invention have excellent stability against heat and moisture, and thus the generation of related substances in a formulation containing them can be suppressed. , Low hygroscopicity, convenient and safe raw material storage and manufacturing process In addition, teneligliptin edicylate crystalline forms Ⅲ, Ⅳ and Ⅵ have an advantage of reducing the size of the pharmaceutical composition by having a molecular weight smaller than that of conventional hydrobromide.

1 is an X-ray powder diffraction diagram of teneligliptin edicylate amorphous.
FIG. 2 is an X-ray powder diffraction diagram of tenerigliptin edicylate crystalline Form I.
3 is an X-ray powder diffraction diagram of teneligliptin edicylate crystalline form III.
4 is an X-ray powder diffraction diagram of tenerigliptin edicylate crystalline form IV.
5 is an X-ray powder diffraction diagram of tenerigliptin edicylate crystalline form VI.
Figure 6 is a differential scanning calorie analysis diagram of teneligliptin edicylate amorphous.
7 is a differential scanning calorie analysis diagram of tenerigliptin edicylate crystalline Form I.
Figure 8 is a differential scanning calorie analysis diagram of tenerigliptin edicylate crystalline form Ⅲ.
9 is a differential scanning calorie analysis diagram of tenerigliptin edicylate crystalline form IV.
Figure 10 is a differential scanning calorie analysis diagram of tenerigliptin edicylate crystalline form VI.
11 is a thermogravimetric analysis diagram of tenerigliptin edicylate amorphous.
Fig. 12 is a thermogravimetric analysis of tenerigliptin edicylate crystalline form I.
13 is a thermogravimetric analysis diagram of crystalline form III of teneligliptin edicylate.
14 is a thermogravimetric analysis diagram of crystalline form IV of teneligliptin edicylate.
15 is a thermogravimetric analysis diagram of crystalline form VI of tenerigliptin edicylate.

Hereinafter, the present invention will be described in more detail by examples. These examples are for illustrative purposes only, and it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Comparative example One: Tenerigliptin Edicylate Amorphous manufacture

Tenerigliptin free base (3 g) was stirred in isopropanol (80 mL) at room temperature, and ethane-1,2-disulfonic acid (3.3 g) was dissolved in isopropanol (20 mL) and added dropwise to the stirring solution. Thereafter, the resulting solid was filtered and washed with isopropanol. The thus obtained solid was dried under reduced pressure to obtain teneligliptin edisylate.

X-ray powder diffraction analysis, differential scanning calorimetry, and thermogravimetric analysis of the obtained teneligliptin edisylate were performed, and the results are shown in Figs. 1, 6 and 11, respectively, and it was confirmed that it is amorphous. .

Comparative example 2: Tenerigliptin Edicylate Preparation of crystalline form I

Tenerigliptin edisylate amorphous (1 g) was suspended in ethanol (5 mL), followed by heating, and the resulting solid was stirred. Thereafter, it was filtered and washed with ethanol. The crystals thus obtained were dried under reduced pressure or oven dried at 70° C. to obtain a crystal form.

X-ray powder diffraction analysis, differential scanning calorimetry, and thermogravimetric analysis of the obtained teneligliptin edisylate crystalline form were performed, and the results are shown in FIGS. 2, 7 and 12, respectively, and this It was called edicylate crystalline form I.

To the characteristic peaks (peak) appeared in the X-ray powder diffraction diagram of Figure 2 were shown in Table 1, where '2θ' is 'I / I _0' the diffraction angle, denotes the relative intensity of the peaks (peak) . The diffraction angle has a deviation range of ±0.2°.

Endothermic point (differential scanning calorimetry, DSC): 276.95°C

No. 2θ I/I ₀ (%) No. 2θ I/I ₀ (%) One 5.871 2.7 14 21.991 36.5 2 9.050 19.1 15 22.292 80.4 3 10.314 23.0 16 23.138 26.4 4 11.414 34.9 17 23.536 7.0 5 11.868 30.2 18 25.290 8.7 6 13.119 49.0 19 25.846 6.7 7 14.585 16.6 20 26.309 6.9 8 17.141 27.6 21 26.675 8.3 9 17.815 59.4 22 27.622 7.5 10 18.741 27.7 23 28.433 4.6 11 19.864 100.0 24 29.126 5.0 12 20.365 81.2 25 29.870 7.7 13 21.454 36.0 26 31.153 7.9

Comparative example 3: Tenerigliptin Edicylate Preparation of crystalline form I

Tenerigliptin edisylate amorphous (1 g) was suspended in ethanol (5 mL), followed by stirring for 5 days or more. Then, it was filtered and washed with ethanol. The crystals thus obtained were dried under reduced pressure or oven dried at 70° C. to obtain a crystal form.

The obtained teneligliptin edisylate crystalline form was measured for X-ray powder diffraction, and it was confirmed that it was the same crystalline form as the crystalline form obtained in Comparative Example 2.

Comparative example 4: Tenerigliptin Edicylate Preparation of crystalline form Ⅱ

Tenerigliptin edisylate amorphous (1 g) was suspended in acetonitrile (5 mL), and heated to stir for 2 hours. Thereafter, it was filtered and washed with acetonitrile to obtain a crystalline form.

X-ray powder diffraction analysis and differential scanning calorimetry analysis of the obtained teneligliptin edicylate crystalline form were performed, and the results are shown below, and this was referred to as tenerigliptin edicylate crystalline form Ⅱ.

X-ray powder diffractogram (2θ): 9.2, 9.9, 10.7, 11.6, 12.4, 12.9, 13.8, 14.4, 15.0, 15.4, 15.5, 16.8, 17.2, 17.6, 18.4, 19.1, 20.1, 20.9, 21.5, 22.0, 22.8 , 23.1, 23.6, 23.9, 24.8, 26.5, 27.6, 28.8

Endothermic point (differential scanning calorimetry, DSC): 206.98°C, 282.21°C

Heating point (differential scanning calorimetry, DSC): 200.61°C

Comparative example 5: Tenerigliptin Edicylate Preparation of crystalline form Ⅱ

Tenerigliptin edisylate amorphous (1 g) was suspended in acetonitrile (5 mL) and stirred at room temperature for 2 to 3 days. Then, it was filtered and washed with acetonitrile.

The obtained teneligliptin edisylate crystalline form was measured for X-ray powder diffraction, and it was confirmed that it was the same crystalline form as the crystalline form obtained in Comparative Example 4.

Example One: Tenerigliptin Edicylate Preparation of crystalline form Ⅲ

Tenerigliptin edisylate crystalline Form II was dried under reduced pressure.

X-ray powder diffraction analysis, differential scanning calorimetry, and thermogravimetric analysis of the obtained teneligliptin edisylate crystalline form were performed, and the results are shown in Figs. 3, 8 and 13, respectively, and this It was called edicylate crystalline form Ⅲ.

To the characteristic peaks (peak) shown in FIG. X-ray powder diffraction pattern of Figure 3 were shown in Table 2, where '2θ' is 'I / I _0' the diffraction angle, denotes the relative intensity of the peaks (peak) . The diffraction angle has a deviation range of ±0.2°.

Endothermic point (differential scanning calorimetry, DSC): 199.40°C, 281.16°C

Exothermic point (differential scanning calorimetry, DSC): 206.69°C

No. 2θ I/I ₀ (%) No. 2θ I/I ₀ (%) One 9.346 45.5 16 21.459 40.0 2 10.806 7.6 17 22.156 21.8 3 11.750 38.3 18 22.486 39.1 4 12.509 10.1 19 23.010 45.5 5 12.965 59.7 20 24.081 12.8 6 13.554 40.3 21 24.258 14.4 7 14.009 23.5 22 24.974 20.4 8 14.639 20.6 23 25.720 26.7 9 15.737 27.2 24 26.879 22.2 10 17.116 11.8 25 27.332 10.3 11 17.876 45.2 26 28.004 15.2 12 18.688 100.0 27 28.674 4.1 13 19.442 13.3 28 32.887 6.6 14 20.555 47.8 29 35.188 4.1 15 20.941 71.4

Example 2: Tenerigliptin Edicylate Preparation of crystalline form IV

Tenerigliptin edicylate crystalline form II (1 g) or III form (1 g) was suspended in water/acetonitrile = 2/98 (5 mL), followed by stirring at room temperature for 2 hours. Then, it was filtered and washed with acetonitrile. The crystals thus obtained were dried under reduced pressure or oven dried at 70° C. to obtain a crystal form.

X-ray powder diffraction analysis, differential scanning calorimetry, and thermogravimetric analysis of the obtained teneligliptin edisylate crystal form were performed, and the results are shown in FIGS. 4, 9 and 14, respectively, and It was called edicylate crystal form IV.

To the characteristic peaks (peak) appeared in the X-ray powder diffraction pattern of FIG. 4 were shown in Table 3, where the '2θ' is 'I / I _0' the diffraction angle, denotes the relative intensity of the peaks (peak) . The diffraction angle has a deviation range of ±0.2°.

Endothermic point (differential scanning calorimetry, DSC): 93.29°C, 281.93°C

No. 2θ I/I ₀ (%) No. 2θ I/I ₀ (%) One 8.955 7.6 18 21.591 46.5 2 9.493 4.4 19 22.103 69.2 3 10.743 10.3 20 22.376 88.2 4 11.491 10.3 21 23.227 31.3 5 11.479 11.2 22 24.005 64.4 6 12.639 90.5 23 24.731 10.9 7 13.910 12.0 24 25.424 5.3 8 14.840 13.8 25 26.058 5.5 9 15.154 50.7 26 26.817 29.1 10 16.218 54.7 27 28.052 21.6 11 16.936 8.5 28 28.246 23.9 12 17.801 47.5 29 29.846 19.7 13 18.276 61.7 30 29.969 16.9 14 19.067 11.5 31 31.241 9.0 15 19.761 17.0 32 32.249 10.3 16 20.390 100.0 33 33.927 7.1 17 21.101 12.3

Example 3: Tenerigliptin Edicylate Preparation of crystalline form IV

Tenerigliptin edicylate crystalline form II (1 g) or III form (1 g) was stored at 40°C, 75% RH or 25°C, 60% RH for 1 day or longer.

X-ray powder diffraction diagram of the obtained teneligliptin edisylate crystalline form was measured, and it was confirmed that it was the same crystalline form as the crystalline form obtained in Example 2.

Comparative example 6: Tenerigliptin Edicylate Preparation of crystalline form V

Tenerigliptin edicylate amorphous (1 g) was suspended in water/acetonitrile = 2/98 (5 mL), and then heated and stirred for 2 hours. Thereafter, it was filtered and washed with acetonitrile to obtain a crystalline form.

X-ray powder diffraction analysis and differential scanning calorimetry analysis of the obtained teneligliptin edisylate crystalline form were performed, and the results are shown below, and this was referred to as tenerigliptin edicylate crystalline form V.

X-ray powder diffractogram (2θ): 8.9, 9.5, 10.7, 11.4, 11.5, 12.6, 13.8, 14.3, 14.8, 15.1, 16.2, 16.9, 17.3, 17.8, 18.2, 19.0, 19.7, 20.4, 21.1, 21.5, 22.1 , 22.2, 22.5, 23.2, 24.0, 24.7, 25.4, 26.8, 27.2, 28.0, 29.8, 31.2, 32.3, 33.9, 35.2

Endothermic point (differential scanning calorimetry, DSC): 74.32, 283.53℃

Example 4: Tenerigliptin Edicylate Preparation of crystalline form VI

Tenerigliptin edisylate crystalline form V was dried under reduced pressure to obtain a crystalline form.

X-ray powder diffraction analysis, differential scanning calorimetry, and thermogravimetric analysis of the obtained teneligliptin edisylate crystalline form were performed, and the results are shown in Figs. 5, 10 and 15, respectively, and this It was called edicylate crystalline form VI.

To the characteristic peaks (peak) appeared in the X-ray powder diffraction pattern of Figure 5 also were shown in Table 4, where '2θ' is 'I / I _0' the diffraction angle, denotes the relative intensity of the peaks (peak) . The diffraction angle has a deviation range of ±0.2°.

Endothermic point (differential scanning calorimetry, DSC): 285.25°C

No. 2θ I/I ₀ (%) No. 2θ I/I ₀ (%) One 5.850 8.7 19 25.097 14.5 2 10.161 4.8 20 25.380 26.5 3 11.889 10.5 21 25.629 7.8 4 13.272 6.9 22 26.490 16.8 5 13.970 88.4 23 27.212 20.4 6 14.502 100.0 24 28.845 6.0 7 15.469 48.2 25 28.920 5.8 8 16.422 31.8 26 29.959 5.4 9 17.507 95.8 27 31.000 2.4 10 18.867 9.2 28 31.516 7.4 11 20.171 75.2 29 31.816 6.2 12 20.788 62.6 30 32.319 4.7 13 21.645 26.9 31 32.795 8.3 14 21.775 33.6 32 34.197 6.9 15 22.362 40.3 33 35.092 4.5 16 23.090 51.2 34 38.433 4.3 17 24.045 8.1 35 39.080 2.8 18 24.562 9.3

Example 5: Tenerigliptin Edicylate Preparation of crystalline form VI

Tenerigliptin edicylate amorphous (1 g) was suspended in acetonitrile (5 mL), and then heated and stirred for 2 hours. Thereafter, water (0.1 mL) was added dropwise, heat was added, and the mixture was stirred for 2 hours, which was filtered and washed with acetonitrile. The crystals thus obtained were dried under reduced pressure or oven dried at 70° C. to obtain a crystal form.

The obtained teneligliptin edisylate crystalline form was measured for X-ray powder diffraction, and it was confirmed that it was the same crystalline form as the crystalline form obtained in Example 4.

Manufacturing example One: Tenerigliptin Edicylate Dimethylformamide Preparation of solvate

Tenerigliptin free base (3 g) was dissolved in dimethylformamide (18 mL) and stirred, and then ethane-1,2-disulfonic acid (3.3 g) was dissolved in dimethylformamide (6 mL). It was added dropwise to half the price. Thereafter, the resulting solid was filtered and washed with dimethylformamide. The thus obtained solid was dried under reduced pressure to obtain a dimethylformamide solvate of teneligliptin edicylate.

X-ray powder diffraction analysis, differential scanning calorimetry, and thermogravimetric analysis of the obtained teneligliptin edicylate solvate in dimethylformamide were performed, and the results are shown below.

X-ray powder diffractogram (2θ): 9.8, 11.1, 11.6, 12.7, 13.7, 14.4, 15.3, 15.8, 16.6, 17.0, 17.7, 18.0, 18.6, 19.6, 20.0, 20.6, 21.3, 21.7, 22.2, 22.9, 23.3 , 23.8, 24.7, 25.3, 25.7, 26.0, 26.6, 27.3, 27.6, 28.2, 28.6, 28.8, 29.3, 29.7, 31.2, 32.0, 33.4, 33.7, 35.0, 36.4, 37.2, 38.2, 38.7, 39.7

Endothermic point (differential scanning calorimetry, DSC): 175℃, 287℃

Weight reduction (thermogravimetric analysis, TGA): 10% (175℃)

Manufacturing example 2: Tenerigliptin Edicylate Dimethylformamide Preparation of solvate

Tenerigliptin edisylate amorphous (1 g) was added to dimethylformamide/water = 7/1 (6 mL), and then heated to completely dissolve. Thereafter, the temperature was slowly lowered to room temperature, and the resulting solid was filtered and washed with dimethylformamide to obtain a dimethylformamide solvate of teneligliptin edicylate.

The X-ray powder diffraction diagram of the obtained dimethylformamide solvate of teneligliptin edisylate was measured to confirm that it had the same crystal form as the solvate obtained in Preparation Example 1.

Example 6: Tenerigliptin Edicylate Preparation of crystalline form VI

After suspending the dimethylformamide solvate (1 g) of teneligliptin edisylate obtained in Preparation Example 1 or 2 in water/acetonitrile = 2/98 (5 mL), heat was added and stirred for 2 hours. . Then, it was filtered and washed with acetonitrile. The crystals thus obtained were dried under reduced pressure or oven dried at 70° C. to obtain a crystal form.

The obtained teneligliptin edisylate crystalline form was measured for X-ray powder diffraction, and it was confirmed that it was the same crystalline form as the crystalline form obtained in Example 4.

Example 7: Tenerigliptin Edicylate Preparation of crystalline form VI

After suspending the dimethylformamide solvate (1 g) of teneligliptin edisylate obtained in Preparation Example 1 or 2 in water/acetonitrile = 2/98 (5 mL), at room temperature for 2 to 3 days Stirring or seed (0.1wt%, crystalline form VI) was added and stirred for 2 hours. Then, it was filtered and washed with acetonitrile. The crystals thus obtained were dried under reduced pressure or oven dried at 70° C. to obtain a crystal form.

The obtained teneligliptin edisylate crystalline form was measured for X-ray powder diffraction, and it was confirmed that it was the same crystalline form as the crystalline form obtained in Example 4.

X-ray powder Diffraction analysis

X-ray powder diffraction analysis (XRD) obtained a diffraction pattern in the range of 3 to 40 °2θ using a powder X-ray diffractometer. Powder X-ray diffraction analysis conditions are as follows.

-Device: Bruker A26X1 D2 Phaser

-Time per step: 0.5 s

-Scanning method: Continuous PSD fast

-Detector: Lynxeye (1D mode)

Differential Scanning Calorie Analysis

Differential scanning calorimetry (DSC) was performed using the Q2000 model of the TA instrument. About 2-3 mg of a sample was put in an aluminum pan, covered with a perforated lid, and a sample required for a DSC experiment was prepared. After recording the correct weight, it was heated to 25 to 250° C. at a rate of 10° C./min under nitrogen.

Thermal weight analysis

Thermogravimetric analysis (TGA) was performed using the Q50 model of the TA instrument. About 10 mg of a sample was put in a platinum pan to prepare a sample required for a TGA experiment. It was heated to 25 ~ 600 ℃ at a rate of 10 ℃ / min under nitrogen.

Experimental example 1: thermal stability test

Tenerigliptin edicylate amorphous, crystalline form I, III, IV, and VI obtained in Comparative Examples and Examples were each 20 mg in a polyethylene bag and 40±2℃ with an aluminum pouch, Stored at 75±5% RH. After 4, 8, and 16 weeks, each sample was taken out, and powder X-ray diffraction analysis was performed to evaluate the stability of the crystal form, and analyzed by high-performance liquid chromatography to evaluate the occurrence and increase of related substances.

Powder X-ray diffraction analysis results and high-performance liquid chromatography analysis results are shown in Tables 5 and 6, respectively.

Time (weeks) 40℃/75% RH 0 Amorphous Crystalline Ⅰ Crystalline Ⅲ Crystalline Ⅳ Crystalline VI 4 Amorphous Keep crystalline Keep crystalline Keep crystalline Keep crystalline 8 Amorphous Keep crystalline Keep crystalline Keep crystalline Keep crystalline 16 Amorphous Keep crystalline Keep crystalline Keep crystalline Keep crystalline

Time (weeks) 40℃/75% RH Amorphous Crystalline Ⅰ Crystalline Ⅲ Crystalline Ⅳ Crystalline VI 0 99.39 99.32 99.40 99.27 99.19 4 98.11 98.84 99.47 99.25 99.23 8 97.25 97.11 99.34 99.10 99.33 16 96.70 94.21 99.38 99.37 99.38

As shown in Table 5, the amorphous and all crystalline forms did not change in properties for 16 weeks at 40°C and 75% RH.

However, as shown in Table 6, it was confirmed that the purity of the amorphous and crystalline form I was continuously changed at 40°C and 75% RH, whereas the crystalline forms Ⅲ, Ⅳ, and Ⅵ did not change in purity.

In particular, it was found that tenerigliptin edicylate crystalline form VI showed the best stability up to 16 weeks without the occurrence or increase of related substances among crystalline forms.

Experimental example 2: hygroscopicity test

The teneligliptin edisylate amorphous and crystalline forms I, III, IV, and VI obtained in Comparative Examples and Examples were respectively used as dynamic vapor absorption and desorption devices, DVS (dynamic vapor absorption, VTI SGA-100, TA). Instruments) under isothermal conditions of 25°C and relative humidity of 2 to 98% at intervals of 5% RH by repeating moisture absorption and dehumidification once, and the results are shown in Table 7.

Crystal form 25℃/80% RH Amorphous 16.5% Crystal form Ⅰ 17.5% Crystalline Ⅲ 5.7% Crystal form Ⅳ 3.8% Crystalline form VI 4.2%

As a result of DVS analysis, it was confirmed that the types Ⅲ, Ⅳ, and Ⅵ showed relatively less hygroscopicity than the amorphous and crystalline types Ⅰ. Particularly, the types Ⅳ and Ⅵ showed lower hygroscopicity than the amorphous and crystalline type Ⅰ based on EP (25℃, 80% relative humidity).

Therefore, through the thermal stability test and hygroscopicity test described above, it was confirmed that crystalline form VI is the most stable, and since form VI has excellent properties with respect to moisture, the generation of related substances to moisture in the formulation containing it was confirmed. By suppressing it, not only can the stability of the teneligliptin edisylate formulation be greatly improved, but it can be seen that the raw material storage and manufacturing process are convenient and safe.

Claims (15)

In X-ray powder diffraction analysis, the value of the diffraction angle (2θ) at which I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) is 10% or more is 9.3±0.2, 11.8± 0.2, 12.5±0.2, 13.0±0.2, 13.6±0.2, 14.0±0.2, 14.6±0.2, 15.7±0.2, 17.1±0.2, 17.9±0.2, 18.7±0.2, 19.4±0.2, 20.6±0.2, 20.9±0.2, Tenerigliptin Edisil with 21.5±0.2, 22.2±0.2, 22.5±0.2, 23.0±0.2, 24.1±0.2, 24.3±0.2, 25.0±0.2, 25.7±0.2, 26.9±0.2, 27.3±0.2 and 28.0±0.2 Salt crystalline form Ⅲ. According to claim 1, In the differential scanning calorimetry analysis, the first endothermic point is 199.40°C, the second endothermic point is 281.16°C, and the exothermic point is 206.69°C. Tenerigliptin edicylate crystalline form Ⅲ. In X-ray powder diffraction analysis, the value of the diffraction angle (2θ) at which I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) is 10% or more is 10.7±0.2, 11.5± 0.2, 12.6±0.2, 13.9±0.2, 14.8±0.2, 15.2±0.2, 16.2±0.2, 17.8±0.2, 18.3±0.2, 19.1±0.2, 19.8±0.2, 20.4±0.2, 21.1±0.2, 21.6±0.2, Tenerigliptin Edisil with 22.1±0.2, 22.4±0.2, 23.2±0.2, 24.0±0.2, 24.7±0.2, 26.8±0.2, 28.1±0.2, 28.2±0.2, 29.8±0.2, 30.0±0.2 and 32.2±0.2 Salt crystalline form IV. According to claim 3, In the differential scanning calorimetry analysis, the first endothermic point is 93.29 ℃, the second endothermic point is 281.93 ℃ Tenerigliptin edicylate crystalline form IV. In X-ray powder diffraction analysis, the value of the diffraction angle (2θ) at which I/I ₀ (I: intensity of the peak at each diffraction angle, I ₀ : intensity of the largest peak) is 10% or more is 11.9±0.2, 14.0± 0.2, 14.5±0.2, 15.5±0.2, 16.4±0.2, 17.5±0.2, 20.2±0.2, 20.8±0.2, 21.6±0.2, 21.8±0.2, 22.4±0.2, 23.1±0.2, 25.1±0.2, 25.4±0.2, Tenerigliptin edisylate crystalline form VI with 26.5±0.2 and 27.2±0.2. The teneligliptin edisylate crystalline form VI according to claim 5, wherein the endothermic point is 285.26°C in the differential scanning calorimetry analysis. Tenerigliptin edicylate crystalline form Ⅲ according to claim 1 comprising the step of suspending teneligliptin edisylate amorphous in acetonitrile, stirring by heating or stirring at room temperature, and then filtering and drying under reduced pressure. Method of manufacturing. Tenerigliptin edisylate amorphous form is suspended in acetonitrile, stirred by heating or stirred at room temperature, filtered, suspended in a mixed solvent of water and acetonitrile, stirred at room temperature, filtered and dried under reduced pressure or 60 A method for producing tenerigliptin edicylate crystalline form IV according to claim 3, comprising oven drying at 80°C. A third comprising the step of suspending teneligliptin edicylate amorphous in acetonitrile, stirring by applying heat or stirring at room temperature, and then filtering and storing at 40°C, 75% RH or 25°C, 60% RH Method for producing tenerigliptin edicylate crystalline form IV according to claim. A preparation comprising the step of suspending the teneligliptin edicylate crystalline form Ⅲ according to claim 1 in a mixed solvent of water and acetonitrile, stirred at room temperature, filtered and dried under reduced pressure or oven dried at 60 to 80°C. Method for producing tenerigliptin edicylate crystalline form IV according to item 3. Tenerigliptin edicylate crystalline form Ⅳ according to claim 3, comprising the step of storing the teneligliptin edicylate crystalline form Ⅲ according to claim 1 at 40°C, 75% RH or 25°C, 60% RH Mold manufacturing method. Tenerigliptin edicylate crystalline form VI according to claim 5 comprising the step of suspending teneligliptin edisylate amorphous in a mixed solvent of water and acetonitrile, stirring by applying heat, filtering and drying under reduced pressure. Mold manufacturing method. Suspending teneligliptin edicylate amorphous in acetonitrile, stirring by applying heat, adding water dropwise, stirring by applying heat, filtering and drying under reduced pressure or oven drying at 60 to 80°C. The method for producing tenerigliptin edicylate crystalline form VI according to claim 5. A step of suspending the dimethylformamide solvate of teneligliptin edicyl acid salt in a mixed solvent of water and acetonitrile, stirring by heating or stirring at room temperature, filtering and drying under reduced pressure or oven drying at 60 to 80°C. The method for producing tenerigliptin edicylate crystalline form VI according to claim 5 comprising a. The group consisting of tenerigliptin edicylate crystalline form Ⅲ according to claim 1, tenerigliptin edicylate crystalline form Ⅳ according to claim 3, and tenerigliptin edicylate crystalline form VI according to claim 5 A pharmaceutical composition for treating type 2 diabetes comprising at least one crystalline form selected from together with a pharmaceutically acceptable carrier.

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