Linagliptin crystal and production method thereof

Abstract

To provide a novel polymorph of linagliptin that is stable, and to provide a method for producing a novel polymorph of linagliptin by a safe and simple method that facilitates commercial mass production.SOLUTION: Provided is a novel polymorph of linagliptin that is a compound 1-[ (4-methyl-quinazolin-2- yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine having a peaks at 2θ(°)=6.9, 7.6, 9.2, 14.5, 17.7, 20.9±0.2θ in powder X-ray diffraction. The invention also relates to a method of producing the same.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to novel crystalline forms of linagliptin and methods for preparing same. [Background technology]

[0002] Linagliptin (JAN, INN) has the chemical name 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, and is a drug that selectively inhibits biliary excretion of dipeptidyl peptidase-4 (DPP-4) and is clinically used as a drug for type 2 diabetes (trade name: Trajenta (registered trademark) tablets).

[0003] Numerous applications have been filed for crystalline forms of linagliptin, and for example, polymorphs A to E are disclosed in Japanese Patent No. 5323684 (Patent Document 1). However, it is described that polymorphs A and B are interconverted at 25±15°C, and it is thought that there is a possibility of transition from one crystalline form to another at room temperature. Therefore, these polymorphs are not suitable for the production of pharmaceuticals that require a certain level of quality to be maintained. Furthermore, it is described that polymorphs C, D, and E require a drying step at a high temperature of 70 to 100°C or a melting step at 150°C to obtain these polymorphs, which is not preferable as an industrial production method.

[0004] Japanese Patent Application Laid-Open No. 2018-177769 discloses polymorph F (Patent Document 2). However, to obtain this polymorph, the suspension after crystallization must be stirred for 12 hours or more. Furthermore, looking at the examples, more than 20 v / w of solvent is used relative to linagliptin, which results in poor production efficiency.

[0005] Furthermore, Japanese Patent Application Laid-Open No. 2018-527363 discloses a linagliptin crystalline form having peaks at diffraction angles (2θ±0.2°) of 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, and 22.0 in an X-ray diffraction spectrum (XRD) (Patent Document 3). In the method for producing this crystalline form, (1) adding the linagliptin 4-hydroxybenzoate salt to water or an organic solvent, adding a base, and then stirring; (2) A step of filtering the reaction product of the above step (1), washing the filtered crystals with water and an organic solvent, and drying them. It is described as including.

[0006] However, the stirring time in the above step (1) is preferably 5 to 30 minutes. If the stirring time is longer, not only will the generation of impurities not be suppressed, but the insufficient production of polymorphs will also lead to poor filtration. Therefore, considering the time required for the solid-liquid separation operation, it can be said that this method is not suitable for industrial production processes. Furthermore, heptane, hexane, diethyl ether, methyl tert-butyl ether, and isopropyl ether are listed as organic solvents to be used in the above step (2), which have a high risk of electrostatic ignition, but the use of these solvents alone is not preferred.

[0007] Furthermore, International Publication No. 2013 / 171756 discloses stable amorphous linagliptin (Patent Document 4). However, obtaining this amorphous form requires a step of completely removing the solvent from the linagliptin solution, which is not a preferred industrial production method. Furthermore, WO 2014 / 083554 also discloses amorphous linagliptin (Patent Document 5). However, no data on stability is provided, and the issue of linagliptin's crystalline form transition at room temperature remains unresolved.

[0008] In addition, WO 2013 / 074817 discloses polymorphic Forms I to XXIV of linagliptin (Patent Document 6), WO 2013 / 128379 discloses polymorphic Forms I and II of linagliptin (Patent Document 7), WO 2020 / 042939 discloses crystalline form F of linagliptin (Patent Document 8), Indian patent application IN201611032051 discloses polymorphic Form M of linagliptin (Patent Document 9), and Indian patent application IN2014MU02250 discloses polymorphic Form AL of linagliptin (Patent Document 10).

[0009] Although various novel crystalline forms of linagliptin have been introduced in the above-mentioned patents, sufficient data on the stability of these substances has not been presented, and the problem of the crystalline form transition of linagliptin at room temperature has not yet been resolved. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Patent No. 5323684 Publication [Patent Document 2] Japanese Patent Application Publication No. 2018-177769 [Patent Document 3] Special Publication No. 2018-527363 [Patent Document 4] International Publication No. 2013 / 171756 [Patent Document 5] International Publication No. 2014 / 083554 [Patent Document 6] International Publication No. 2013 / 074817 [Patent Document 7] International Publication No. 2013 / 128379 [Patent Document 8] International Publication No. 2020 / 042939 [Patent Document 9] Indian Patent Application IN201611032051 [Patent Document 10] Indian Patent Application IN2014MU02250 Summary of the Invention [Problem to be solved by the invention]

[0011] In view of the above-mentioned current situation, an object of the present invention is to provide a novel polymorph of linagliptin which is more stable than the previously known polymorphs A, B, and C of linagliptin. Another object of the present invention is to provide a method for producing a novel polymorph of linagliptin by a safe and simple method that allows for easy commercial mass production. [Means for solving the problem]

[0012] In order to solve the above problems, the present inventors have conducted extensive research and have found that a stable novel polymorph can be obtained by slowly precipitating crystals from a methanol solution of linagliptin or a mixed solution of methanol and methyl tert-butyl ether, followed by solid-liquid separation and drying, thereby completing the present invention.

[0013] Thus, in one aspect, the present invention comprises: (1) A novel polymorph of linagliptin, which is the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, exhibiting peaks at 2θ (°) = 6.9, 7.6, 9.2, 14.5, 17.7, and 20.9 ± 0.2θ in powder X-ray diffraction.

[0014] In another aspect, the present invention provides: (2) A novel polymorph of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, having the following lattice constants:

[0015] [Table 1]

[0016] It is a novel polymorph of linagliptin characterized by:

[0017] Furthermore, the present invention specifically relates to (3) A novel polymorph of linagliptin having the powder X-ray diagram shown in Figure 1.

[0018] In yet another aspect, the present invention provides: (4) A method for preparing a novel polymorph of linagliptin, which is the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, having peaks at 2θ(°)=6.9, 7.6, 9.2, 14.5, 17.7, and 20.9±0.2θ in powder X-ray diffraction, the method comprising: (a) obtaining a methanol solution of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, (b) adding a solvent to the methanol solution or cooling the solution to prepare a solution in which 45% or less of the charged amount of crystals are superdissolved; (c) obtaining crystals from the solution; (d) repeating the steps (b) and (c) as necessary; (e) filtering the resulting suspension; and (f) drying at a temperature of 30°C or higher; The method is characterized by comprising: [Effects of the Invention]

[0019] The novel polymorph of linagliptin according to the present invention does not transition to other polymorphs at room temperature when analyzed using a powder X-ray diffractometer, and is therefore more suitable for the production of pharmaceuticals that require maintaining a certain level of quality than polymorphs A and B. Furthermore, compared to the hydrated polymorph C, it has the advantage of being more stable against temperature and maintaining a consistent quality. Furthermore, the novel polymorphic form of linagliptin of the present invention has an extremely low amount of residual solvent and is therefore suitable as an active ingredient in pharmaceutical compositions. Therefore, it has the advantage of being extremely useful as a pharmaceutical ingredient.

[0020] Furthermore, the novel polymorph of linagliptin provided by the present invention can be produced by slowly crystallizing linagliptin using methanol or a mixed solvent of methanol and methyl tert-butyl ether in an amount of 10 v / w or less relative to linagliptin as a recrystallization solvent, and then drying the resulting wet crystals at 30°C or higher.

[0021] Therefore, this method is easier to mass-produce commercially and safer than the method for producing polymorphs C, D, and E (WO 2007 / 128721), which requires heating at 70°C or higher; the method for producing an amorphous form (WO 2013 / 171756), which requires a step of completely removing the solvent from the linagliptin solution; the method described in JP 2018-527363 A, which has a limited stirring time during crystallization and uses a single solvent that carries a high risk of electrostatic ignition; and the method for producing polymorph F (JP 2018-177769 A), which is estimated to use 20 v / w or more of solvent. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is a powder X-ray diagram of a novel polymorph of linagliptin provided by the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0023] Specifically, the novel polymorph of linagliptin provided by the present invention can be produced by slowly crystallizing linagliptin using methanol or a mixed solvent of methanol and methyl tert-butyl ether (hereinafter sometimes referred to as "MTBE") in an amount of 10 v / w or less relative to linagliptin as a recrystallization solvent, and then drying the resulting wet crystals at 30°C or higher.

[0024] Meanwhile, a method for obtaining polymorphic Form C of linagliptin has already been clarified, and for example, Japanese Patent No. 6602909 reports a method comprising the following steps: (a) refluxing 1-[(4-methyl-quinazolin-2-yl)methyl)-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in methanol to obtain a methanolic solution; (b) cooling the methanolic solution to a temperature of 40-60°C; (c) adding a solvent; (d) cooling the resulting suspension first to 15-25°C and then to 0-5°C to obtain crystals; (e) filtering the crystals by suction; and (f) drying under vacuum at a temperature of 70°C;

[0025] However, after studying the crystallization method with reference to the above method, we found that a new polymorph, not polymorph C, could be obtained by controlling the crystals to grow slowly and ensuring that the proportion of superdissolved crystals did not exceed 45%. The present invention was completed by evaluating the physical and pharmaceutical properties such as stability and solubility of the novel polymorphic form finally obtained and confirming its usefulness.

[0026] The linagliptin used in the present invention can be prepared by the methods described in Patent Document 1 (Example 1) and Patent Document 7 (Example 11), for example. [Example]

[0027] Hereinafter, the embodiments of the present invention will be described in detail with reference to examples and various test examples.

[0028] Example 1: Preparation of novel polymorphs of linagliptin Linagliptin (5.0 g, 9.8 mmol) was added to methanol (22.5 mL) and heated to 55°C to dissolve. The mixture was then cooled to 45°C, and methyl tert-butyl ether (10.0 mL) and 0.025 g of linagliptin seed crystals were added at the same temperature. Methyl tert-butyl ether (12.5 mL) was then added at the same temperature, and the mixture was stirred at 45°C for 1 hour. The mixture was then cooled to 40°C. After stirring at 40°C for 1 hour, the mixture was cooled to 35°C, stirred at 35°C for 1 hour, cooled to 20°C, stirred at 20°C for 1 hour, and then cooled to 0-5°C. After stirring at 0-5°C for 1 hour, the precipitated crystals were filtered. The filtrate was washed with a 1:1 mixed solvent of methanol and methyl tert-butyl ether (10.0 mL) and dried under reduced pressure at 60°C to obtain 3.51 g of a novel polymorph of linagliptin as white crystals.

[0029] Residual solvent values ​​were 10 ppm for methanol and 51 ppm for methyl tert-butyl ether (see Test Example 1 below). The powder X-ray diffraction pattern of the obtained crystals was as shown in FIG. The crystallization rate when not overdissolved, the crystallization rate, and the proportion of overdissolved crystals were calculated by the following methods, and the results are shown in Table 2 below.

[0030] A: Calculation of crystallization rate The crystallization rate of linagliptin was calculated from the refractive index of the solution using the calibration curve method. The calibration curve was prepared from the refractive index and crystallization rate of a uniformly dissolved solution of linagliptin (a mixed solvent of 45 mL of methanol and 45 mL of MTBE) at the preparation points (11 points) shown in Table 2 below.

[0031] [Table 2]

[0032] B: Crystallization rate when not overdissolved The crystallization rate when the solution was not over-dissolved was calculated as follows. Using a mixed solvent of 22.5 mL of methanol and 22.5 mL of methyl tert-butyl ether, saturated solutions of linagliptin were prepared at 45°C, 40°C, 35°C, 20°C, and 0 to 5°C. The crystallization rate was calculated from the refractive index of each solution using the above calibration curve.

[0033] C: Percentage of superdissolved crystals The crystallization rate of the proportion of overdissolved crystals was calculated by subtracting the crystallization rate of the current solution (calculated by filtering the crystals from the suspension and using the above calibration curve from the refractive index of the filtrate) from the crystallization rate when not overdissolved. The super-dissolved state was measured using a refractometer (model: RA-620) manufactured by Kyoto Electronics Manufacturing Co., Ltd. at a measurement temperature of 10°C. The results are shown in Table 3 below.

[0034] [Table 3]

[0035] Example 2: Preparation of novel polymorphs of linagliptin Linagliptin (3.0 g, 5.9 mmol) was added to methanol (13.5 mL) and heated to 55°C to dissolve. The mixture was then cooled to 45°C, and methyl tert-butyl ether (6.0 mL) and 0.015 g of linagliptin seed crystals were added at the same temperature. Methyl tert-butyl ether (7.5 mL) was then added at the same temperature, and the mixture was stirred at 45°C for 1 hour. The mixture was then cooled to 40°C, stirred at 40°C for 1 hour, cooled to 35°C, stirred at 35°C for 1 hour, and then cooled to 0-5°C. After stirring at 0-5°C for 24 hours, the precipitated crystals were filtered. The filtrate was washed with a 1:1 mixed solvent of methanol and methyl tert-butyl ether (6.0 mL) and dried under reduced pressure at 60°C to obtain 1.98 g of the novel polymorph of linagliptin as white crystals. The powder X-ray diffraction pattern of the obtained crystals is shown in FIG. The crystallization rate and the proportion of superdissolved crystals were calculated by the method shown in Example 1. The results are shown in Table 4.

[0036] [Table 4]

[0037] Example 3: Preparation of novel polymorphs of linagliptin 5.0 g (9.8 mmol) of linagliptin was added to 25.0 mL of methanol and heated to 55°C to dissolve. The mixture was then cooled to 45°C and stirred at the same temperature for 4 hours, after which the precipitated crystals were filtered. The obtained crystals were dried under reduced pressure at 30°C to obtain a novel polymorph of linagliptin as white crystals. The powder X-ray diffraction pattern of the obtained crystals is shown in FIG.

[0038] The conditions for measuring powder X-ray diffraction in Examples 1 to 3 are as follows. <Powder X-ray diffraction> Powder X-ray diffraction measurements were performed using RIGAKU's Ultima IV. X-ray:Cu / 40kV / 30mA Divergence slit: 1 / 2° Divergence vertical limit slit: 10.00 mm Scattering slit: 1 / 2° Receiving slit: 0.15 mm Monochrome receiving slit: 0.8 mm Scan speed: 2.0000° / min Sampling width: 0.0200° Scanning range: 2.0000~40.0000°

[0039] From the powder X-ray diffraction diagram, the lattice constants shown in Table 1 above were obtained.

[0040] Test Example 1: Residual Solvent Test The novel polymorphs of linagliptin obtained in each example were observed for the level of residual solvent under the following residual solvent test conditions. <Residual solvent test conditions> Gas chromatograph: Agilent Technologies 8890 Detector: Hydrogen flame ionization detector Column: The inner surface of a fused silica tube having an inner diameter of 0.32 mm and a length of 30 m is coated with 6% cyanopropylphenyl-94% dimethylpolysiloxane for gas chromatography to a thickness of 1.8 mm (AGILENT DB-624 is used). Column temperature: Inject at a constant temperature of around 40°C, maintain for 3 minutes, then increase the temperature at a rate of 5°C per minute until it reaches 65°C, and 10°C per minute until it reaches 180°C. After that, increase the temperature at a rate of 60°C per minute until it reaches 210°C, and maintain this temperature for 5 minutes. Inlet temperature: constant temperature around 250°C Detector temperature: constant temperature around 250°C Carrier gas: Helium Flow rate: 35cm / sec Split ratio: 1:20 Area measurement range: Approximately 15 minutes Headspace sampler: Agilent Technologies 7697A Equilibrium temperature in the vial: constant temperature around 80°C Equilibration time in vial: 40 minutes Loop temperature: Constant temperature around 95°C Transfer line temperature: Constant temperature around 105°C Carrier gas: Helium Pressure time: 30 seconds Sample injection volume: 1.0 mL

[0041] As a result, the residual solvent values ​​of the novel polymorph of linagliptin of the present invention prepared in Example 1 were 10 ppm for methanol and 51 ppm for methyl tert-butyl ether, which was an extremely low residual solvent value.

[0042] Test Example 2: Storage stability test The stability of the crystalline form of the novel polymorph of linagliptin of the present invention at room temperature and at 40°C / 75% RH was investigated. The stability at 40°C / 75% RH was compared with that of linagliptin polymorph C as a control. The results are shown in Tables 5 and 6 below.

[0043] Table 5: Stability of novel polymorphs at room temperature

[0044] [Table 5]

[0045] Table 6: Stability at 40°C / 75%RH

[0046] [Table 6]

[0047] As is clear from the results shown in each table, the novel polymorph of linagliptin of the present invention does not undergo transition of crystal form and is understood to have excellent storage stability. [Industrial Applicability]

[0048] As described above, the novel polymorph of linagliptin provided by the present invention can be easily and safely produced on a commercial scale. Furthermore, the novel polymorphic form of linagliptin of the present invention has an extremely low amount of residual solvent and is therefore suitable as an active ingredient in pharmaceutical compositions. In this respect, its industrial applicability is enormous.

Claims

1. A novel polymorph of linagliptin, which is the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, having peaks at 2θ (°) = 6.9, 7.6, 9.2, 14.5, 17.7, and 20.9 ± 0.2θ in powder X-ray diffraction.

2. 1. A novel polymorph of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, having the following lattice constants: Table 1 A novel polymorph of linagliptin characterized by

3. A novel polymorph of linagliptin having the powder X-ray diagram shown in Figure 1.

4. 1. A method for preparing a novel polymorph of linagliptin, which is the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, having peaks at 2θ (°) = 6.9, 7.6, 9.2, 14.5, 17.7, and 20.9 ± 0.2θ in X-ray powder diffraction, the method comprising: (a) obtaining a methanol solution of the compound 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine; (b) adding a solvent to the methanol solution or cooling the solution to prepare a solution in which 45% or less of the crystals are superdissolved; (c) obtaining crystals from the solution; (d) repeating the steps (b) and (c) as necessary; (e) filtering the resulting suspension; and (f) drying at a temperature of 30°C or higher; A method comprising:

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