Crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-piperidine-1-yl)-xanthine

Abstract

To provide a crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine, which exhibits superior stability.SOLUTION: Provided is a crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine, which exhibits at least three peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in X-ray powder diffraction (diffraction angle 2θ) by Cu-Kα radiation.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine. [Background technology]

[0002] 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (hereinafter sometimes referred to as linagliptin) is known to inhibit dipeptidyl peptidase. Dipeptidyl peptidase is an enzyme involved in the decomposition of incretin, and it is believed that the inhibition of dipeptidyl peptidase increases the concentration of glucagon-like peptide-1 (GLP-1) in the blood, leading to an increase in serum insulin concentration and a decrease in blood glucose level. Therefore, the linagliptin is used as a drug for treating diabetes (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2016-222734 A Summary of the Invention [Problem to be solved by the invention]

[0004] In general, compounds used as active ingredients of medicines are required to be stable. For example, the crossover point of thermodynamic stability of polymorph A and polymorph B described in Patent Document 1 is 25±15°C, and the crystal form may be converted during the manufacturing process of the medicine. Therefore, polymorph A and polymorph B may exist as a mixture in the obtained medicine. The presence of different polymorphs in a pharmaceutical preparation may affect the dissolution rate of the active ingredient. Similarly, polymorph C and polymorph D are also thought to undergo a crystal form transition due to heat, and this crystal form transition was an irreversible transition. In addition, linagliptin has low solubility in water, and the bioavailability of currently commercially available linagliptin formulations has been reported to be about 30%. The object of the present invention is to provide a crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine that exhibits superior stability and solubility. [Means for solving the problem]

[0005] The present inventors have conducted extensive research into the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, which has excellent stability and solubility, and have surprisingly found a new crystalline form having a specific peak in powder X-ray diffraction (diffraction angle 2θ). The present invention is based on these findings. Thus, the present invention provides [1] A crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, which exhibits at least three peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα radiation; [2] The crystalline form according to [1], wherein the crystalline form exhibits at least four peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ); [3] The crystalline form according to [1] or [2], wherein the crystalline form exhibits peaks at 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ); [4] The crystalline form according to any one of [1] to [3], which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. [5] A crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, which exhibits at least four peaks selected from the group consisting of 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα radiation; [6] The crystalline form according to [5], wherein the crystalline form exhibits at least five peaks selected from the group consisting of 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ). [7] The crystalline form according to [5] or [6], wherein the crystalline form exhibits peaks at 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ). [8] The crystalline form according to any one of [5] to [7], having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in FIG. 2. [9] A pharmaceutical composition for treating diabetes, comprising the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of [1] to [8] as an active ingredient.

[10] Use of the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of [1] to [8] in the manufacture of a pharmaceutical composition for treating diabetes.

[11] A method for treating diabetes, comprising administering to a patient an effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of [1] to [8]; and

[12] 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of [1] to [8] for use in a method for treating diabetes. Regarding. Effect of the Invention

[0006] The crystalline form of linagliptin of the present invention can exhibit excellent stability with little generation of impurities, and can also exhibit excellent solubility in water. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 is a powder X-ray diffraction pattern of the crystalline form (1) of linagliptin of the present invention. [Diagram 2] FIG. 1 is a powder X-ray diffraction pattern of the crystalline form (2) of linagliptin of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] [1] Crystalline form (1) The crystalline form (1) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine of the present invention exhibits at least three peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation, preferably at least four peaks, and most preferably five peaks.

[0009] Linagliptin The linagliptin has the following formula (1): [ka] It is a compound represented by the formula: and exhibits dipeptidyl peptidase inhibitory activity. Dipeptidyl peptidase is an enzyme that breaks down incretins, and inhibiting dipeptidyl peptidase can increase the concentration of glucagon-like peptide-1 (GLP-1) in the blood. This action induces an increase in serum insulin concentration and a decrease in blood glucose level. In Japan, it is sold under the trade name Trajenta.

[0010] Powder X-ray diffraction The linagliptin crystalline form (1) exhibits at least three peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. The five peaks are characteristic peaks of the linagliptin crystalline form (1) of the present invention. Therefore, the linagliptin crystalline form (1) of the present invention can be specified by any combination of three peaks, but the most preferred combination is the peaks of 6.9°±0.2°, 20.8°±0.2°, and 7.6°±0.2°.

[0011] The linagliptin crystalline form (1) preferably exhibits at least four peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. The five peaks are characteristic peaks of the linagliptin crystalline form (1) of the present invention. Therefore, the linagliptin crystalline form (1) of the present invention can be specified by any combination of four peaks, and the most preferred combination is 6.9°±0.2°, 20.8°±0.2°, 7.6°±0.2°, and 9.3°±0.2°.

[0012] More preferably, the linagliptin crystalline form (1) exhibits peaks at 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. The five peaks are characteristic peaks of the linagliptin crystalline form (1) of the present invention, and the linagliptin crystalline form (1) of the present invention can be identified by a combination of the five peaks.

[0013] The linagliptin crystalline form (1) may have a peak at 7.3°±0.2° and / or a peak at 17.7°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation, in addition to the three to five peaks. That is, it may have at least 4 to 6 peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, 20.8°±0.2° and 7.3°±0.2°. In addition, it may have at least 4 to 6 peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, 20.8°±0.2° and 17.7°±0.2°. Furthermore, it may have at least 5 to 7 peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, 20.8°±0.2°, 7.3°±0.2°, and 17.7°±0.2°. The crystalline form (1) of linagliptin most preferably has a powder crystal diffraction pattern as set forth in FIG.

[0014] The error of the peak at the diffraction angle 2θ in the powder X-ray diffraction spectrum of the linagliptin crystalline form (1) of the present invention is about ±0.2°. This error arises due to the equipment used for the measurement, the sample preparation, the data analysis method, etc., and is common general knowledge in the technical field. Furthermore, the linagliptin crystalline form (1) of the present invention also includes those having the same peak pattern in the powder X-ray diffraction (diffraction angle 2θ) but different relative intensities of the peaks. In this specification, the relative intensity is the relative value of each peak area when the peak with the largest area at the diffraction angle 2θ in the powder X-ray diffraction spectrum is set to 100.

[0015] The linagliptin crystalline form (1) of the present invention has an endothermic peak at 173.3° C.±5° C. as determined by differential thermal analysis. The linagliptin crystalline form (1) of the present invention is presumed to be a hydrate. The linagliptin crystalline form (1) of the present invention can be used as an active ingredient in a pharmaceutical composition for treating diabetes. The linagliptin crystalline form (1) of the present invention has excellent stability, and the pharmaceutical composition also shows excellent stability. Therefore, the crystalline form (1) of linagliptin of the present invention can be used for the preparation of a pharmaceutical composition for treating diabetes.

[0016] The bulk density of the crystalline form (1) of the present invention is, but is not limited to, 0.15 to 0.25 g / mL, preferably 0.18 to 0.22 g / mL. The tap density of the crystalline form (1) of the present invention is, but is not limited to, 0.32 to 0.42 g / mL, preferably 0.35 to 0.39 g / mL, more preferably 0.36 to 0.38 g / mL, for example, 0.37 g / mL. By having the bulk density and the like within the above ranges, the crystalline form (1) can exhibit properties different from other crystalline forms of linagliptin.

[0017] [2] Crystalline form (2) The crystalline form (2) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine of the present invention exhibits at least four peaks selected from the group consisting of 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation, preferably at least five peaks, more preferably six peaks.

[0018] Powder X-ray diffraction The linagliptin crystalline form (2) exhibits at least four peaks selected from the group consisting of 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. The six peaks are characteristic peaks of the linagliptin crystalline form (2) of the present invention. Therefore, the linagliptin crystalline form (2) of the present invention can be specified by any combination of four peaks, but the most preferred combination is 6.9°±0.2°, 15.4°±0.2°, 17.9°±0.2°, and 20.8°±0.2°.

[0019] The linagliptin crystalline form (2) preferably exhibits at least five peaks selected from the group consisting of 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. The six peaks are characteristic peaks of the linagliptin crystalline form (2) of the present invention. Therefore, the linagliptin crystalline form (2) of the present invention can be specified by any combination of five peaks, and the most preferred combination is 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, and 20.8°±0.2°.

[0020] More preferably, the linagliptin crystalline form (2) exhibits peaks at 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. The six peaks are characteristic peaks of the linagliptin crystalline form (2) of the present invention, and the linagliptin crystalline form of the present invention can be identified by a combination of the six peaks.

[0021] The linagliptin crystalline form (2) may have, in addition to the four to six peaks, one or more peaks selected from the group consisting of 7.1°±0.2°, 13.7°±0.2°, 14.5°±0.2°, and 16.2°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. That is, it may have at least 4 to 10 peaks selected from the group consisting of 6.9°±0.2°, 7.1°±0.2°, 10.4°±0.2°, 13.7°±0.2°, 14.5°±0.2°, 15.4°±0.2°, 16.2°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2. The crystalline form (2) of linagliptin most preferably has a powder crystal diffraction pattern as shown in FIG.

[0022] The error of the peak at the diffraction angle 2θ in the powder X-ray diffraction spectrum of the linagliptin crystalline form (2) of the present invention is about ±0.2°. This error is caused by the equipment used for the measurement, the sample preparation, the data analysis method, etc., and is common general knowledge in the technical field. Furthermore, the linagliptin crystalline form (2) of the present invention also includes those having the same peak pattern in the powder X-ray diffraction (diffraction angle 2θ) but different relative intensities of the peaks. In this specification, the relative intensity is the relative value of each peak area when the peak with the largest area at the diffraction angle 2θ in the powder X-ray diffraction spectrum is set to 100. It is presumed that the linagliptin crystalline form (2) of the present invention is not a hydrate.

[0023] The bulk density of the crystalline form (2) of the present invention is, but is not limited to, 0.15 to 0.25 g / mL, preferably 0.18 to 0.22 g / mL. The tap density of the crystalline form (2) of the present invention is, but is not limited to, 0.32 to 0.42 g / mL, preferably 0.35 to 0.39 g / mL, more preferably 0.36 to 0.38 g / mL, for example, 0.37 g / mL. By having the bulk density and the like within the above ranges, the crystalline form (2) can exhibit properties different from other crystalline forms of linagliptin.

[0024] Method for producing crystalline forms of linagliptin The first method for producing the crystalline form of linagliptin of the present invention includes the steps of (a) dissolving 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in methanol by heating at 40 to 65°C to obtain a methanol solution, (b1) adding seed crystals to the methanol solution at 35 to 45°C and confirming crystal precipitation, (c) cooling the resulting suspension to 15°C or lower to obtain crystals, (d) filtering the crystals, and (e) drying the resulting crystals under reduced pressure at 20 to 100°C. The seed crystals are crystals of crystalline form (1) or crystalline form (2). The seed crystals of crystalline form (1) or crystalline form (2) can be obtained by the second production method described below.

[0025] Furthermore, the second method for producing the crystalline form of linagliptin of the present invention includes the steps of: (a) heating 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 dissolve it at 40 to 65°C to obtain a methanol solution; (b2) adding tert-butyl methyl ether at 35 to 45°C and checking for crystal precipitation; (c) cooling the obtained suspension to 15°C or lower to obtain crystals; (d) filtering the crystals; and (e) drying the obtained crystals under reduced pressure at 20 to 100°C. The first and second production methods for the crystalline form (1) of linagliptin of the present invention are the same in steps (a), (c), (d) and (e), but differ in step (b1) of the first production method from step (b2) of the second production method. Below, the common steps are described together, and the different steps are described individually.

[0026] 《Process (a)》 In the step (a), linagliptin is dissolved in methanol by heating at 40 to 65°C to obtain a methanol solution. The dissolution temperature is preferably 40 to 60°C, more preferably 40 to 50°C. The amount of methanol relative to linagliptin is not particularly limited as long as the crystalline form of the present invention is obtained, but is 0.5 to 30 times (weight / weight), preferably 1 to 10 times, more preferably 1.5 to 5 times the amount of linagliptin. Methanol with a purity of 97% or more may be used. Linagliptin is preferably dissolved in methanol while stirring. A known method may be used for stirring, and for example, a stirrer, a stirring blade, a magnetic stirrer, or the like may be appropriately selected and used. The methanol solution is preferably cooled to about 40°C. The cooling method is not limited, and for example, the methanol solution may be left in a water bath or at room temperature.

[0027] 《Process (b1)》 In the step (b1), seed crystals are added to the methanol solution at 35 to 45° C., and crystal precipitation is confirmed. The amount of seed crystals is not particularly limited, but for example, 0.001 to 5% by weight of the obtained crystals may be added as seed crystals, preferably 0.01 to 3% by weight, more preferably 0.02 to 2% by weight, even more preferably 0.04 to 1% by weight, and most preferably 0.05 to 0.5% by weight. Crystal precipitation can be confirmed by visual observation. After the crystal precipitation is confirmed, the methanol solution is stirred at 40°C to promote the growth of the crystals. The stirring method is not particularly limited, but a stirrer, stirring blade, or magnetic stirrer may be used, and stirring is performed at 150 to 350 rpm, preferably 200 to 300 rpm. The stirring time is also not particularly limited, but is, for example, 10 minutes to 10 hours, preferably 20 minutes to 3 hours, and more preferably 40 minutes to 2 hours. If the stirring time is too short, crystal precipitation may be insufficient, and if it is too long, decomposition of linagliptin may occur.

[0028] 《Process (b2)》 In the step (b2), tert-butyl methyl ether is added at 35 to 45° C., and crystal precipitation is confirmed. The amount of tert-butyl methyl ether is not particularly limited, but is, for example, 0.5 to 5 times the amount of the methanol solution, preferably 1 to 4 times, more preferably 1.5 to 3 times, and even more preferably 1.7 to 2.5 times. The method of adding tert-butyl methyl ether is also not limited, but it is preferably added dropwise to the methanol solution. Crystal precipitation can be confirmed by visual observation. After the precipitation of crystals is confirmed, the methanol solution is stirred at 40°C to promote the growth of crystals. The stirring method is not particularly limited, but a stirrer, stirring blade, or magnetic stirrer may be used, and stirring is performed at 150 to 350 rpm, preferably 200 to 300 rpm. The stirring time is also not particularly limited, but is, for example, 5 minutes to 10 hours, preferably 10 minutes to 2 hours, more preferably 20 minutes to 2 hours, and even more preferably 30 minutes to 1 hour. If the stirring time is too short, crystal precipitation may be insufficient, and if it is too long, decomposition of linagliptin may occur.

[0029] 《Process (c)》 In the step (c), the obtained suspension is cooled to 15°C or less to obtain crystals. The cooling temperature is not limited as long as it is 15°C or less, but is preferably 0 to 10°C, and more preferably 0 to 5°C. Preferably, the suspension is stirred after cooling to promote crystal growth. The stirring method is not particularly limited, but a stirrer, stirring blade, or magnetic stirrer may be used, and stirring is performed at 150 to 350 rpm, and preferably 200 to 300 rpm. The stirring time is also not particularly limited, but is, for example, 10 minutes to 10 hours, preferably 20 minutes to 3 hours, and more preferably 40 minutes to 2 hours.

[0030] 《Process (d)》 In the step (d), the crystals are filtered. The filtration is not particularly limited, but can be performed, for example, by vacuum filtration (suction filtration), pressure filtration, or centrifugal filtration using filter paper or the like. Here, the filtered crystals may be washed. The solvent used for washing the crystals is preferably the same as that used for producing the crystals, and therefore, methanol or a methanol / tert.-butyl methyl ether solution or the like is used.

[0031] 《Process (e)》 In the step (e), the obtained crystals are dried under reduced pressure at 20 to 100° C., preferably 20 to 70° C., and more preferably 30 to 60° C. The pressure for the reduced pressure drying is, for example, 0.1 atmosphere (atm) or less, and preferably 0.05 atmosphere or less.

[0032] The linagliptin crystal form (1) and the crystal form (2) of the present invention have slightly different peaks at diffraction angles 2θ in the powder X-ray diffraction spectrum. However, they can be obtained by the same manufacturing method and have basically the same properties. As described above, the crystal form (1) and the crystal form (2) differ in whether they are hydrates or not, and are reversible.

[0033] [3] Pharmaceutical composition The crystalline form of the present invention can be used as an active ingredient of a pharmaceutical composition. Specifically, it can be used as an active ingredient of a pharmaceutical composition for treating type 2 diabetes. That is, the crystalline form of the present invention can be used for the manufacture of a pharmaceutical composition for treating diabetes. In addition, the crystalline form of the present invention can be used in a method for treating diabetes, which includes a step of administering an effective amount of the crystalline form to a patient. Furthermore, the crystalline form of the present invention is a crystalline form for use in a method for treating diabetes. The pharmaceutical composition may contain the active ingredient in an amount of 0.01 to 99% by weight, preferably 0.1 to 80% by weight, although it is not limited thereto. The dosage when using a pharmaceutical composition may be appropriately determined depending on the age, sex, weight, severity of symptoms, administration method, etc. of the patient, and the pharmaceutical composition may be administered orally or parenterally.

[0034] The dosage form of the pharmaceutical composition is not particularly limited, and examples thereof include oral preparations such as powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, and pills, and parenteral preparations such as injections, external liquid preparations, ointments, suppositories, creams for topical administration, and eye drops.

[0035] The pharmaceutical composition can be manufactured according to a conventional method using, for example, excipients such as gelatin, sodium alginate, starch, corn starch, white sugar, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean lecithin, sucrose, fatty acid esters, talc, magnesium stearate, polyethylene glycol, magnesium silicate, anhydrous silicic acid, or synthetic aluminum silicate, binders, disintegrants, surfactants, lubricants, flow enhancers, diluents, preservatives, colorants, fragrances, flavorings, stabilizers, moisturizers, preservatives, or antioxidants.

[0036] Examples of parenteral administration methods include injection (subcutaneous, intravenous, etc.) or rectal administration. Among these, injections are most preferably used. For example, in the preparation of injections, in addition to the active ingredient, for example, water-soluble solvents such as physiological saline or Ringer's solution, water-insoluble solvents such as vegetable oil or fatty acid ester, isotonicity agents such as glucose or sodium chloride, solubilizers, stabilizers, preservatives, suspending agents, or emulsifiers can be optionally used.

[0037] Furthermore, the administration form is not limited to pharmaceuticals, and various forms are possible, such as functional foods and health foods (including beverages), or food and beverages that can be given to animals as feed. EXAMPLES

[0038] The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited thereto.

[0039] Example 1 In this example, linagliptin crystal form (1) was prepared. 40 g (85 mmol) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (linagliptin) was mixed with 100 g of methanol and heated to 40-50°C to dissolve. The mixture was then filtered while hot and washed with 20 g of methanol. The filtrate was cooled to 40°C and seed crystals were added. After confirming crystal precipitation, the mixture was stirred at 40°C for 1 hour. The suspension was cooled to 0-5°C and stirred for 1 hour. The crystals were filtered and washed with 60 g of methanol. The wet crystals were dried under reduced pressure at 30-60°C to obtain 35 g (74 mmol) of white linagliptin crystals.

[0040] Example 2 In this example, linagliptin crystal form (1) was prepared by a process different from that of Example 1. 33 g (70 mmol) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (linagliptin) was mixed with 82.5 g of methanol and heated to 40-50°C to dissolve. The mixture was then filtered while hot and washed with 16.5 g of methanol. The filtrate was cooled to 40°C and 198 g of tert.-butyl methyl ether was added dropwise. After confirming crystal precipitation, the mixture was stirred at 40°C for 30 minutes. The suspension was cooled to 0-5°C and stirred for 1 hour. The crystals were filtered and washed with a mixture of 22 g of methanol and 44 g of tert.-butyl methyl ether. The wet crystals were dried under reduced pressure at 30 to 60° C. to obtain 31 g (66 mmol) of white linagliptin crystals.

[0041] <Powder X-ray diffraction measurement> The crystals obtained in Example 1 or Example 2 were stored overnight at room temperature with a humidity of 50% or more in a general laboratory, and then subjected to powder X-ray diffraction measurement under the following conditions. Equipment: BRUKER D2 PHASER 2 nd Gen Target: CuKα Scanning range: 3.0~40.0° Step width: 0.02° Time: 0.40 seconds Table 1 and FIG. 1 show the powder X-ray diffraction measurement results of the crystals obtained in Example 1, and Table 2 shows the powder X-ray diffraction measurement results of the crystals obtained in Example 2.

[0042] [Table 1]

[0043] [Table 2]

[0044] As shown in Tables 1 and 2 and Figure 1, the largest peak was observed at 6.9°, and relatively large peaks were also observed at 20.8°, 7.6°, 9.3°, and 14.5°. In addition, a peak was also observed at 7.3° near the shoulder of 6.9°, and a peak was also observed at 17.7°, indicating the same crystal form. The powder X-ray diffraction of the crystalline form (1) of the present invention is stable, and no change was observed in the powder X-ray diffraction peaks even after storage for 6 months at 25° C., 60% RH, or 40° C., 75% RH.

[0045] Example 3 In this example, linagliptin crystal form (2) was prepared. 10 g (21 mmol) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (linagliptin) was mixed with 30 g of methanol and heated to 40-50°C to dissolve. The mixture was then cooled to 40°C and seed crystals were added. After confirming crystal precipitation, the mixture was stirred at 40°C for 1 hour. The suspension was cooled to 0-5°C and stirred for 1 hour. The crystals were filtered and washed with 15 g of methanol. The wet crystals were dried under reduced pressure at 30-60°C to obtain 8.6 g (18 mmol) of white linagliptin crystals. <Powder X-ray diffraction measurement> The obtained crystals were immediately subjected to powder X-ray diffraction measurement under the following conditions. Equipment: BRUKER D2 PHASER 2 nd Gen Target: CuKα Scanning range: 3.0~40.0° Step width: 0.02° Time: 0.40 seconds Table 3 and FIG. 2 show the powder X-ray diffraction measurements.

[0046] [Table 3]

[0047] Example 4 In this example, linagliptin crystal form (2) was prepared. 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (linagliptin) 10g (21mmol) and methanol 30g were mixed and heated to 40-50°C to dissolve. Then, it was cooled to 40°C and seed crystals were added. After confirming crystal precipitation, it was stirred at 40°C for 1 hour and 30 minutes. The suspension was cooled to 0-5°C and stirred for 1 hour. The crystals were filtered and washed with 15g of methanol. The wet crystals were dried under reduced pressure at 30-60°C to obtain 8.6g (18mmol) of white linagliptin crystals. <Powder X-ray diffraction measurement> The obtained crystals were immediately subjected to powder X-ray diffraction measurement under the following conditions. Equipment: BRUKER D2 PHASER 2 nd Gen Target: CuKα Scanning range: 3.0~40.0° Step width: 0.02° Time: 0.40 seconds Powder X-ray diffraction measurements are shown in Table 4. The powder X-ray diffraction of the crystalline form (2) of the present invention was stable in a non-hygroscopic environment, and no change in the powder X-ray diffraction peaks was observed.

[0048] [Table 4]

[0049] Stability testing The storage stability of the crystalline form (1) of linagliptin obtained in Example 1 and the crystalline form (2) of linagliptin obtained in Example 3 was examined. The purity of linagliptin in crystalline form (1) was measured by HPLC after storage under the three storage conditions listed in Table 5. The purity of linagliptin in crystalline form (2) was measured by HPLC after storage under the storage conditions listed in Table 6.

[0050] [Table 5]

[0051] [Table 6]

[0052] As shown in Tables 5 and 6, the crystalline forms (1) and (2) of the present invention exhibited excellent storage stability.

[0053] Accelerated stability testing and stress testing The linagliptin crystal form (1) obtained in Example 1 and the crystal form C (polymorph C) obtained by the manufacturing method described in Patent Document 1 were subjected to an accelerated storage stability test (40°C, 75% RH, double polyethylene bag) and a stress test (40°C, 75% RH, unpackaged). Specifically, impurities observed at retention times of 11.74 (min) and 20.02 (min) (referred to as impurities 1 and 2, respectively) were measured by HPLC.

[0054] [Table 7]

[0055] As shown in Table 7, in crystalline form C, impurity 2 was detected from two weeks and impurity 1 was detected from three months in both the accelerated test and the stress test, and both increased at six months. On the other hand, in crystalline form (1) of the present invention, impurity 2 was only detected at six months in the accelerated test, and impurities 1 and 2 were only detected at six months in the stress test, and the crystalline form was stable.

[0056] Solubility test The solubility in water of the linagliptin crystalline form (1) obtained in Example 1 and the crystalline form A (polymorph A) obtained by the production method described in Patent Document 1 was measured. 0.1 g of linagliptin in crystalline form (1) or crystalline form A was added to 40 mL of water and stirred at 200 rpm at 37.0±0.5° C. or 20.0±0.5° C., and the solubility was measured after 10 minutes, 30 minutes, and 1 hour.

[0057] [Table 8]

[0058] As shown in Table 8, crystalline form (1) exhibited superior solubility in water compared to crystalline form A.

[0059] Bulk density The bulk density of the linagliptin crystal form (1) obtained in Example 1, and the crystal form A (polymorph A) and crystal form C (polymorph C) obtained by the production method described in Patent Document 1 were measured according to the method described in the Japanese Pharmacopoeia.

[0060] [Table 9] [Industrial Applicability]

[0061] The crystalline forms of linagliptin of the present invention can be used as active ingredients in pharmaceutical compositions for the treatment of type 2 diabetes.

Claims

1. A crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine exhibiting at least three peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα radiation.

2. The crystalline form of claim 1, wherein the crystalline form exhibits at least four peaks selected from the group consisting of 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ).

3. The crystalline form according to claim 1 or 2, wherein the crystalline form exhibits peaks at 6.9°±0.2°, 7.6°±0.2°, 9.3°±0.2°, 14.5°±0.2°, and 20.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ).

4. 4. The crystalline form of any one of claims 1 to 3, having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in Figure 1.

5. A crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine exhibiting at least four peaks selected from the group consisting of 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα radiation.

6. The crystalline form of claim 5, wherein the crystalline form exhibits at least five peaks selected from the group consisting of 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ).

7. The crystalline form according to claim 5 or 6, wherein the crystalline form exhibits peaks at 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, 20.8°±0.2°, and 23.8°±0.2° in powder X-ray diffraction (diffraction angle 2θ).

8. 8. The crystalline form of any one of claims 5 to 7, having a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in Figure 2.

9. A pharmaceutical composition for treating diabetes comprising the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of claims 1 to 8 as an active ingredient.

10. Use of the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of claims 1 to 8 for the manufacture of a pharmaceutical composition for the treatment of diabetes.

11. 9. A method for treating diabetes, comprising administering to a patient an effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of claims 1 to 8.

12. 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine according to any one of claims 1 to 8 for use in a method for the treatment of diabetes.

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