KR102442536B1 - Crystalline form of linagliptin and preparation method thereof - Google Patents

Abstract

The present invention relates to a linagliptin crystalline form and a method for producing the same, and the linagliptin crystalline form according to the present invention has excellent thermal stability and can be reproducibly prepared as a single crystalline form, and thus can be mass-produced with a constant quality. It can be usefully used as a pharmaceutical composition for the treatment of diabetes.

Description

Linagliptin crystal form and manufacturing method thereof

The present invention relates to a novel linagliptin crystalline form, a method for preparing the same, and a pharmaceutical composition for treating diabetes comprising the same as an active ingredient.

Linagliptin (8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazoline) -2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione) is usefully used as a raw material for the treatment of diabetes.

Linagliptin was approved by the U.S. Food and Drug Administration in 2011 as a treatment for type 2 diabetes, and is currently sold worldwide under the trade name of ^tradjenta .

Diabetes mellitus is classified into two types according to its mechanism: type 1 diabetes, in which insulin is not secreted at all due to the destruction of beta cells, and type 2 diabetes, in which insulin action is reduced and insufficient secretion is achieved due to insulin resistance. have. Currently, the majority (about 95%) of diabetic patients belong to type 2 diabetes. Type 2 diabetes is treated with diet, exercise, and drug therapy, and insulin or blood sugar-lowering drugs are used for drug therapy.

Recently, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) among the hypoglycemic agents used for type 2 diabetes have received great attention. It stimulates insulin secretion.

Linagliptin, a recently developed DPP-4 inhibitor, is excreted mostly through bile and the gastrointestinal tract, whereas the main excretion route of existing DPP-4 inhibitors is the kidney. It has the advantage that it can be administered.

International Publication No. WO2007/128721 discloses anhydrous polymorph A and anhydrous polymorph B of linagliptin which can be obtained depending on ambient temperature, these two polymorphs being interconverted at 25±15° C. to room temperature states that it exists as a mixture of the two polymorphs. According to WO 2007/128721, pure polymorph A can be obtained when heated to a high temperature of 40° C. or higher, and pure polymorph B can be obtained when cooled to 10° C. or lower. In addition, the above patent discloses polymorphs C, D and E of different forms, but does not mention the physicochemical properties of these polymorphs, and crystallizes at a high temperature of 70° C. to obtain these polymorphs. It is not suitable for practical production processes because it requires drying or melting at 150°C.

International Publication No. WO2013/074817 discloses polymorphs I to XXIII of linagliptin and X-ray diffraction spectra (XRD) thereof, but does not mention the physicochemical properties of each polymorph.

International Publication No. WO2013/128379 discloses polymorphs I to II of linagliptin and XRD data thereof. However, the claimed polymorph I exhibits a crystalline pattern similar to that of polymorph XXII disclosed in WO2013/074817.

International Publication No. WO2013/171756 discloses a method for producing amorphous linagliptin, which includes recovering the amorphous form by spray-drying the solution.

International Publication No. WO2014/083554 discloses a method for preparing an amorphous form comprising the step of contacting a reaction mixture containing an acid addition salt of linagliptin with a base and water.

However, although novel crystalline forms have been introduced in various ways through the above-mentioned patents, physical and chemical advantages are not presented for such materials, and conversion between polymorphic forms of linagliptin at room temperature has not been solved. Such conversion between crystalline polymorphs at room temperature of linagliptin may have many problems not only in manufacturing and storing drug substances of constant quality, but also in the formulation process for manufacturing finished drugs. In the formulation process, the mixture containing the drug substance may be subjected to processes such as stirring, drying, and pulverization, and heat generated in this process may cause a problem in that polymorphs are converted or the ratio between polymorphs is changed. In addition, it is difficult to maintain a constant polymorph or to ensure that the ratio between polymorphs is maintained during storage of the finished pharmaceutical product thus prepared at room temperature.

Accordingly, there is a need for a novel linagliptin crystalline form having improved physicochemical properties capable of being prepared and stored as a pure polymorph at room temperature and maintaining the pure polymorph in the formulation process.

International Patent Application No. WO2007/128721 International Patent Application No. WO2013/074817 International Patent Application No. WO2013/128379 International Patent Application No. WO2013/171756 International Patent Application No. WO2014/083554

Accordingly, an object of the present invention is to provide a novel linagliptin crystalline form that has excellent thermal stability, can be reproducibly prepared as a single crystalline form, and can be mass-produced, and a method for preparing the same.

Another object of the present invention is to provide a salt of linagliptin 4-hydroxybenzoic acid used in the method for preparing the crystalline form of linagliptin and a method for preparing the same.

Another object of the present invention is to provide a pharmaceutical composition for the treatment of diabetes comprising the linagliptin crystalline form as an active ingredient.

According to the above object, the present invention provides that linagliptin represented by the following formula (1) is 5.6, 9.8, 11.2, 11.8, 13.1, 14.4, 14.9, 16.1, 16.4, 18.4, 18.8, 19.9 in X-ray diffraction spectrum (XRD). , comprising peaks at diffraction angles (2θ±0.2°) of 20.2, 20.7, and 22.0.

[Formula 1]

According to another object, the present invention provides a method comprising: (1) adding linagliptin 4-hydroxybenzoic acid salt represented by the following Chemical Formula 2 to water or an organic solvent, adding a base, and then stirring; and (2) filtering the reactant of step (1), washing the filtered crystals with water and an organic solvent, and drying the linagliptin crystalline form.

[Formula 2]

According to another object of the present invention, linagliptin 4-hydroxybenzoic acid salt represented by the following Chemical Formula 2, which is an intermediate used for preparing linagliptin crystalline form, is provided.

[Formula 2]

According to another object, the present invention provides a method comprising: (i) reacting linagliptin represented by the following formula (1) with 4-hydroxybenzoic acid represented by the following formula (3) in a solvent; and (ii) obtaining crystals from the solution obtained in step (i).

[Formula 1]

[Formula 3]

According to another object of the present invention, there is provided a pharmaceutical composition for treating diabetes comprising the linagliptin crystalline form as an active ingredient.

The novel linagliptin crystalline form according to the present invention has excellent thermal stability and can be reproducibly prepared as a single crystalline form, and thus can be mass-produced with constant quality, so it can be usefully used as a pharmaceutical composition for the treatment of diabetes.

1 is a graph showing the results of X-ray diffraction spectroscopy of the linagliptin crystalline form prepared in Example 2.
2 is a graph showing the results of differential scanning calorimetry (DSC) of the linagliptin crystalline form prepared in Example 2;

Hereinafter, the present invention will be described in more detail.

In the present invention, linagliptin represented by the following formula (1) is 5.6, 9.8, 11.2, 11.8, 13.1, 14.4, 14.9, 16.1, 16.4, 18.4, 18.8, 19.9, 20.2 in X-ray diffraction spectrum (XRD). , which contains peaks at diffraction angles (2θ±0.2°) of 20.7 and 22.0, provides a crystalline form of linagliptin:

[Formula 1]

The linagliptin crystalline form is characterized by a characteristic 2θ (2 theta) diffraction angle peak shown in X-ray powder diffraction spectroscopy (XRP) irradiated with a Cu-Kα light source. Specifically, the linagliptin crystalline form according to the present invention is 5.6, 9.8, 11.2, 11.8, 13.1, 14.4, 14.9, 16.1, 16.4, 18.4, 18.8, 19.9, 20.2, 20.7 in X-ray powder diffraction analysis (XRPD) analysis. , 22.0, 23.6, 24.3, 25.1, 26.4, 27.2, 29.9, 30.9, 31.8, 33.2 and 34.3 show characteristic peaks at diffraction angles (2θ±0.2) (see FIG. 1 ).

Furthermore, the linagliptin crystalline form is characterized by exhibiting two endothermic peaks at about 173° C. and 206° C. in differential scanning calorimetry (DSC) (see FIG. 2 ).

In addition, the present invention provides a method for producing the linagliptin crystalline form. The linagliptin crystalline form can be prepared by reacting linagliptin 4-hydroxybenzoic acid salt represented by the following Chemical Formula 2 in water or an organic solvent in the presence of a base, as shown in Scheme 1 below.

[Scheme 1]

Specifically, the method for preparing the linagliptin crystalline form comprises the steps of (1) adding the linagliptin 4-hydroxybenzoic acid salt to water or an organic solvent, adding a base, and then stirring; and (2) filtering the reactant of step (1), washing the filtered crystals with water and an organic solvent, and drying.

In the case of step (1), the solvent is alcohol such as methyl alcohol or ethyl alcohol; acetone; Water or the like can be used, and it is preferable to use water alone. Water can dissolve various bases, it is possible to avoid the use of various kinds of organic solvents frequently used in the preparation of known crystalline forms, and to remove the separated excess acid. The solvent may be used in an amount of 5 to 20 times by volume, preferably 8 to 15 times by volume, based on the volume of the linagliptin 4-hydroxybenzoic acid salt.

Furthermore, the base is basified with linagliptin 4-hydroxybenzoic acid salt to form a linagliptin crystal form, and an organic or inorganic base can be used, specifically sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, Potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc. can be used. The base may be used in an amount of 1 to 10 equivalents, preferably 5 to 10 equivalents, based on 1 equivalent of the linagliptin 4-hydroxybenzoic acid salt. When the solvent and the base are included within the above range, the basification reaction is completed within a short stirring time, so that the generation of impurities is small, and the reaction can be completed by minimizing the residual of linagliptin 4-hydroxybenzoic acid.

Thereafter, the solution to which the base is added is stirred so that the basification reaction occurs well so that linagliptin can be produced in a crystalline form. If the stirring time is long, the formation of the linagliptin crystalline form is poor, which leads to poor filtration, so it is preferable to perform the basification reaction by stirring for 5 to 30 minutes. The basification reaction may be carried out at 0 to 60 °C, preferably at 10 to 30 °C.

In the case of step (2), washing is performed to prevent residual acid that may remain in the linagliptin crystalline form. Specifically, the linagliptin crystalline form obtained by filtration is thoroughly washed with water and then washed with an organic solvent. Heptane, hexane, diethyl ether, methyl tertiary butyl ether, isopropyl ether, etc. may be used as the organic solvent, and more crystalline linagliptin crystalline form may be obtained through washing of the organic solvent. The washed crystals may be dried for at least one day with a hot air or vacuum at 60° C. to obtain a crystalline form of linagliptin in the form of crystals. The dried linagliptin crystalline form can maintain the crystalline form even when heated to 120 °C.

The present invention provides a linagliptin 4-hydroxybenzoic acid salt represented by Formula 2 above and a method for preparing the same. The linagliptin 4-hydroxybenzoic acid salt may be prepared and used to obtain the linagliptin crystalline form, and the preparation method of the linagliptin 4-hydroxybenzoic acid salt is as follows.

Specifically, the linagliptin 4-hydroxybenzoic acid salt represented by Formula 2 may be prepared by the steps of (i) reacting linagliptin represented by Formula 1 with 4-hydroxybenzoic acid represented by Formula 3 below in a solvent; and (ii) obtaining crystals from the solution obtained in step (i).

[Formula 3]

As the solvent of step (i), methyl alcohol, ethyl alcohol, isopropyl alcohol, water, etc. may be used, and ethyl alcohol may be preferably used.

The linagliptin crystalline form according to the present invention exists as a single phase at room temperature, and has a stable single phase form required in the pharmaceutical industry by eliminating the risk of polymorphic transformation. In addition, since the manufacturing method is relatively simple, safe, and reproducible, it is commercially applicable in various ways.

Furthermore, the present invention provides a pharmaceutical composition for the treatment of diabetes comprising the linagliptin crystalline form as an active ingredient.

The pharmaceutical composition may include conventional pharmaceutically acceptable carriers and/or excipients in addition to the active ingredient, and conventional preparations in the pharmaceutical field, for example, tablets, capsules, troches, solutions, suspensions, etc. It can be formulated as a formulation for oral administration or a formulation for parenteral administration.

A solid preparation for oral administration may be prepared by mixing one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can also be used. .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, freeze-dried preparations, suppositories, and the like. Vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, and injectable esters such as ethyl oleate can be used as the non-aqueous solvent or suspension solution, and the suppository base includes Witepsol, Macrogol, Tween 61, Cacao fat, laurin fat, glycerol, gelatin, etc. can be used.

The human dose of the pharmaceutical composition may vary depending on the patient's age, weight, sex, dosage form, health condition and disease level, and is 0.1 to 20 mg/kg, preferably 1 to 20 mg/kg, based on the linagliptin active ingredient. In an amount of 10 mg/kg, it may be administered in divided doses from once a day to several times at regular time intervals.

Furthermore, the linagliptin crystalline form may be used in combination with one or more other known drugs having an effect on the treatment of diabetes.

Hereinafter, the present invention will be described in more detail by way of Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

<Example>

Example 1: Preparation of linagliptin 4-hydroxybenzoic acid salt

After adding 30 g of linagliptin (Intercore Corporation) to the reactor, and adding a solvent of 240 ml of ethyl alcohol, the reaction mixture was heated to about 70° C. and then stirred for about 15 minutes to completely dissolve. After adjusting the temperature of the dissolved reaction solution to about 60° C., 1 equivalent of 4-hydroxybenzoic acid was added to the clear reaction solution. After stirring at the same temperature for about 4 hours, the resulting crystals were filtered, washed with 90 ml of ethyl alcohol, and dried under hot air at about 60° C. to obtain 34.8 g of linagliptin 4-hydroxybenzoic acid salt (yield: 90%, Purity: 88.2% (4-hydroxybenzoic acid 11.6%), Melting point: 204°C).

¹ H-NMR (DMSO- d ⁶ , 300 MHz) δ 8.22 (d, 1H)), 7.89 (dd, 1H, J = 5.4 Hz), 7.80-7.74 (m, 3H), 7.65 (dd, 1H, J ) = 5.4 Hz), 6.76 (d, 2H), 5.31 (s, 2H), 4.90 (s, 2H), 3.68 (d, 2H), 3.56 (d, 2H), 3.38 (s, 3H), 3.07-2.99 (m, 2H), 2.93-2.90 (m, 1H), 2.87 (s, 3H), 1.92-1.89 (m, 1H), 1.81-1.80 (m, 1H), 1.76 (s, 3H), 1.64 (m) , 1H), 1.38-1.37 (m, 1H).

Example 2 : Linagliptin Preparation of crystalline form - (1)

20.0 g of the linagliptin 4-hydroxybenzoic acid salt prepared in Example 1 was put into the reactor, and an aqueous solution in which 12.0 g of sodium hydroxide was dissolved in 300 ml of water was added. After stirring at about 25° C. for 15 minutes, the reaction mixture was filtered, washed with 200 ml of water, and then dried under air at about 60° C. to obtain 14.0 g of a solid compound (yield: 91%). Then, 10 g of the solid compound was added to the reactor, 100 ml of water was added, and then stirred at about 25° C. for 10 minutes. The reaction mixture was filtered, washed with 100 ml of water, then with 50 ml of heptane, and then vacuum dried at about 60° C. to obtain 9.29 g of linagliptin crystalline form (yield: 93%, purity: 99.8%, melting point: 202° C.) .

Example 3: Preparation of linagliptin crystalline form - (2)

9.24 g of linagliptin crystalline form was obtained in the same manner as in Example 2, except that 50 ml of methyl tertiary butyl ether was used instead of 50 ml of heptane in Example 2 (yield: 92%, purity: 99.8%) , Melting point: 203℃).

Example 4: Preparation of linagliptin crystalline form - (3)

4.75 g of linagliptin crystalline form was obtained in the same manner as in Example 2, except that 5.0 g of the filtered crystals in Example 2 were used instead of 10.0 g, and 50 ml of isopropyl ether was used instead of 50 ml of heptane. (Yield: 91%, purity: 99.8%, melting point: 203°C).

Test Example 1: X-ray diffraction spectrum (XRD) analysis of linagliptin crystalline form

For the linagliptin crystalline form prepared in Example 2, Cu-Kα radiation (wavelength λ=1.54184 Å) using a D2 phaser X-ray powder diffraction spectrometer (Bruker, Germany) was used. ) to measure the X-ray diffraction spectrum (XRD) of the linagliptin crystalline form, and the results are shown as an XRD graph in FIG. 1 .

Test Example 2: Differential scanning calorimetry (DSC) analysis of linagliptin crystalline form

The differential scanning calorimetry of the linagliptin crystalline form prepared in Example 2 was measured at a rate of +1 °C/min using a differential scanning calorimetry (DSC 1, Mettler Toledo, Switzerland), and the results were measured It is shown as a DSC graph in FIG. 2 .

test example 3: high performance liquid chromatography ( HPLC ) Purity determination by analysis

Each of the compounds prepared in Examples was subjected to HPLC analysis under the conditions of Tables 1 and 2 below to determine the purity of each.

column Capcell pak C18 UG120 column,
4.6 mm X 150 mm (diameter X height), 5㎛ (Shiseido) mobile phase A = phosphate 2.0g / 1000ml, pH 2.5±0.1
B = methanol : acetonitrile = 55 : 45 test solution Test specimen 10 mg/20 mL
in mobile phase A : acetonitrile = 70 : 30 column temperature 40 ℃ detector wavelength UV, 218 nm injection volume 2 μl flow rate 1.5 mL/min operating time 25 minutes

gradient system time (minutes) Mobile phase A (%) Mobile phase B (%) 0 65 35 9 55 45 16 25 75 18 25 75 18.01 65 35 23 65 35 25 65 35

test example 4: Melting point measurement

The melting point of each compound prepared in Examples was measured using a melting point analyzer (B-545, Buchi, Switzerland).

From the XRD graph of FIG. 1 and the DSC graph of FIG. 2 showing the results of Test Examples 1 and 2, the linagliptin crystalline form prepared in the Example is a compound represented by Formula 1, and 5.6, 9.8, 11.2, Includes peaks at diffraction angles (2θ±0.2°) of 11.8, 13.1, 14.4, 14.9, 16.1, 16.4, 18.4, 18.8, 19.9, 20.2, 20.7, 22.0, and endothermic peaks at 173°C and 206°C in DSC analysis It can be confirmed that the

Accordingly, the linagliptin crystalline form according to the present invention has excellent thermal stability, so it is easy to store and maintain at room temperature, and can be prepared as a pure polymorph, so it can be expected that it can be usefully used as a pharmaceutical.

Claims (10)

Linagliptin represented by the following formula (1) is 5.6, 9.8, 11.2, 11.8, 13.1, 14.4, 14.9, 16.1, 16.4, 18.4, 18.8, 19.9, 20.2, 20.7, contains a peak at a diffraction angle of 22.0 (2θ±0.2°),
wherein the linagliptin crystalline form exhibits endothermic peaks at 173° C. and 206° C. in differential scanning calorimetry (DSC) analysis.
[Formula 1]

According to claim 1,
The linagliptin further comprises a peak at a diffraction angle selected from the group consisting of 23.6, 24.3, 25.1, 26.4, 27.2, 29.9, 30.9, 31.8, 33.2 and 34.3±0.2° on the X-ray diffraction spectrum, Linagliptin crystalline form.
delete (1) adding linagliptin 4-hydroxybenzoic acid salt represented by the following formula (2) to water or an organic solvent, adding a base, and stirring; and
(2) Filtering the reactant of step (1), washing the filtered crystals with water and an organic solvent, and drying the method, comprising the step of drying the linagliptin crystalline form of claim 1 .
[Formula 2]

5. The method of claim 4,
A method for producing a crystalline form of linagliptin, in which the filtered crystals in step (2) are sequentially washed with water and an organic solvent.
5. The method of claim 4,
In the step (2), the organic solvent is at least one selected from the group consisting of heptane, hexane, diethyl ether, methyl tertiary butyl ether and isopropyl ether, the method for producing a crystalline form of linagliptin.
delete 5. The method of claim 4,
Linagliptin 4-hydroxybenzoic acid salt represented by Formula 2 is
(i) reacting linagliptin represented by the following formula (1) with 4-hydroxybenzoic acid represented by the following formula (3) in a solvent; and
(ii) a method for producing a crystalline form of linagliptin comprising the step of obtaining a crystal from the solution obtained in step (i).

[Formula 1]

[Formula 3]

9. The method of claim 8,
The method for producing a crystalline form of linagliptin, wherein the solvent of step (i) is at least one selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol and water.
A pharmaceutical composition for treating diabetes, comprising the linagliptin crystalline form of claim 1 as an active ingredient.

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