WO2017047970A1 - Linagliptin crystal form, and preparation method therefor - Google Patents

Abstract

The present invention relates to a linagliptin crystal form, and a preparation method therefor. According to the present invention, the linagliptin crystal form has excellent thermal stability and can be reproducibly prepared into a single crystal form, thereby enabling mass production with consistent quality, and thus can be useful as a pharmaceutical composition for treating diabetes.

Description

Linagliptin crystal form and preparation method thereof

The present invention relates to a novel linagliptin crystal form and a preparation method thereof, 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-methylquinazolin -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 US Food and Drug Administration in 2011 for the treatment of type 2 diabetes and is currently sold under the trade name Tratraenta ^™ worldwide.

Diabetes is classified into two types according to its mechanism. Type 1 diabetes, in which beta cells are destroyed and no insulin is secreted, and type 2 diabetes, in which insulin action is reduced due to insulin resistance and sufficient secretion is not achieved. have. Currently, the majority (about 95%) of diabetics belong to type 2 diabetes. Type 2 diabetes is treated with diet therapy, exercise therapy and drug therapy. Drug therapy uses insulin or hypoglycemic agents.

Recently, a dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) among the hypoglycemic agents used for type 2 diabetes has been attracting much attention, and the blood concentration of GLP-1, which is one of the pathogenesis factors of diabetes, has been increased. It acts to promote insulin secretion.

Linagliptin is a recently-developed DPP-4 inhibitor, which is a single dose for patients with impaired renal or hepatic function, since the primary excretory pathway of conventional DPP-4 inhibitors is the kidneys, while most are excreted through the bile and gastrointestinal tract. There is an advantage that can be administered.

International publication WO2007 / 128721 discloses anhydrous polymorph A and anhydrous polymorph B of linagliptin, which can be obtained depending on the ambient temperature, both of which are converted at 25 ± 15 ° C. to room temperature. Discloses the presence of a mixture of 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 cooling to 10 ° C. or lower. In addition, the patent discloses other forms of polymorphs C, D and E, but does not mention the physicochemical properties of these polymorphs, as well as crystals at high temperatures of 70 ° C. to obtain these polymorphs. It is not suitable for practical production processes because it requires a process of drying or melting at 150 ° C.

International publication WO2013 / 074817 discloses polymorphs I to XXIII of linagliptin and its X-ray diffraction spectrum (XRD), but does not mention the physicochemical properties of each polymorph.

International publication WO2013 / 128379 discloses polymorphs I and II of linagliptin and its XRD data. The claimed polymorph I exhibits a crystalline pattern similar to polymorph XXII disclosed in WO2013 / 074817.

International publication WO2013 / 171756 discloses a process for preparing amorphous linagliptin, which involves spray drying the solution to recover the amorphous form.

International publication WO2014 / 083554 discloses a process for the preparation of amorphous form comprising contacting a reaction mixture containing an acid addition salt of linagliptin to a base and water.

However, despite the introduction of a variety of new crystalline forms through the above-mentioned patents, no specific physicochemical advantages are presented for such materials, and they do not solve the conversion between linagliptin polymorphs at room temperature. The conversion of linagliptin between polycrystalline polymorphs at room temperature may have many problems not only in the manufacture and storage of the drug substance of a certain quality, but also in the formulation process for preparing the drug product. In the formulation process, the mixture containing the drug substance may be subjected to a process such as stirring, drying, or pulverization, which may cause a problem in that the polymorph is converted or the ratio between the polymorphs is changed by the heat generated in the process. In addition, it is difficult to maintain a constant polymorph or to maintain a ratio between polymorphs during storage of the thus prepared medicinal product at room temperature.

Accordingly, there is a need for a novel linagliptin crystalline form with improved physicochemical properties that can be produced and stored as a pure polymorph at room temperature and maintain a pure polymorph in the formulation process.

Accordingly, an object of the present invention is to provide a novel linagliptin crystal form and a method for producing the same, which are excellent in thermal stability, can be reproducibly produced in a single crystal form, and can be mass-produced.

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

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

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

[Formula 1]

According to another object of the present invention, the present invention comprises the steps of: (1) adding a linagliptin 4-hydroxybenzoic acid salt represented by the following formula (2) in water or an organic solvent, adding a base and then stirring; And (2) filtering the reactants of step (1), and washing the filtered crystals with water and an organic solvent and drying the linagliptin crystal form.

[Formula 2]

According to another object, the present invention provides a linagliptin 4-hydroxybenzoic acid salt represented by the following general formula (2), which is an intermediate used in the preparation of linagliptin crystal form.

[Formula 2]

According to another object of the present invention, the present invention comprises the steps of (i) reacting linagliptin represented by the formula (1) and 4-hydroxybenzoic acid represented by the formula (3) in a solvent; And (ii) obtaining crystals from the solution obtained in the step (i), a process for preparing linagliptin 4-hydroxybenzoic acid salt.

[Formula 1]

[Formula 3]

According to another object, the present invention provides a pharmaceutical composition for treating diabetes comprising the linagliptin crystal form as an active ingredient.

The novel linagliptin crystalline form according to the present invention is not only excellent in thermal stability and can be reproducibly produced in a single crystalline form, and thus can be used as a pharmaceutical composition for treating diabetes because it can be mass produced in a certain quality.

1 is a graph showing the results of the X-ray diffraction spectroscopy of the linagliptin crystal form prepared in Example 2.

FIG. 2 is a graph showing the results of differential scanning calorimetry (DSC) of linagliptin crystalline form prepared in Example 2. FIG.

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

In the present invention, linagliptin represented by the following Chemical 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 the X-ray diffraction spectrum (XRD) Linagliptin crystal form comprising peaks at diffraction angles (2θ ± 0.2 °) of 20.7, 22.0:

[Formula 1]

The linagliptin crystal form is characterized by characteristic 2θ (2 theta) diffraction angle peaks shown in the X-ray powder diffraction spectrometer irradiated with Cu-Kα light source. Specifically, linagliptin crystal 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, 22.0, in X-ray powder diffraction analysis Characteristic peaks are shown at diffraction angles (2θ ± 0.2 °) of 23.6, 24.3, 25.1, 26.4, 27.2, 29.9, 30.9, 31.8, 33.2 and 34.3 (see FIG. 1).

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

The present invention also provides a method for producing the linagliptin crystal form. The linagliptin crystal form may be prepared by reacting linagliptin 4-hydroxybenzoic acid salt represented by the following formula (2) in the presence of a base in water or an organic solvent, as shown in Scheme 1 below.

Scheme 1

Specifically, the method for preparing linagliptin crystal form includes the steps of: (1) adding the linagliptin 4-hydroxybenzoic acid salt to water or an organic solvent, further adding a base, followed by stirring; And (2) filtering the reactants of step (1), and washing and drying the filtered crystals with water and an organic solvent.

In the case of step (1), the solvent is alcohol such as methyl alcohol, ethyl alcohol; Acetone; Water etc. can be used and it is preferable to use water independently. Water can dissolve a variety of bases, avoid the use of various types of organic solvents that were often used in the preparation of known crystalline forms, and remove excess acid that has been separated. The solvent may be used in an amount of 5 to 20 vol, preferably 8 to 15 vol, based on the volume of linagliptin 4-hydroxybenzoic acid salt.

Further, the base may be reacted with linagliptin 4-hydroxybenzoic acid salt to form linagliptin crystal form, and organic or inorganic base may be used, and specifically, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, Potassium hydrogen carbonate, sodium carbonate, potassium carbonate and the like 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 linagliptin 4-hydroxybenzoic acid salt. When the solvent and the base are included in the above range, the basic reaction is completed within a short stirring time, less impurities are generated, and the reaction can be completed by minimizing the residual of linagliptin 4-hydroxybenzoic acid.

The solution to which the base is added is then stirred to allow the basicization reaction to occur so that linagliptin can be produced in crystalline form. If the stirring time is longer, the production of linagliptin crystal form is poor, which leads to poor filtration, and therefore, it is preferable to stir for 5 to 30 minutes and to carry out the basic reaction. The basic reaction can be reacted at 0 to 60 ℃, it is preferred to react at 10 to 30 ℃.

In the case of step (2), the step of washing in order to prevent the remaining of the acid that may remain in the linagliptin crystal form, specifically, the linagliptin crystal form obtained by filtration is washed sufficiently with water and then washed with an organic solvent. The organic solvent may be heptane, hexane, diethyl ether, methyl tertiary butyl ether, isopropyl ether, and the like. A more crystalline linagliptin crystal form may be obtained by washing the organic solvent. The washed crystals may be dried at least 60 days in a hot air or vacuum at 60 ° C. to obtain linagliptin crystalline form. The dried linagliptin crystal form may maintain the crystal form even when heated to 120 ° C.

The present invention provides a linagliptin 4-hydroxybenzoic acid salt represented by the formula (2) and a preparation method thereof. The linagliptin 4-hydroxybenzoic acid salt may be prepared and used to obtain the linagliptin crystal form, and the method for preparing the linagliptin 4-hydroxybenzoic acid salt is as follows.

Specifically, the linagliptin 4-hydroxybenzoic acid salt represented by Formula 2 includes (i) reacting linagliptin represented by Formula 1 with 4-hydroxybenzoic acid represented by Formula 3 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, and the like may be used, and ethyl alcohol may be preferably used.

Linagliptin crystal form according to the present invention exists in a single phase at room temperature, and has the form of a stable single phase required in the pharmaceutical industry by eliminating the risk of polymorphic transformation. In addition, the manufacturing method is relatively simple, safe and reproducible, so that it can be applied to various commercially.

Furthermore, the present invention provides a pharmaceutical composition for treating diabetes comprising the linagliptin crystal form as an active ingredient.

The pharmaceutical composition may include, in addition to the active ingredient, conventional pharmaceutically acceptable carriers and / or excipients, and the like, which are conventional agents in the pharmaceutical field, for example, tablets, capsules, troches, solutions, suspensions, and the like. It may be formulated into a preparation for oral administration or a preparation for parenteral administration.

Solid form preparations 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 the simple excipients, lubricants such as magnesium stearate and talc may be used. As a liquid preparation for oral administration, suspending agents, liquid solutions, emulsions, and syrups are used. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be used. .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent or suspension solvent, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, injectable esters such as ethyl oleate, etc. may be used, and the bases of the suppositories may be Uthepsol, macrogol, Tween 61, Cacao butter, laurin butter, glycerol, gelatin and the like can be used.

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

Furthermore, the linagliptin crystalline form may be used in combination with one or more other known agents having therapeutic effects on diabetes.

Hereinafter, the present invention will be described in more detail with reference to the following 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 Salts

30 g of linagliptin (Intercore Corporation) was added to the reactor, 240 ml of ethyl alcohol was added thereto, and the reaction mixture was heated to about 70 ° C., and then stirred for about 15 minutes to completely dissolve it. After the temperature of the dissolved reaction solution was adjusted 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 off, washed with 90 ml of ethyl alcohol, and warmly dried 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 캜).

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 Preparation of Linagliptin Crystalline Form (1)

20.0 g of linagliptin 4-hydroxybenzoic acid salt prepared in Example 1 was added to 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 hot-dried at about 60 ° C. to obtain 14.0 g of a solid compound (yield: 91%). Thereafter, 10 g of the solid compound was added to the reactor, and 100 ml of water was added thereto, followed by stirring at about 25 ° C. for 10 minutes. The reaction mixture was filtered, washed with 100 ml of water and then with 50 ml of heptane and 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 crystals were 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 ° C).

Example 4 Preparation of Linagliptin Crystalline Form (3)

4.75 g of linagliptin crystals were 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 占 폚).

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

Cu-Kα radiation (wavelength λ = 1.54184 Å) using a D2 phaser X-ray powder diffraction spectrometer (Bruker, Germany) for the linagliptin crystal form prepared in Example 2 ) And X-ray diffraction spectrum (XRD) of linagliptin crystal form was measured, and the result is shown in the XRD graph in FIG.

Test Example 2: Differential Scanning Calorimetry (DSC) Analysis of Linagliptin Crystalline Form

Differential scanning calorimetry of linagliptin crystalline form prepared in Example 2 was measured at a rate of +1 ℃ / min using a differential scanning calorimetry (DSC 1, Mettler Toledo, Switzerland), and the result 2 is shown in the DSC graph.

Test Example 3 Measurement of Purity by High Performance Liquid Chromatography (HPLC) Analysis

Each compound prepared in the Examples was analyzed by HPLC under the conditions of Tables 1 and 2 below to obtain the respective purity.

column	Capcell pak C18 UG120 column, 4.6 mm x 150 mm (diameter X height), 5 μm (Shiseido)
Mobile phase	A = phosphate 2.0 g / 1000 ml, 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
Working time	25 mins

Gradient system
Time (min)	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 the Examples was measured using a melting point meter (B-545, Buchi, Switzerland).

From the XRD graph of FIG. 1 and the DSC graph of FIG. 2 showing the results of Experimental Examples 1 and 2, the linagliptin crystal form prepared in Example is a compound represented by Chemical Formula 1, wherein 5.6, 9.8, 11.2, Endothermic peaks at 173 ° C. and 206 ° C., including 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 It can be seen that.

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

Claims (10)

1. 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, in the X-ray diffraction spectrum (XRD) Linagliptin crystal form comprising a peak at a diffraction angle of 22.0 (2θ ± 0.2 °).

   [Formula 1]

   
2. The method of 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.
3. The method according to claim 1 or 2,

   Linagliptin crystalline form exhibits endothermic peaks at 173 ℃ and 206 ℃ in differential scanning calorimetry (DSC) analysis.
4. (1) adding linagliptin 4-hydroxybenzoic acid salt represented by the following formula (2) to water or an organic solvent, adding a base, and then stirring; And

   (2) filtering the reactants of step (1), washing and drying the filtered crystals with water and an organic solvent, a process for preparing linagliptin crystal form.

   [Formula 2]

   
5. The method of claim 4, wherein

   In step (2), the filtered crystals are washed sequentially with water and an organic solvent, linagliptin crystal form.
6. The method of claim 4, wherein

   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, linagliptin crystalline method.
7. Linagliptin 4-hydroxybenzoic acid salt represented by the following formula (2).

   [Formula 2]

   
8. (i) reacting linagliptin represented by Formula 1 with 4-hydroxybenzoic acid represented by Formula 3 in a solvent; And

   (ii) a process for obtaining linagliptin 4-hydroxybenzoic acid salt comprising the step of obtaining crystals from the solution obtained in step (i).

   [Formula 1]

   

   [Formula 3]

   
9. The method of claim 8,

   The solvent of step (i) is at least one selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol and water, linagliptin 4-hydroxybenzoic acid salt manufacturing method.
10. A pharmaceutical composition for treating diabetes comprising the linagliptin crystalline form of claim 1 as an active ingredient.

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