Crystal form of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine

Abstract

This provides a crystalline form of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine that exhibits excellent stability. [Solution] A crystalline form of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine is provided, which shows 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) by Cu-Kα irradiation.

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 Art

[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 degradation of incretin, and it is considered that by inhibiting dipeptidyl peptidase, the concentration of glucagon-like peptide-1 (GLP-1) in the blood increases, and an increase in serum insulin concentration and a decrease in blood glucose level occur. Therefore, the said linagliptin is used as a therapeutic agent for diabetes (Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] Generally, compounds used as active ingredients in pharmaceuticals require stability. For example, the thermodynamic stability crossover point for polymorphs A and B described in Patent Document 1 is 25±15°C, and there is a possibility that their crystalline form may change during the pharmaceutical manufacturing process. Therefore, they may exist as a mixture of polymorphs A and B in the resulting pharmaceutical product. The presence of different polymorphs in a pharmaceutical formulation may affect the dissolution rate of the active ingredient. Similarly, polymorphs C and D are also thought to undergo a crystalline form change due to heat, and this crystalline form change was irreversible. Furthermore, linagliptin has low solubility in water, and the bioavailability of currently available linagliptin formulations is reported to be approximately 30%. The object of the present invention is to provide a crystalline form of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine that exhibits excellent stability and solubility. [Means for solving the problem]

[0005] The inventors diligently studied the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine, which has excellent stability and solubility. As a result, they surprisingly discovered a new crystalline form that exhibits a specific peak in powder X-ray diffraction (diffraction angle 2θ). This invention is based on these findings. Therefore, the present invention is [1] The crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine 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) by Cu-Kα irradiation, [2] The crystal morphology described in [1] shows 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 crystal morphology described in [1] or [2], which shows 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] A crystal morphology according to any of [1] to [3] having substantially the same powder X-ray diffraction pattern as the powder X-ray diffraction pattern shown in Figure 1, [5] The crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine 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) induced by Cu-Kα irradiation. [6] The crystal morphology described in [5] shows 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 crystal morphology described in [5] or [6] shows 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 crystal morphology described in any of [5] to [7] has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in Figure 2. A pharmaceutical composition for the treatment of diabetes, comprising the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine as described in any of [9][1] to [8], Use of the crystalline form of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine as described in any of

[10] [1] to [8] in the manufacture of a pharmaceutical composition for the treatment of diabetes, A method for treating diabetes, comprising the step of administering an effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine, as described in any of

[11] [1] to [8], to a patient, and

[12] For use in the treatment of diabetes, 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine, as described in any of [1] to [8] Regarding. [Effects of the Invention]

[0006] The crystalline form of linagliptin according to the present invention exhibits excellent stability with minimal impurity formation. Furthermore, the crystalline form of linagliptin according to the present invention exhibits excellent solubility in water. [Brief explanation of the drawing]

[0007] [Figure 1] This is a powder X-ray diffraction diagram of the crystalline form (1) of linagliptin according to the present invention. [Figure 2] This is a powder X-ray diffraction diagram of the crystalline form (2) of linagliptin according to the present invention. [Modes for carrying out the invention]

[0008] [1] Crystal form (1) The crystalline form (1) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine of the present invention shows 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) by Cu-Kα irradiation, preferably showing at least four peaks, and most preferably showing five peaks.

[0009] Linagliptin The linagliptin mentioned above is given by the following formula (1) [ka] This compound, represented by [formula], exhibits inhibitory activity against dipeptidyl peptidase. Dipeptidyl peptidase is an enzyme that breaks down incretins, and inhibiting it 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 levels. In Japan, it is marketed under the brand name Trajenta.

[0010] Powder X-ray diffraction The crystalline form (1) of linagliptin 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) induced by Cu-Kα irradiation. These five peaks are characteristic of the crystalline form (1) of linagliptin according to the present invention. Therefore, any combination of three peaks can identify the crystalline form (1) of linagliptin according to the present invention, but the combination of peaks 6.9°±0.2°, 20.8°±0.2°, and 7.6°±0.2° is most preferred.

[0011] The crystalline form (1) of linagliptin 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 crystalline form (1) of linagliptin of the present invention. Therefore, the crystalline form (1) of linagliptin of the present invention can be identified by any combination of four peaks, but most preferably by the combination of the peaks of 6.9° ± 0.2°, 20.8° ± 0.2°, 7.6° ± 0.2°, and 9.3° ± 0.2°.

[0012] The crystalline form (1) of linagliptin more preferably exhibits peaks 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 crystalline form (1) of linagliptin of the present invention. The crystalline form (1) of linagliptin of the present invention can be identified by the combination of the five peaks.

[0013] The crystalline form (1) of linagliptin may have a peak of 7.3° ± 0.2° and / or a peak of 17.7° ± 0.2° in addition to the above 3 to 5 peaks in powder X-ray diffraction (diffraction angle 2θ) using Cu-Kα irradiation. 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°. Also, 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 the linagliptin preferably has the powder X-ray diffraction pattern shown in FIG. 1.

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

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

[0016] The bulk density of the crystalline form (1) of the present invention 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 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 other properties within the above range, the crystalline form (1) can exhibit properties different from other crystalline forms of linagliptin.

[0017] [2] Crystal form (2) The crystalline form (2) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine of the present invention shows 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) by Cu-Kα irradiation, preferably showing at least five peaks, and more preferably showing six peaks.

[0018] Powder X-ray diffraction The crystalline form (2) of linagliptin 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) induced by Cu-Kα irradiation. These six peaks are characteristic of the crystalline form (2) of linagliptin of the present invention. Therefore, any combination of the four peaks can identify the crystalline form (2) of linagliptin of the present invention, but the combination of the peaks 6.9°±0.2°, 15.4°±0.2°, 17.9°±0.2°, and 20.8°±0.2° is most preferred.

[0019] The crystalline form (2) of linagliptin 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) by Cu-Kα irradiation. The six peaks are characteristic peaks of the crystalline form (2) of linagliptin of the present invention. Therefore, any combination of the five peaks can identify the crystalline form (2) of linagliptin of the present invention, but the combination of the peaks 6.9°±0.2°, 10.4°±0.2°, 15.4°±0.2°, 17.9°±0.2°, and 20.8°±0.2°.

[0020] The crystalline form (2) of linagliptin more preferably shows 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) by Cu-Kα irradiation. These six peaks are characteristic peaks of the crystalline form (2) of linagliptin of the present invention, and the crystalline form of linagliptin of the present invention can be identified by the combination of these six peaks.

[0021] The crystalline form (2) of linagliptin may have, in addition to the 4 to 6 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) by 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 the linagliptin most preferably has the powder crystal diffraction pattern shown in Figure 2.

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

[0023] The bulk density of the crystalline form (2) of the present invention 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 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 other properties within the above ranges, the crystalline form (2) can exhibit properties different from other crystalline forms of linagliptin.

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

[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-buty-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine in methanol to dissolve it at 40-65°C to obtain a methanol solution; (b) adding tert.-butylmethyl ether at 35-45°C and confirming crystal precipitation; (c) cooling the obtained suspension to 15°C or below to obtain crystals; (d) filtering the crystals; and (e) drying the obtained crystals under reduced pressure at 20-100°C. The first and second methods for producing the crystalline form (1) of linagliptin in the present invention have identical steps (a), (c), (d), and (e), but differ in step (b1) of the first method and step (b2) of the second method. Below, common steps are described together, and differing steps are described individually.

[0026] 《Process (a)》 In step (a) above, linagliptin is heated in methanol to dissolve at 40-65°C to obtain a methanol solution. The dissolution temperature is preferably 40-60°C, and more preferably 40-50°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 0.5-30 times the amount (weight / weight) of linagliptin, preferably 1-10 times, and more preferably 1.5-5 times. Methanol with a purity of 97% or higher may be used. The dissolution of linagliptin in methanol is preferably carried out with stirring. Any known method of stirring may be used; for example, a stirrer, stirring blades, or a magnetic stirrer can be appropriately selected and used. The methanol solution is preferably cooled to about 40°C. The cooling method is not limited, but for example, the methanol solution may be left in a water bath or at room temperature.

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

[0028] 《Process (b2)》 In step (b2) above, tert.-butyl methyl ether is added at 35-45°C, and crystal precipitation is confirmed. The amount of tert.-butyl methyl ether is not particularly limited, but for example, it is 0.5 to 5 times the amount of 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 not limited, but it is preferable to add it dropwise to the methanol solution. Crystal precipitation can be confirmed visually. After confirming crystal precipitation, the methanol solution is stirred at 40°C to promote crystal growth. The stirring method is not particularly limited, but a stirrer, stirring blades, or magnetic stirrer can be used, and the mixture is stirred at 150-350 rpm, preferably 200-300 rpm. The stirring time is also not particularly limited, but for example, it is 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 not be sufficient, and if it is too long, linagliptin decomposition may occur.

[0029] 《Process (c)》 In step (c) above, the obtained suspension is cooled to 15°C or below to obtain crystals. The cooling temperature is not limited as long as it is 15°C or below, 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 blades, or magnetic stirrer may be used, and the 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.

[0030] 《Process (d)》 In step (d) above, the crystals are filtered. The filtration is not particularly limited, but can be carried out by vacuum filtration (suction filtration), pressure filtration, or centrifugal filtration using, for example, filter paper. The filtered crystals may be washed at this point. The solvent used to wash the crystals is preferably the same one used in the production of the crystals, so methanol or a methanol / tert.-butylmethyl ether solution is used.

[0031] 《Process (e)》 In step (e) above, 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 reduced pressure drying is, for example, 0.1 atmospheres (atm) or less, and preferably 0.05 atmospheres or less.

[0032] The crystalline forms (1) and (2) of linagliptin in this invention differ slightly in the diffraction angle 2θ peak 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 difference between crystalline form (1) and crystalline form (2) lies in whether or not it is a hydrate, and this difference is reversible.

[0033] [3] Pharmaceutical composition The crystalline form of the present invention can be used as an active ingredient in pharmaceutical compositions. Specifically, it can be used as an active ingredient in pharmaceutical compositions for the treatment of type 2 diabetes. That is, the crystalline form of the present invention can be used in the manufacture of pharmaceutical compositions for the treatment of diabetes. Furthermore, the crystalline form of the present invention can be used in a method for treating diabetes, which includes the step of administering an effective amount thereof to a patient. Moreover, the crystalline form of the present invention is a crystalline form for use in methods 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 this is not limited to the above. The dosage when using the pharmaceutical composition can be appropriately determined according to the patient's age, sex, weight, severity of symptoms, or method of administration, and it can be administered orally or parenterally.

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

[0035] The aforementioned pharmaceutical composition can be manufactured in accordance with conventional methods using, for example, excipients such as gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitol, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soy lecithin, sucrose, fatty acid esters, talc, magnesium stearate, polyethylene glycol, magnesium silicate, anhydrous silicic acid, or synthetic aluminum silicate, as well as binders, disintegrants, surfactants, lubricants, flow enhancers, diluents, preservatives, colorants, fragrances, flavoring agents, stabilizers, humectants, preservatives, or antioxidants.

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

[0037] Furthermore, the form of administration is not limited to pharmaceuticals; it can also be administered in various forms, such as functional foods or health foods (including beverages), or given to animals as feed in the form of food or drink. [Examples]

[0038] The present invention will be specifically described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0039] Example 1 In this example, crystalline form (1) of linagliptin was prepared. 40 g (85 mmol) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-buty-1-yl)-8-(3-(R)-amino-piperidine-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. By drying the wet crystals under reduced pressure at 30-60°C, 35 g (74 mmol) of white linagliptin crystals were obtained.

[0040] Example 2 In this example, the crystalline form of linagliptin (1) was prepared using a different procedure than in Example 1. 33 g (70 mmol) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-buty-1-yl)-8-(3-(R)-amino-piperidine-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. By drying the wet crystals under reduced pressure at 30-60°C, 31 g (66 mmol) of white linagliptin crystals were obtained.

[0041] Powder X-ray diffraction measurement The crystals obtained in Example 1 or Example 2 were stored overnight in a general laboratory at room temperature and humidity of 50% or higher, and then powder X-ray diffraction measurements were performed 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 Figure 1 show the powder X-ray diffraction measurements of the crystals obtained in Example 1, and Table 2 shows the powder X-ray diffraction measurements 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 obtained 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 observed at 7.3° near the shoulder of 6.9°, and another peak was observed at 17.7°, indicating the same crystal morphology. The powder X-ray diffraction of the crystalline form (1) of the present invention is stable, and no change in the powder X-ray diffraction peak was observed even after storage for 6 months at 25°C, 60%RH or 40°C, 75%RH.

[0045] Example 3 In this example, crystalline form (2) of linagliptin was prepared. 10 g (21 mmol) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-buty-1-yl)-8-(3-(R)-amino-piperidine-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. By drying the wet crystals under reduced pressure at 30-60°C, 8.6 g (18 mmol) of white linagliptin crystals were obtained. Powder X-ray diffraction measurement The obtained crystals were immediately subjected to powder X-ray diffraction measurements 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 Figure 2 show the powder X-ray diffraction measurements.

[0046] [Table 3]

[0047] Example 4 In this example, crystalline form (2) of linagliptin was prepared. 10 g (21 mmol) of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-buty-1-yl)-8-(3-(R)-amino-piperidine-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 and 30 minutes. The suspension was cooled to 0-5°C and stirred for 1 hour. The crystals were filtered and washed with 15 g of methanol. By drying the wet crystals under reduced pressure at 30-60°C, 8.6 g (18 mmol) of white linagliptin crystals were obtained. Powder X-ray diffraction measurement The obtained crystals were immediately subjected to powder X-ray diffraction measurements 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 4 shows the powder X-ray diffraction measurements. The powder X-ray diffraction of the crystal morphology (2) of the present invention was stable in a non-hygroscopic environment, and no changes in the powder X-ray diffraction peaks were observed.

[0048] [Table 4]

[0049] Stability Test The storage stability of the crystalline form of linagliptin obtained in Example 1 (1) and the crystalline form of linagliptin obtained in Example 3 (2) was investigated. Crystal morphology (1) was measured for linagliptin purity by HPLC after storage under the three storage conditions described in Table 5. Crystal morphology (2) was measured for linagliptin purity by HPLC after storage under the storage conditions described 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 Severe Stability Testing》 The crystalline form (1) of linagliptin obtained in Example 1 and crystalline form C (polymorph C) obtained by the manufacturing method described in Patent Document 1 were subjected to accelerated storage stability tests (40°C, 75%RH, double polyethylene bag) and harsh storage stability tests (40°C, 75%RH, unpackaged). Specifically, impurities observed at retention times of 11.74 minutes and 20.02 minutes (referred to as impurities 1 and 2, respectively) were measured by HPLC.

[0054] [Table 7]

[0055] As shown in Table 7, in crystal morphology C, impurity 2 was detected from two weeks and impurity 1 from three months in both accelerated and harsh tests, and both increased over six months. On the other hand, in crystal morphology (1) of the present invention, only impurity 2 was detected at six months in the accelerated test, and only impurities 1 and 2 were detected at six months in the harsh test, indicating stability.

[0056] Solubility Test The solubility in water of the crystalline form (1) of linagliptin obtained in Example 1 and crystalline form A (polymorph A) obtained by the manufacturing 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, stirred at 37.0 ± 0.5 °C or 20.0 ± 0.5 °C at 200 rpm, 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 crystalline form (1) of linagliptin obtained in Example 1, and the bulk density of crystalline form A (polymorph A) and crystalline form C (polymorph C) obtained by the manufacturing 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 form of linagliptin according to the present invention can be used as an active ingredient in pharmaceutical compositions for the treatment of type 2 diabetes.

Claims

1. Crystals of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine that show 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) induced by Cu-Kα irradiation, and the intensity of the highest peak in the peak pattern of the powder X-ray diffraction (I) ０ The ratio of the peak intensity (I) at 12.64°±0.2° to the above (I / I) ０ (Excluding those where the percentage of ×100[%] is 10% or more).

2. Crystals of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine that show 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) induced by Cu-Kα irradiation (excluding those showing a peak at 12.64°±0.2°).

3. The crystal according to claim 1 or 2, having the powder X-ray diffraction pattern shown in the figure below.

4. A pharmaceutical composition for the treatment of diabetes, comprising crystals of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine as an active ingredient, as described in any one of claims 1 to 3.

5. Use of crystals of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine according to any one of claims 1 to 3 in the manufacture of a pharmaceutical composition for the treatment of diabetes.

6. Crystals of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-(3-(R)-amino-piperidine-1-yl)-xanthine according to any one of claims 1 to 3, for use in a method of treating diabetes.

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