WO2021251467A1 - Crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-peperidine-1-yl)-xanthine - Google Patents

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

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WO2021251467A1
WO2021251467A1 PCT/JP2021/022157 JP2021022157W WO2021251467A1 WO 2021251467 A1 WO2021251467 A1 WO 2021251467A1 JP 2021022157 W JP2021022157 W JP 2021022157W WO 2021251467 A1 WO2021251467 A1 WO 2021251467A1
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methyl
crystal
powder
linagliptin
ray diffraction
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PCT/JP2021/022157
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French (fr)
Japanese (ja)
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祐未子 田中
柚美華 清水
朝典 翁長
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有機合成薬品工業株式会社
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Priority to CN202180042237.4A priority patent/CN115916781A/en
Publication of WO2021251467A1 publication Critical patent/WO2021251467A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Definitions

  • the present invention relates to 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine- 1-Il) -Regarding the crystal morphology of xanthine.
  • linagliptin 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-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 incretins, and by inhibiting dipeptidyl peptidase, the concentration of glucagon-like peptide-1 (GLP-1) in the blood increases, the serum insulin concentration increases, and It is believed that a decrease in blood sugar level occurs. Therefore, the linagliptin is used as a therapeutic agent for diabetes (Patent Document 1).
  • a compound used as an active ingredient of a medicine is required to have stability.
  • the intersection of the thermodynamic stability of the polymorph A and the polymorph B described in Patent Document 1 is 25 ⁇ 15 ° C.
  • the crystal morphology may change in the manufacturing process of the pharmaceutical product. Therefore, it may exist as a mixture of polymorph A and polymorph B in the obtained drug.
  • the mixture of different polymorphs in a pharmaceutical product can affect the rate of elution of the active ingredient.
  • it is considered that the crystal morphology of polymorph C and polymorph D is changed by heat, and this change of crystal morphology is an irreversible change.
  • An object of the present invention is 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-, which exhibits excellent stability and solubility. It is to provide the crystalline form of (3- (R) -amino-piperidine-1-yl) -xanthine.
  • the present inventor has excellent stability and solubility of 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- ( As a result of diligent research on the crystal morphology of 3- (R) -amino-piperidine-1-yl) -xanthine, surprisingly, a new crystal morphology having a specific peak in powder X-ray diffraction (diffraction angle 2 ⁇ ). I found. The present invention is based on these findings.
  • the present invention [1] In powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation, 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14 1-[(4-methyl-quinazoline-2-yl) methyl] -3 showing at least three peaks selected from the group consisting of .5 ° ⁇ 0.2 ° and 20.8 ° ⁇ 0.2 ° Crystal form of -methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine, [2] The crystal morphology is 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14 in powder X-ray diffraction (diffraction angle 2 ⁇ ).
  • the crystal morphology is 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15.4 ° ⁇ 0.2 °, 17 in powder X-ray diffraction (diffraction angle 2 ⁇ ).
  • the crystal form of linagliptin of the present invention it is possible to exhibit excellent stability with less generation of impurities. Moreover, the crystal form of linagliptin of the present invention can exhibit excellent solubility in water.
  • Crystal form (1) 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1) of the present invention -Il) -Xanthine crystal morphology (1) is 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. .At least 3 peaks selected from the group consisting of 3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °, preferably at least 4 peaks. Shown, most preferably five peaks.
  • the linagliptin has the following formula (1). It is a compound represented by, and exhibits an inhibitory action on dipeptidyl peptidase. Dipeptidyl peptidase is an enzyme that degrades incretins and can increase the concentration of glucagon-like peptide-1 (GLP-1) in the blood by inhibiting dipeptidyl peptidase. This action induces an increase in serum insulin concentration and a decrease in blood glucose level. It is marketed as Trazenta (trade name) in Japan.
  • GLP-1 glucagon-like peptide-1
  • the crystal morphology (1) of linagliptin is 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. Shows at least three peaks selected from the group consisting of ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °. The five peaks are characteristic of the linagliptin crystal morphology (1) of the present invention. Therefore, the combination of any three peaks can also identify the linagliptin crystal morphology (1) of the present invention. It is possible, but most preferably a combination of peaks of 6.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 7.6 ° ⁇ 0.2 °.
  • the crystal morphology (1) of the linagliptin is preferably 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9. Shows at least four peaks selected from the group consisting of 3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °.
  • the five peaks are characteristic of the linagliptin crystal morphology (1) of the present invention. Therefore, the combination of any of the four peaks can identify the linagliptin crystal morphology (1) of the present invention. It is possible, but most preferably a combination of peaks of 6.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, and 9.3 ° ⁇ 0.2 °. Is.
  • the crystal morphology (1) of the linagliptin is more preferably 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It shows peaks of 3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °.
  • the five peaks are the peaks characteristic of the linagliptin crystal morphology (1) of the present invention, and the crystal morphology (1) of the linagliptin of the present invention can be specified by the combination of the five peaks.
  • the crystal morphology (1) of linagliptin has a peak of 7.3 ° ⁇ 0.2 ° and / / in addition to the above 3 to 5 peaks in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. Alternatively, it may have a peak of 17.7 ° ⁇ 0.2 °. That is, 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2. It may have at least 4-6 peaks selected from the group consisting of ° and 7.3 ° ⁇ 0.2 °.
  • 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 It may have at least 4-6 peaks selected from the group consisting of ° and 17.7 ° ⁇ 0.2 °. Furthermore, 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 It may have at least 5-7 peaks selected from the group consisting of °, 7.3 ° ⁇ 0.2 °, and 17.7 ° ⁇ 0.2 °.
  • the crystal form (1) of the linagliptin most preferably has the powder crystal diffraction pattern shown in FIG.
  • the error of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum in the crystal form (1) of linagliptin of the present invention is about ⁇ 0.2 °. This error is caused by the equipment used for the measurement, the preparation of the sample, the method of data analysis, and the like, and is a common general technical knowledge in the present technical field.
  • the crystal form (1) of linagliptin of the present invention includes those having the same peak pattern of powder X-ray diffraction (diffraction angle 2 ⁇ ) but different relative intensities of peaks.
  • the relative intensity is a relative value of each peak area when the peak area of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum is 100.
  • the crystal form (1) of linagliptin of the present invention has an endothermic peak at 173.3 ° C ⁇ 5 ° C by differential thermal analysis.
  • the crystal form (1) of linagliptin of the present invention is presumed to be a hydrate.
  • the crystal form (1) of linagliptin of the present invention can be used as an active ingredient of a pharmaceutical composition for treating diabetes.
  • the crystal 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 for producing a pharmaceutical composition for treating diabetes.
  • the bulk density of the crystal form (1) of the present invention is not limited, but is 0.15 to 0.25 g / mL, preferably 0.18 to 0.22 g / mL.
  • the tap density of the crystal form (1) of the present invention is not limited, but is 0.32 to 0.42 g / mL, preferably 0.35 to 0.39 g / mL. More preferably, it is 0.36 to 0.38 g / mL, for example, 0.37 g / mL.
  • the crystal form (1) can exhibit properties different from those of other crystal forms of linagliptin.
  • Crystal form (2) 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1) of the present invention -Il) -Xantin crystal morphology (2) is 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. At least four peaks selected from the group consisting of .4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2 °. , Preferably showing at least 5 peaks, more preferably 6 peaks.
  • the crystal form (2) of linagliptin is 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15.4 ° in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It shows at least four peaks selected from the group consisting of ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2 °.
  • the six peaks are characteristic of the linagliptin crystal morphology (2) of the present invention. Therefore, the combination of any of the four peaks can identify the linagliptin crystal morphology (2) of the present invention. Possible, but most preferably a combination of peaks of 6.9 ° ⁇ 0.2 °, 15.4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °. Is.
  • the crystal form (2) of the linagliptin is preferably 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15. At least 5 peaks selected from the group consisting of 4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2 °. show.
  • the six peaks are characteristic of the linagliptin crystal morphology (2) of the present invention. Therefore, the combination of any of the five peaks can identify the linagliptin crystal morphology (2) of the present invention.
  • the crystal morphology (2) of the linagliptin is more preferably 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It shows peaks of .4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2.
  • the six peaks are the peaks characteristic of the linagliptin crystal morphology (2) of the present invention, and the crystal morphology of the linagliptin of the present invention can be specified by the combination of the six peaks.
  • the crystal morphology (2) of linagliptin is 7.1 ° ⁇ 0.2 °, 13.7 ° in addition to the above 4 to 6 peaks in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It may have one or more peaks selected from the group consisting of ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 16.2 ° ⁇ 0.2 °. That is, 6.9 ° ⁇ 0.2 °, 7.1 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 13.7 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2.
  • the crystal form (2) of the linagliptin most preferably has the powder crystal diffraction pattern shown in FIG.
  • the error of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum in the crystal form (2) of linagliptin of the present invention is about ⁇ 0.2 °. This error is caused by the equipment used for the measurement, the preparation of the sample, the method of data analysis, and the like, and is a common general technical knowledge in the present technical field.
  • the crystal form (2) of linagliptin of the present invention includes those having the same peak pattern of powder X-ray diffraction (diffraction angle 2 ⁇ ) but different relative intensities of peaks.
  • the relative intensity is a relative value of each peak area when the peak area of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum is 100. It is presumed that the crystal form (2) of linagliptin of the present invention is not a hydrate.
  • the bulk density of the crystal form (2) of the present invention is not limited, but is 0.15 to 0.25 g / mL, preferably 0.18 to 0.22 g / mL.
  • the tap density of the crystal form (1) of the present invention is not limited, but is 0.32 to 0.42 g / mL, preferably 0.35 to 0.39 g / mL. More preferably, it is 0.36 to 0.38 g / mL, for example, 0.37 g / mL.
  • the first method for producing the crystal form of linagliptin of the present invention is (a) 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl). -8- (3- (R) -Amino-piperidin-1-yl) -xanthin is heated in methanol and dissolved at 40 to 65 ° C. to obtain a methanol solution. (B1) In the methanol solution, 35. A step of adding a seed crystal at ⁇ 45 ° C. to confirm crystal precipitation, (c) a step of cooling the obtained suspension to 15 ° C.
  • the seed crystal is a crystal having a crystal form (1) or a crystal form (2).
  • the crystal form (1) or the crystal form (2) seed crystal can be obtained by the second production method described later.
  • the second method for producing the crystal form of linagliptin of the present invention is (a) 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-).
  • Il) -8- (3- (R) -amino-piperidin-1-yl) -xanthin is heated in methanol and dissolved at 40 to 65 ° C to obtain a methanol solution, (b2) 35 to 45 ° C.
  • a step of adding tert.-butylmethyl ether and confirming crystal precipitation (c) a step of cooling the obtained suspension to 15 ° C. or lower to obtain crystals, (d) a step of filtering the crystals, and a step of filtering the crystals.
  • the step of drying the obtained crystals under reduced pressure at 20 to 100 ° C. is included.
  • the first production method and the second production method of the crystal form (1) of linagliptin of the present invention are the same in steps (a), (c), (d) and (e), and the first production method.
  • the step (b1) of the second manufacturing method is different from the step (b2) of the second manufacturing method.
  • the common processes are collectively described below, and the different processes are described individually.
  • linagliptin is heated in methanol and dissolved at 40 to 65 ° C. to obtain a methanol solution.
  • the melting temperature is preferably 40 to 60 ° C, more preferably 40 to 50 ° C.
  • the amount of methanol with respect to linagliptin is not particularly limited as long as the crystalline form of the present invention can be obtained, but it is 0.5 to 30 times the amount (weight / weight) with respect to linagliptin, preferably 1 to 1 to. The amount is 10 times, more preferably 1.5 to 5 times. Methanol with a purity of 97% or more may be used.
  • the dissolution of linagliptin in methanol is preferably carried out with stirring.
  • the stirring method a known method may be used, and for example, a stirrer, a stirring blade, a magnetic stirrer, or the like 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, a methanol solution may be left in a water bath or at room temperature.
  • ⁇ Process (b1) Seed crystals are added to the methanol solution at 35 to 45 ° C., and crystal precipitation is confirmed.
  • the amount of the seed crystal is not particularly limited, but for example, 0.001 to 5% by weight of the obtained crystal may be added, preferably 0.01 to 3% by weight, and more preferably 0.02 to 2% by weight.
  • the seed crystal may be added in an amount of% by weight, more preferably 0.04 to 1% by weight, and most preferably 0.05 to 0.5% by weight.
  • the crystal precipitation can be confirmed visually.
  • the methanol solution is stirred at 40 ° C. to promote crystal growth.
  • the stirring method is not particularly limited, but a stirrer, a stirring blade, or a 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 it is too short, crystal precipitation may not be sufficient, and if it is too long, linagliptin decomposition may occur.
  • tert.-butylmethyl ether is added at 35 to 45 ° C., and crystal precipitation is confirmed.
  • the amount of tert.-butylmethyl ether is not particularly limited, but is, for example, 0.5 to 5 times, preferably 1 to 4 times, and more preferably 1.5 times the amount of the methanol solution. The amount is up to 3 times, more preferably 1.7 to 2.5 times.
  • the method for adding tert.-butylmethyl ether is also not limited, but it is preferable to add the tert.-butylmethyl ether by dropping it into a methanol solution. The crystal precipitation can be confirmed visually.
  • the methanol solution is stirred at 40 ° C. to promote crystal growth.
  • the stirring method is not particularly limited, but a stirrer, a stirring blade, or a 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, still more preferably 30 minutes to 1 hour. Is. If it is too short, crystal precipitation may not be sufficient, and if it is too long, linagliptin decomposition may occur.
  • the obtained suspension is cooled to 15 ° C. or lower to obtain crystals.
  • the cooling temperature is not limited as long as it is 15 ° C. or lower, but is preferably 0 to 10 ° C., more preferably 0 to 5 ° C.
  • the suspension is stirred after cooling to promote crystal growth.
  • the stirring method is not particularly limited, but a stirrer, a stirring blade, or a 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.
  • the crystals are filtered.
  • Filtration is not particularly limited, but can be performed by, for example, vacuum filtration (suction filtration), pressure filtration, centrifugal filtration, or the like using filter paper or the like.
  • the filtered crystals may be washed. Since the solvent used for washing the crystals is preferably the one used for producing the crystals, methanol or a methanol / tert.-butylmethyl ether solution or the like is used.
  • the obtained crystals are dried under reduced pressure at 20 to 100 ° C., preferably 20 to 70 ° C., more preferably 30 to 60 ° C.
  • the pressure for vacuum drying is, for example, 0.1 atm (atm) or less, preferably 0.05 atm or less.
  • the crystal morphology (1) and the crystal morphology (2) of linagliptin of the present invention have slightly different peaks of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum. However, it can be obtained by the same manufacturing method and has basically the same properties. As described above, the crystal morphology (1) and the crystal morphology (2) are different depending on whether or not they are hydrates, and are reversible.
  • 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 producing 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 comprises a step of administering an effective amount thereof to a patient. Furthermore, the crystalline form of the present invention is a crystalline form for use in a method of treating diabetes.
  • the pharmaceutical composition can contain, but is not limited to, the active ingredient in an amount of 0.01 to 99% by weight, preferably 0.1 to 80% by weight.
  • the dose when the pharmaceutical composition is used can be appropriately determined according to the age, sex, body weight, degree of symptoms, administration method, etc. of the patient, and can be administered orally or parenterally. Is.
  • the dosage form of the pharmaceutical composition is not particularly limited, and for example, powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, rounds and the like.
  • Oral preparations or parenteral preparations such as injections, external solutions, ointments, suppositories, topically administered creams, or eye drops can be mentioned.
  • the pharmaceutical composition includes, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitt, carboxymethyl cellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean residue, sucrose, fatty acid ester, talc, stearic acid.
  • Excipients such as magnesium, polyethylene glycol, magnesium silicate, anhydrous silicate, or synthetic aluminum silicate, binders, disintegrants, surfactants, talc, fluidity promoters, diluents, preservatives, coloring It can be produced according to a conventional method using an agent, a fragrance, a flavoring agent, a stabilizer, a moisturizing agent, a preservative, an antioxidant or the like.
  • parenteral administration methods include injection (subcutaneous, intravenous, etc.), rectal administration, and the like. Of these, injections are most preferably used.
  • a water-soluble solvent such as physiological saline or Ringer's solution, a water-insoluble solvent such as vegetable oil or fatty acid ester, an isotonic agent such as glucose or sodium chloride, etc.
  • a solubilizing agent, a stabilizer, a preservative, a suspending agent, an emulsifier and the like can be arbitrarily used.
  • administration form is not limited to pharmaceutical products, and various forms such as functional foods, health foods (including beverages), or animals can be given in the form of food and drink as feed.
  • Example 1 the crystal form (1) of linagliptin was prepared. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -40 g (85 mmol) of xanthine (linagliptin) and 100 g of methanol were mixed and heated to 40 to 50 ° C. to dissolve. Then, it was filtered hot and washed with 20 g of methanol. The filtrate was cooled to 40 ° C. and seed crystals were added. After confirming the crystal precipitation, the mixture was stirred at 40 ° C.
  • Example 2 the crystal form (1) of linagliptin was prepared by a process different from that of Example 1.
  • 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 33 g (70 mmol) and methanol 82.5 g were mixed and heated to 40-50 ° C to dissolve. Then, it was filtered hot and washed with 16.5 g of methanol. The filtrate was cooled to 40 ° C. and 198 g of tert.-butylmethyl ether was added dropwise.
  • 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.-butylmethyl ether. By drying the wet crystals under reduced pressure at 30 to 60 ° C., 31 g (66 mmol) of white linagliptin crystals were obtained.
  • Example 1 Powder X-ray diffraction measurement
  • Example 2 The crystals obtained in Example 1 or Example 2 were stored in a general laboratory at room temperature and humidity of 50% or more for a whole day and night, and then powder X-ray diffraction was measured under the following conditions.
  • Table 1 and FIG. 1 show the powder X-ray diffraction measurement of the crystal obtained in Example 1, and Table 2 shows the powder X-ray diffraction measurement of the crystal obtained in Example 2.
  • Example 3 the crystal form (2) of linagliptin was prepared.
  • 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 10 g (21 mmol) and methanol 30 g were mixed and heated to 40-50 ° C to dissolve. Then, it cooled to 40 degreeC and the seed crystal was added. After confirming the 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.
  • Example 4 the crystal form (2) of linagliptin was prepared. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 10 g (21 mmol) and methanol 30 g were mixed and heated to 40-50 ° C to dissolve. Then, it cooled to 40 degreeC and the seed crystal was added. After confirming the 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 crystal forms (1) and (2) of the present invention showed excellent storage stability.
  • the impurity 1 was detected from 2 weeks and the impurity 2 was detected from 3 months in both the accelerated test and the severe test, and both increased in 6 months.
  • impurities 1 were detected only in 6 months in the accelerated test and impurities 1 and 2 were detected in 6 months in the severe test, and they were stable.
  • the crystal form (1) showed excellent solubility in water as compared with the crystal form A.
  • the crystalline form of linagliptin of the present invention can be used as an active ingredient of a pharmaceutical composition for treating type 2 diabetes.

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Abstract

The purpose of the present invention is to provide a crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-peperidine-1-yl)-xanthine, which exhibits superior stability.　The above problem can be solved by: the crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-peperidine-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-Ka radiation; or the crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-peperidine-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 X-ray powder diffraction (diffraction angle 2θ) by Cu-Ka radiation.

Description

１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine crystal morphology
　本発明は、１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態に関する。 The present invention relates to 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine- 1-Il) -Regarding the crystal morphology of xanthine.
　１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン（以下、リナグリプチンと称することがある）は、ジペプチジルペプチダーゼを阻害することが知られている。ジペプチジルペプチダーゼは、インクレチンの分解に関与する酵素であり、ジペプチジルペプチダーゼを阻害することにより血中のグルカゴン様ペプチド－１（ＧＬＰ－１）の濃度が高くなり、血清インスリン濃度の上昇、および血糖値の低下が起こると考えられている。従って、前記リナグリプチンは、糖尿病の治療用薬剤として用いられている（特許文献１）。 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-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 incretins, and by inhibiting dipeptidyl peptidase, the concentration of glucagon-like peptide-1 (GLP-1) in the blood increases, the serum insulin concentration increases, and It is believed that a decrease in blood sugar level occurs. Therefore, the linagliptin is used as a therapeutic agent for diabetes (Patent Document 1).
特開２０１６－２２２７３４号公報Japanese Unexamined Patent Publication No. 2016-22734
　一般的に、医薬の有効成分として用いられる化合物は、安定性が求められる。例えば、特許文献１に記載の多形体Ａ及び多形体Ｂの熱力学的安定性の交差点は２５±１５℃であり、医薬品の製造工程で結晶形態が転換する可能性がある。従って、得られた医薬品中で多形体Ａ及び多形体Ｂの混合物として存在する可能性がある。医薬製剤中に異なる多形体が混在すると、有効成分の溶出速度に影響を与える可能性がある。同様に、多形体Ｃ及び多形体Ｄも熱により結晶形態が転移すると考えられ、この結晶形態の転移は不可逆的な転移であった。また、リナグリプチンは、水への溶解性が低く、現在市販されているリナグリプチン製剤のバイオアベイラビリティは、約３０％であると報告されている。
　本発明の目的は、優れた安定性及び溶解性を示す１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態を提供することである。 Generally, a compound used as an active ingredient of a medicine is required to have stability. For example, the intersection of the thermodynamic stability of the polymorph A and the polymorph B described in Patent Document 1 is 25 ± 15 ° C., and the crystal morphology may change in the manufacturing process of the pharmaceutical product. Therefore, it may exist as a mixture of polymorph A and polymorph B in the obtained drug. The mixture of different polymorphs in a pharmaceutical product can affect the rate of elution of the active ingredient. Similarly, it is considered that the crystal morphology of polymorph C and polymorph D is changed by heat, and this change of crystal morphology is an irreversible change. In addition, linagliptin has low solubility in water, and it is reported that the bioavailability of the currently commercially available linagliptin preparation is about 30%.
An object of the present invention is 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-, which exhibits excellent stability and solubility. It is to provide the crystalline form of (3- (R) -amino-piperidine-1-yl) -xanthine.
　本発明者は、優れた安定性及び溶解性を有する１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態について、鋭意研究した結果、驚くべきことに、粉末Ｘ線回折（回折角度２θ）において特定のピークを有する新たな結晶形態を見出した。
　本発明は、こうした知見に基づくものである。
　従って、本発明は、
［１］Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°からなる群から選択される少なくとも３つのピークを示す１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態、
［２］前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°からなる群から選択される少なくとも４つのピークを示す［１］に記載の結晶形態、
［３］前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°のピークを示す［１］又は［２］に記載の結晶形態、
［４］図１で示される粉末Ｘ線回折パターンと実質的に同じ粉末Ｘ線回折パターンを有する、［１］～［３］のいずれかに記載の結晶形態、
［５］Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°からなる群から選択される少なくとも４つのピークを示す１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態、
［６］前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°からなる群から選択される少なくとも５つのピークを示す［５］に記載の結晶形態、
［７］前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°のピークを示す［５］又は［６］に記載の結晶形態、
［８］図２で示される粉末Ｘ線回折パターンと実質的に同じ粉末Ｘ線回折パターンを有する、［５］～［７］のいずれかに記載の結晶形態、
［９］［１］～［８］のいずれかに記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態を有効成分として含む、糖尿病治療用医薬組成物、
［１０］［１］～［８］のいずれかに記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態の糖尿病治療用医薬組成物の製造への使用、
［１１］［１］～［８］のいずれかに記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの有効量を患者に投与する工程を含む、糖尿病の治療方法、及び
［１２］糖尿病の治療方法における使用のための、［１］～［８］のいずれかに記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン、
に関する。 The present inventor has excellent stability and solubility of 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- ( As a result of diligent research on the crystal morphology of 3- (R) -amino-piperidine-1-yl) -xanthine, surprisingly, a new crystal morphology having a specific peak in powder X-ray diffraction (diffraction angle 2θ). I found.
The present invention is based on these findings.
Therefore, the present invention
[1] In powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation, 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14 1-[(4-methyl-quinazoline-2-yl) methyl] -3 showing at least three peaks selected from the group consisting of .5 ° ± 0.2 ° and 20.8 ° ± 0.2 ° Crystal form of -methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine,
[2] The crystal morphology is 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14 in powder X-ray diffraction (diffraction angle 2θ). The crystal morphology according to [1], which shows at least four peaks selected from the group consisting of .5 ° ± 0.2 ° and 20.8 ° ± 0.2 °.
[3] The crystal morphology is 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14 in powder X-ray diffraction (diffraction angle 2θ). The crystal morphology according to [1] or [2], which shows peaks of .5 ° ± 0.2 ° and 20.8 ° ± 0.2 °.
[4] The crystal form according to any one of [1] to [3], which has substantially the same powder X-ray diffraction pattern as the powder X-ray diffraction pattern shown in FIG. 1.
[5] In powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation, 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17 1-[(4-methyl- Kinazoline-2-yl) Methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthin crystal form,
[6] The crystal morphology is 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17 in powder X-ray diffraction (diffraction angle 2θ). The crystal morphology according to [5], which shows at least 5 peaks selected from the group consisting of 9.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 °. ,
[7] The crystal morphology is 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17 in powder X-ray diffraction (diffraction angle 2θ). The crystal morphology according to [5] or [6], which shows peaks of 9.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 °.
[8] The crystal form according to any one of [5] to [7], which has substantially the same powder X-ray diffraction pattern as the powder X-ray diffraction pattern shown in FIG. 2.
[9] 1- [(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8 according to any one of [1] to [8]. -(3- (R) -Amino-piperidine-1-yl) -A pharmaceutical composition for treating diabetes, which comprises a crystal form of xanthine as an active ingredient.
[10] 1- [(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8 according to any one of [1] to [8]. -(3- (R) -Amino-piperidine-1-yl) -Xanthine in crystalline form for use in the manufacture of pharmaceutical compositions for the treatment of diabetes,
[11] 1- [(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 according to any one of [1] to [8]. -(3- (R) -amino-piperidine-1-yl) -for use in a method of treating diabetes, including the step of administering an effective amount of xanthine to a patient, and [12] a method of treating diabetes, [12] 1]-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3-) according to any one of [8]. (R) -amino-piperidine-1-yl) -xanthine,
Regarding.
　本発明のリナグリプチンの結晶形態によれば、不純物の生成が少なく優れた安定性を示すことができる。また、本発明のリナグリプチンの結晶形態は、優れた水への溶解性を示すことができる。 According to the crystal form of linagliptin of the present invention, it is possible to exhibit excellent stability with less generation of impurities. Moreover, the crystal form of linagliptin of the present invention can exhibit excellent solubility in water.
本発明のリナグリプチンの結晶形態（１）の粉末Ｘ線回折図である。It is a powder X-ray diffraction pattern of the crystal form (1) of linagliptin of this invention. 本発明のリナグリプチンの結晶形態（２）の粉末Ｘ線回折図である。It is a powder X-ray diffraction pattern of the crystal form (2) of linagliptin of this invention.
［１］結晶形態（１）
　本発明の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態（１）は、Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°からなる群から選択される少なくとも３つのピークを示し、好ましくは少なくとも４つのピークを示し、最も好ましくは５つのピークを示す。 [1] Crystal form (1)
1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1) of the present invention -Il) -Xanthine crystal morphology (1) is 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9 in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. .At least 3 peaks selected from the group consisting of 3 ° ± 0.2 °, 14.5 ° ± 0.2 °, and 20.8 ° ± 0.2 °, preferably at least 4 peaks. Shown, most preferably five peaks.
《リナグリプチン》
　前記リナグリプチンは、下記式（１）
Figure JPOXMLDOC01-appb-C000001
 で表される化合物であり、ジペプチジルペプチダーゼの阻害作用を示す。ジペプチジルペプチダーゼはインクレチンを分解する酵素であり、ジペプチジルペプチダーゼを阻害することにより血中のグルカゴン様ペプチド－１（ＧＬＰ－１）の濃度を高めることができる。この作用により、血清インスリン濃度の上昇、及び血糖値の低下を誘導する。日本ではトラゼンタ（商品名）として市販されている。 《Linagliptin》
The linagliptin has the following formula (1).
Figure JPOXMLDOC01-appb-C000001
 It is a compound represented by, and exhibits an inhibitory action on dipeptidyl peptidase. Dipeptidyl peptidase is an enzyme that degrades incretins and can increase the concentration of glucagon-like peptide-1 (GLP-1) in the blood by inhibiting dipeptidyl peptidase. This action induces an increase in serum insulin concentration and a decrease in blood glucose level. It is marketed as Trazenta (trade name) in Japan.
《粉末Ｘ線回折》
　前記リナグリプチンの結晶形態（１）は、Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°からなる群から選択される少なくとも３つのピークを示す。前記５つのピークは、本発明のリナグリプチンの結晶形態（１）に特徴的なピークである、従っていずれの３つのピークの組み合わせによっても、本発明のリナグリプチンの結晶形態（１）を特定することができるが、最も好ましくは６．９°±０．２°、２０．８°±０．２°、及び７．６°±０．２°のピークの組み合わせである。 << Powder X-ray diffraction >>
The crystal morphology (1) of linagliptin is 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. Shows at least three peaks selected from the group consisting of ± 0.2 °, 14.5 ° ± 0.2 °, and 20.8 ° ± 0.2 °. The five peaks are characteristic of the linagliptin crystal morphology (1) of the present invention. Therefore, the combination of any three peaks can also identify the linagliptin crystal morphology (1) of the present invention. It is possible, but most preferably a combination of peaks of 6.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, and 7.6 ° ± 0.2 °.
　前記リナグリプチンの結晶形態（１）は、好ましくはＣｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°からなる群から選択される少なくとも４つのピークを示す。前記５つのピークは、本発明のリナグリプチンの結晶形態（１）に特徴的なピークである、従っていずれの４つのピークの組み合わせによっても、本発明のリナグリプチンの結晶形態（１）を特定することができるが、最も好ましくは６．９°±０．２°、２０．８°±０．２°、７．６°±０．２°、及び９．３°±０．２°のピークの組み合わせである。 The crystal morphology (1) of the linagliptin is preferably 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9. Shows at least four peaks selected from the group consisting of 3 ° ± 0.2 °, 14.5 ° ± 0.2 °, and 20.8 ° ± 0.2 °. The five peaks are characteristic of the linagliptin crystal morphology (1) of the present invention. Therefore, the combination of any of the four peaks can identify the linagliptin crystal morphology (1) of the present invention. It is possible, but most preferably a combination of peaks of 6.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, 7.6 ° ± 0.2 °, and 9.3 ° ± 0.2 °. Is.
　前記リナグリプチンの結晶形態（１）は、より好ましくはＣｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°のピークを示す。前記５つのピークは、本発明のリナグリプチンの結晶形態（１）に特徴的なピークである、５つのピークの組み合わせによって、本発明のリナグリプチンの結晶形態（１）を特定することができる。 The crystal morphology (1) of the linagliptin is more preferably 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9 in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. It shows peaks of 3 ° ± 0.2 °, 14.5 ° ± 0.2 °, and 20.8 ° ± 0.2 °. The five peaks are the peaks characteristic of the linagliptin crystal morphology (1) of the present invention, and the crystal morphology (1) of the linagliptin of the present invention can be specified by the combination of the five peaks.
　前記リナグリプチンの結晶形態（１）は、Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、前記３～５つのピークに加えて、７．３°±０．２°のピーク、及び／又は１７．７°±０．２°のピークを有してもよい。
　すなわち、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、２０．８°±０．２°及び７．３°±０．２°からなる群から選択される少なくとも４～６のピークを有してもよい。
　また、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、２０．８°±０．２°及び１７．７°±０．２°からなる群から選択される少なくとも４～６のピークを有してもよい。
　更に、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、２０．８°±０．２°、７．３°±０．２°、及び１７．７°±０．２°からなる群から選択される少なくとも５～７のピークを有してもよい。
　前記リナグリプチンの結晶形態（１）は、最も好ましくは図１に記載の粉末結晶回折パターンを有する。 The crystal morphology (1) of linagliptin has a peak of 7.3 ° ± 0.2 ° and / / in addition to the above 3 to 5 peaks in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. Alternatively, it may have a peak of 17.7 ° ± 0.2 °.
That is, 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14.5 ° ± 0.2 °, 20.8 ° ± 0.2. It may have at least 4-6 peaks selected from the group consisting of ° and 7.3 ° ± 0.2 °.
In addition, 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14.5 ° ± 0.2 °, 20.8 ° ± 0.2 It may have at least 4-6 peaks selected from the group consisting of ° and 17.7 ° ± 0.2 °.
Furthermore, 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14.5 ° ± 0.2 °, 20.8 ° ± 0.2 It may have at least 5-7 peaks selected from the group consisting of °, 7.3 ° ± 0.2 °, and 17.7 ° ± 0.2 °.
The crystal form (1) of the linagliptin most preferably has the powder crystal diffraction pattern shown in FIG.
　本発明のリナグリプチンの結晶形態（１）における粉末Ｘ線回折スペクトルにおける回折角２θのピークの誤差は約±０．２°である。この誤差は、測定に用いられた機器、試料の調製、及びデータ解析の方法などにより生じるものであり、本技術分野における技術常識である。更に、本発明のリナグリプチンの結晶形態（１）には、粉末Ｘ線回折（回折角度２θ）のピークパターンが同じであるが、ピークの相対強度が異なるものも含まれる。本明細書において、相対強度とは、粉末Ｘ線回折スペクトルにおける回折角２θのピークのうち、ピーク面積が最大のものを１００とした際の、各ピーク面積の相対値である。 The error of the peak of the diffraction angle 2θ in the powder X-ray diffraction spectrum in the crystal form (1) of linagliptin of the present invention is about ± 0.2 °. This error is caused by the equipment used for the measurement, the preparation of the sample, the method of data analysis, and the like, and is a common general technical knowledge in the present technical field. Further, the crystal 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 intensities of peaks. In the present specification, the relative intensity is a relative value of each peak area when the peak area of the peak of the diffraction angle 2θ in the powder X-ray diffraction spectrum is 100.
　本発明のリナグリプチンの結晶形態（１）は、示差熱分析により１７３．３℃±５℃に吸熱ピークを有する。本発明のリナグリプチンの結晶形態（１）は、水和物であると推定される。
　本発明のリナグリプチンの結晶形態（１）は、糖尿病治療用医薬組成物の有効成分として用いることができる。本発明のリナグリプチンの結晶形態（１）は、優れた安定性を有しており、医薬組成物も優れた安定性を示す。
　従って、本発明のリナグリプチンの結晶形態（１）は、糖尿病治療用医薬組成物の製造に使用することができる。 The crystal form (1) of linagliptin of the present invention has an endothermic peak at 173.3 ° C ± 5 ° C by differential thermal analysis. The crystal form (1) of linagliptin of the present invention is presumed to be a hydrate.
The crystal form (1) of linagliptin of the present invention can be used as an active ingredient of a pharmaceutical composition for treating diabetes. The crystal 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 for producing a pharmaceutical composition for treating diabetes.
　本発明の結晶形態（１）のかさ密度は、限定されるものではないが、０．１５～０．２５ｇ／ｍＬであり、好ましくは、０．１８～０．２２ｇ／ｍＬである。また、本発明の結晶形態（１）のタップ密度は、限定されるものではないが、０．３２～０．４２ｇ／ｍＬであり、好ましくは、０．３５～０．３９ｇ／ｍＬであり、より好ましくは０．３６～０．３８ｇ／ｍＬであり、例えば０．３７ｇ／ｍＬである。かさ密度等が前記範囲であることによって、結晶形態（１）は、リナグリプチンの他の結晶形態と異なる性質を示すことができる。 The bulk density of the crystal form (1) of the present invention is not limited, but is 0.15 to 0.25 g / mL, preferably 0.18 to 0.22 g / mL. The tap density of the crystal form (1) of the present invention is not limited, but is 0.32 to 0.42 g / mL, preferably 0.35 to 0.39 g / mL. More preferably, it is 0.36 to 0.38 g / mL, for example, 0.37 g / mL. When the bulk density and the like are in the above range, the crystal form (1) can exhibit properties different from those of other crystal forms of linagliptin.
［２］結晶形態（２）
　本発明の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態（２）は、Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°からなる群から選択される少なくとも４つのピークを示し、好ましくは少なくとも５つのピークを示し、より好ましくは６つのピークを示す。 [2] Crystal form (2)
1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1) of the present invention -Il) -Xantin crystal morphology (2) is 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15 in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. At least four peaks selected from the group consisting of .4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 °. , Preferably showing at least 5 peaks, more preferably 6 peaks.
《粉末Ｘ線回折》
　前記リナグリプチンの結晶形態（２）は、Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°からなる群から選択される少なくとも４つのピークを示す。前記６つのピークは、本発明のリナグリプチンの結晶形態（２）に特徴的なピークである、従っていずれの４つのピークの組み合わせによっても、本発明のリナグリプチンの結晶形態（２）を特定することができるが、最も好ましくは６．９°±０．２°、１５．４°±０．２°、１７．９°±０．２°、及び２０．８°±０．２°のピークの組み合わせである。 << Powder X-ray diffraction >>
The crystal form (2) of linagliptin is 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. It shows at least four peaks selected from the group consisting of ± 0.2 °, 17.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 °. The six peaks are characteristic of the linagliptin crystal morphology (2) of the present invention. Therefore, the combination of any of the four peaks can identify the linagliptin crystal morphology (2) of the present invention. Possible, but most preferably a combination of peaks of 6.9 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, and 20.8 ° ± 0.2 °. Is.
　前記リナグリプチンの結晶形態（２）は、好ましくはＣｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°からなる群から選択される少なくとも５つのピークを示す。前記６つのピークは、本発明のリナグリプチンの結晶形態（２）に特徴的なピークである、従っていずれの５つのピークの組み合わせによっても、本発明のリナグリプチンの結晶形態（２）を特定することができるが、最も好ましくは６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、及び２０．８°±０．２°のピークの組み合わせである。 The crystal form (2) of the linagliptin is preferably 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15. At least 5 peaks selected from the group consisting of 4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 °. show. The six peaks are characteristic of the linagliptin crystal morphology (2) of the present invention. Therefore, the combination of any of the five peaks can identify the linagliptin crystal morphology (2) of the present invention. It can, but most preferably 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17.9 ° ± 0.2 °, and 20.8. It is a combination of peaks of ° ± 0.2 °.
　前記リナグリプチンの結晶形態（２）は、より好ましくはＣｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２のピークを示す。前記６つのピークは、本発明のリナグリプチンの結晶形態（２）に特徴的なピークである、６つのピークの組み合わせによって、本発明のリナグリプチンの結晶形態を特定することができる。 The crystal morphology (2) of the linagliptin is more preferably 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15 in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. It shows peaks of .4 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2. The six peaks are the peaks characteristic of the linagliptin crystal morphology (2) of the present invention, and the crystal morphology of the linagliptin of the present invention can be specified by the combination of the six peaks.
　前記リナグリプチンの結晶形態（２）は、Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、前記４～６つのピークに加えて、７．１°±０．２°、１３．７°±０．２°、１４．５°±０．２°、及び１６．２°±０．２°からなる群から選択される１つ以上のピークを有してもよい。
　すなわち、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°、及び２３．８°±０．２からなる群から選択される少なくとも４～１０のピークを有してもよい。
　前記リナグリプチンの結晶形態（２）は、最も好ましくは図２に記載の粉末結晶回折パターンを有する。 The crystal morphology (2) of linagliptin is 7.1 ° ± 0.2 °, 13.7 ° in addition to the above 4 to 6 peaks in powder X-ray diffraction (diffraction angle 2θ) by Cu—Kα irradiation. It may have one or more peaks selected from the group consisting of ± 0.2 °, 14.5 ° ± 0.2 °, and 16.2 ° ± 0.2 °.
That is, 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. It may have at least 4-10 peaks selected from the group consisting of 2.
The crystal form (2) of the linagliptin most preferably has the powder crystal diffraction pattern shown in FIG.
　本発明のリナグリプチンの結晶形態（２）における粉末Ｘ線回折スペクトルにおける回折角２θのピークの誤差は約±０．２°である。この誤差は、測定に用いられた機器、試料の調製、及びデータ解析の方法などにより生じるものであり、本技術分野における技術常識である。更に、本発明のリナグリプチンの結晶形態（２）には、粉末Ｘ線回折（回折角度２θ）のピークパターンが同じであるが、ピークの相対強度が異なるものも含まれる。本明細書において、相対強度とは、粉末Ｘ線回折スペクトルにおける回折角２θのピークのうち、ピーク面積が最大のものを１００とした際の、各ピーク面積の相対値である。本発明のリナグリプチンの結晶形態（２）は、水和物ではないと推定される。 The error of the peak of the diffraction angle 2θ in the powder X-ray diffraction spectrum in the crystal form (2) of linagliptin of the present invention is about ± 0.2 °. This error is caused by the equipment used for the measurement, the preparation of the sample, the method of data analysis, and the like, and is a common general technical knowledge in the present technical field. Further, the crystal form (2) of linagliptin of the present invention includes those having the same peak pattern of powder X-ray diffraction (diffraction angle 2θ) but different relative intensities of peaks. In the present specification, the relative intensity is a relative value of each peak area when the peak area of the peak of the diffraction angle 2θ in the powder X-ray diffraction spectrum is 100. It is presumed that the crystal form (2) of linagliptin of the present invention is not a hydrate.
　本発明の結晶形態（２）のかさ密度は、限定されるものではないが、０．１５～０．２５ｇ／ｍＬであり、好ましくは、０．１８～０．２２ｇ／ｍＬである。また、本発明の結晶形態（１）のタップ密度は、限定されるものではないが、０．３２～０．４２ｇ／ｍＬであり、好ましくは、０．３５～０．３９ｇ／ｍＬであり、より好ましくは０．３６～０．３８ｇ／ｍＬであり、例えば０．３７ｇ／ｍＬである。かさ密度等が前記範囲であることによって、結晶形態（２）は、リナグリプチンの他の結晶形態と異なる性質を示すことができる。 The bulk density of the crystal form (2) of the present invention is not limited, but is 0.15 to 0.25 g / mL, preferably 0.18 to 0.22 g / mL. The tap density of the crystal form (1) of the present invention is not limited, but is 0.32 to 0.42 g / mL, preferably 0.35 to 0.39 g / mL. More preferably, it is 0.36 to 0.38 g / mL, for example, 0.37 g / mL. When the bulk density and the like are in the above range, the crystal morphology (2) can exhibit properties different from those of other crystal morphologies of linagliptin.
《リナグリプチンの結晶形態の製造方法》
　本発明のリナグリプチンの結晶形態の第１の製造方法は、（ａ）１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンをメタノール中で加熱して４０～６５℃で溶解し、メタノール溶液を得る工程、（ｂ１）前記メタノール溶液に、３５～４５℃で種結晶を加え、結晶析出を確認する工程、（ｃ）得られた懸濁液を１５℃以下まで冷却し、結晶を得る工程、（ｄ）前記結晶をろ過する工程、及び（ｅ）得られた結晶を２０～１００℃で減圧乾燥する工程、を含む。前記種結晶は、結晶形態（１）又は結晶形態（２）の結晶である。結晶形態（１）又は結晶形態（２）種結晶は、後述の第２の製造方法によって取得することができる。 << Manufacturing method of crystal form of linagliptin >>
The first method for producing the crystal form of linagliptin of the present invention is (a) 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl). -8- (3- (R) -Amino-piperidin-1-yl) -xanthin is heated in methanol and dissolved at 40 to 65 ° C. to obtain a methanol solution. (B1) In the methanol solution, 35. A step of adding a seed crystal at ~ 45 ° C. to confirm crystal precipitation, (c) a step of cooling the obtained suspension to 15 ° C. or lower to obtain a crystal, (d) a step of filtering the crystal, and ( e) The step of drying the obtained crystals under reduced pressure at 20 to 100 ° C. is included. The seed crystal is a crystal having a crystal form (1) or a crystal form (2). The crystal form (1) or the crystal form (2) seed crystal can be obtained by the second production method described later.
　また、本発明のリナグリプチンの結晶形態の第２の製造方法は、（ａ）１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンをメタノール中で加熱して４０～６５℃で溶解し、メタノール溶液を得る工程、（ｂ２）３５～４５℃でtert.-ブチルメチルエーテルを加え、結晶析出を確認する工程、（ｃ）得られた懸濁液を１５℃以下まで冷却し、結晶を得る工程、（ｄ）前記結晶をろ過する工程、及び（ｅ）得られた結晶を２０～１００℃で減圧乾燥する工程、を含む。
　本発明のリナグリプチンの結晶形態（１）の第１の製造方法と第２の製造方法とは、工程（ａ）、（ｃ）、（ｄ）及び（ｅ）は同一であり、第１製造方法の工程（ｂ１）と、第２製造方法の工程（ｂ２）とが異なる。以下に、共通する工程はまとめて記載し、異なる工程は個別に記載する。 The second method for producing the crystal form of linagliptin of the present invention is (a) 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-). Il) -8- (3- (R) -amino-piperidin-1-yl) -xanthin is heated in methanol and dissolved at 40 to 65 ° C to obtain a methanol solution, (b2) 35 to 45 ° C. A step of adding tert.-butylmethyl ether and confirming crystal precipitation, (c) a step of cooling the obtained suspension to 15 ° C. or lower to obtain crystals, (d) a step of filtering the crystals, and a step of filtering the crystals. (E) The step of drying the obtained crystals under reduced pressure at 20 to 100 ° C. is included.
The first production method and the second production method of the crystal form (1) of linagliptin of the present invention are the same in steps (a), (c), (d) and (e), and the first production method. The step (b1) of the second manufacturing method is different from the step (b2) of the second manufacturing method. The common processes are collectively described below, and the different processes are described individually.
《工程（ａ）》
　前記工程（ａ）においては、リナグリプチンをメタノール中で加熱して４０～６５℃で溶解し、メタノール溶液を得る。溶解温度は、好ましくは４０～６０℃であり、より好ましくは４０～５０℃である。リナグリプチンに対するメタノールの量は、本発明の結晶形態が得られる限りにおいて、特に限定されるものではないが、リナグリプチンに対して０．５～３０倍量（重量／重量）であり、好ましくは１～１０倍量であり、より好ましくは１．５～５倍量である。メタノールは、純度９７％以上のものを使用すればよい。
　リナグリプチンのメタノールへの溶解は、好ましくは攪拌しながら行う。攪拌の方法は、公知の方法を使用すればよいが、例えば撹拌機、攪拌羽根、又はマグネティックスターラーなどを適宜選択して用いることができる。前記メタノール溶液は、好ましくは４０℃程度まで冷却する。冷却の方法は、限定されないが、例えばメタノール溶液を水浴又は室温に放置すればよい。 << Process (a) >>
In the step (a), linagliptin is heated in methanol and dissolved at 40 to 65 ° C. to obtain a methanol solution. The melting temperature is preferably 40 to 60 ° C, more preferably 40 to 50 ° C. The amount of methanol with respect to linagliptin is not particularly limited as long as the crystalline form of the present invention can be obtained, but it is 0.5 to 30 times the amount (weight / weight) with respect to linagliptin, preferably 1 to 1 to. The amount is 10 times, more preferably 1.5 to 5 times. Methanol with a purity of 97% or more may be used.
The dissolution of linagliptin in methanol is preferably carried out with stirring. As the stirring method, a known method may be used, and for example, a stirrer, a stirring blade, a magnetic stirrer, or the like 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, a methanol solution may be left in a water bath or at room temperature.
《工程（ｂ１）》
　前記工程（ｂ１）においては、前記メタノール溶液に、３５～４５℃で種結晶を加え、結晶析出を確認する。種結晶の量は特に限定されないが、例えば得られる結晶の０．００１～５重量％の種結晶を加えればよく、好ましくは０．０１～３重量％であり、より好ましくは０．０２～２重量％であり、更に好ましくは０．０４～１重量％であり、最も好ましくは０．０５～０．５重量％の種結晶を加えればよい。
　結晶析出の確認は、目視で行うことができる。結晶の析出を確認した後に、メタノール溶液を４０℃で攪拌し、結晶の成長を促進させる。攪拌方法は、特に限定されないが、撹拌機、攪拌羽根、又はマグネティックスターラーを用いればよく、１５０～３５０ｒｐｍ、好ましくは２００～３００ｒｐｍで攪拌する。攪拌時間も特に限定されるものではないが、例えば１０分～１０時間であり、好ましくは２０分～３時間であり、より好ましくは４０分～２時間である。短すぎると結晶の析出が十分でないことがあり、長すぎるとリナグリプチンの分解が起こることがある。 << 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 the seed crystal is not particularly limited, but for example, 0.001 to 5% by weight of the obtained crystal may be added, preferably 0.01 to 3% by weight, and more preferably 0.02 to 2% by weight. The seed crystal may be added in an amount of% by weight, more preferably 0.04 to 1% by weight, and most preferably 0.05 to 0.5% by weight.
The crystal precipitation can be confirmed visually. After confirming the precipitation of crystals, the methanol solution is stirred at 40 ° C. to promote crystal growth. The stirring method is not particularly limited, but a stirrer, a stirring blade, or a 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 it is too short, crystal precipitation may not be sufficient, and if it is too long, linagliptin decomposition may occur.
《工程（ｂ２）》
　前記工程（ｂ２）においては、３５～４５℃でtert.-ブチルメチルエーテルを加え、結晶析出を確認する。tert.-ブチルメチルエーテルの量は、特に限定されるものではないが、例えば、メタノール溶液の０．５～５倍量であり、好ましくは１～４倍量であり、より好ましくは１．５～３倍量であり、更に好ましくは１．７～２．５倍量である。tert.-ブチルメチルエーテルの添加方法も限定されるものではないが、メタノール溶液への滴下により添加することが好ましい。
　結晶析出の確認は、目視で行うことができる。結晶の析出を確認した後に、メタノール溶液を４０℃で攪拌し、結晶の成長を促進させる。攪拌方法は、特に限定されないが、撹拌機、攪拌羽根、又はマグネティックスターラーを用いればよく、１５０～３５０ｒｐｍ、好ましくは２００～３００ｒｐｍで攪拌する。攪拌時間も特に限定されるものではないが、例えば５分～１０時間であり、好ましくは１０分～２時間であり、より好ましくは２０分～２時間であり、更に好ましくは３０分～１時間である。短すぎると結晶の析出が十分でないことがあり、長すぎるとリナグリプチンの分解が起こることがある。 << Process (b2) >>
In the step (b2), tert.-butylmethyl ether is added at 35 to 45 ° C., and crystal precipitation is confirmed. The amount of tert.-butylmethyl ether is not particularly limited, but is, for example, 0.5 to 5 times, preferably 1 to 4 times, and more preferably 1.5 times the amount of the methanol solution. The amount is up to 3 times, more preferably 1.7 to 2.5 times. The method for adding tert.-butylmethyl ether is also not limited, but it is preferable to add the tert.-butylmethyl ether by dropping it into a methanol solution.
The crystal precipitation can be confirmed visually. After confirming the precipitation of crystals, the methanol solution is stirred at 40 ° C. to promote crystal growth. The stirring method is not particularly limited, but a stirrer, a stirring blade, or a 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, still more preferably 30 minutes to 1 hour. Is. If it is too short, crystal precipitation may not be sufficient, and if it is too long, linagliptin decomposition may occur.
《工程（ｃ）》
　前記工程（ｃ）においては、得られた懸濁液を１５℃以下まで冷却し、結晶を得る。冷却温度は、１５℃以下であれば限定されないが、好ましくは０～１０℃であり、より好ましくは０～５℃である。好ましくは、冷却後に懸濁液を攪拌し、結晶の成長を促す。攪拌方法は、特に限定されないが、撹拌機、攪拌羽根、又はマグネティックスターラーを用いればよく、１５０～３５０ｒｐｍ、好ましくは２００～３００ｒｐｍで攪拌する。攪拌時間も特に限定されるものではないが、例えば１０分～１０時間であり、好ましくは２０分～３時間であり、より好ましくは４０分～２時間である。 << Process (c) >>
In the step (c), the obtained suspension is cooled to 15 ° C. or lower to obtain crystals. The cooling temperature is not limited as long as it is 15 ° C. or lower, but is preferably 0 to 10 ° C., 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, a stirring blade, or a 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.
《工程（ｄ）》
　前記工程（ｄ１）においては、前記結晶をろ過する。ろ過は、特に限定されるものではないが、例えばろ紙等を用いて、減圧ろ過(吸引ろ過)、圧ろ過、又は遠心ろ過などで行うことができる。ここで、ろ過した結晶を洗浄してもよい。結晶の洗浄に用いる溶媒は、結晶の製造に用いたものが好ましいため、メタノール又はメタノール／tert.-ブチルメチルエーテル溶液等を使用する。 << Process (d) >>
In the step (d1), the crystals are filtered. Filtration is not particularly limited, but can be performed by, for example, vacuum filtration (suction filtration), pressure filtration, centrifugal filtration, or the like using filter paper or the like. Here, the filtered crystals may be washed. Since the solvent used for washing the crystals is preferably the one used for producing the crystals, methanol or a methanol / tert.-butylmethyl ether solution or the like is used.
《工程（ｅ）》
　前記工程（ｅ）においては、得られた結晶を２０～１００℃、好ましくは２０～７０℃、より好ましくは３０～６０℃で減圧乾燥する。減圧乾燥の圧力は、例えば０．１気圧（ａｔｍ）以下であり、好ましくは０．０５気圧以下である。 << Process (e) >>
In the step (e), the obtained crystals are dried under reduced pressure at 20 to 100 ° C., preferably 20 to 70 ° C., more preferably 30 to 60 ° C. The pressure for vacuum drying is, for example, 0.1 atm (atm) or less, preferably 0.05 atm or less.
　本発明のリナグリプチンの結晶形態（１）及び結晶形態（２）は、粉末Ｘ線回折スペクトルにおける回折角２θのピークが若干異なる。しかしながら、同じ製造方法で取得することが可能であり、基本的に同じ性質を有する。前記のとおり、結晶形態（１）及び結晶形態（２）は、水和物であるか否かで異なっており、可逆的である。 The crystal morphology (1) and the crystal morphology (2) of linagliptin of the present invention have slightly different peaks of the diffraction angle 2θ in the powder X-ray diffraction spectrum. However, it can be obtained by the same manufacturing method and has basically the same properties. As described above, the crystal morphology (1) and the crystal morphology (2) are different depending on whether or not they are hydrates, and are reversible.
［３］医薬組成物
　本発明の結晶形態は、医薬組成物の有効成分として用いることができる。具体的には、２型糖尿病の治療用医薬組成物の有効成分として使用することができる。すなわち、本発明の結晶形態は、糖尿病の治療用医薬組成物の製造に使用できる。また、本発明の結晶形態は、その有効量を患者に投与する工程を含む、糖尿病の治療方法に用いることができる。更に、本発明の結晶形態は、糖尿病の治療方法における使用のための、結晶形態である。
　前記医薬組成物は、これに限定されるものではないが、前記有効成分を０．０１～９９重量％、好ましくは０．１～８０重量％の量で含有することができる。医薬組成物を用いる場合の投与量は、患者の年齢、性別、体重、症状の程度、又は投与方法などに応じて適宜決定することができ、経口的に又は非経口的に投与することが可能である。 [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 producing 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 comprises a step of administering an effective amount thereof to a patient. Furthermore, the crystalline form of the present invention is a crystalline form for use in a method of treating diabetes.
The pharmaceutical composition can contain, but is not limited to, the active ingredient in an amount of 0.01 to 99% by weight, preferably 0.1 to 80% by weight. The dose when the pharmaceutical composition is used can be appropriately determined according to the age, sex, body weight, degree of symptoms, administration method, etc. of the patient, and can be administered orally or parenterally. Is.
　前記医薬組成物の投与剤型としては、特に限定がなく、例えば、散剤、細粒剤、顆粒剤、錠剤、カプセル剤、懸濁液、エマルジョン剤、シロップ剤、エキス剤、若しくは丸剤等の経口剤、又は注射剤、外用液剤、軟膏剤、坐剤、局所投与のクリーム、若しくは点眼薬などの非経口剤を挙げることができる。 The dosage form of the pharmaceutical composition is not particularly limited, and for example, powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, rounds and the like. Oral preparations or parenteral preparations such as injections, external solutions, ointments, suppositories, topically administered creams, or eye drops can be mentioned.
　前記医薬組成物は、例えば、ゼラチン、アルギン酸ナトリウム、澱粉、コーンスターチ、白糖、乳糖、ぶどう糖、マンニット、カルボキシメチルセルロース、デキストリン、ポリビニルピロリドン、結晶セルロース、大豆レシチン、ショ糖、脂肪酸エステル、タルク、ステアリン酸マグネシウム、ポリエチレングリコール、ケイ酸マグネシウム、無水ケイ酸、又は合成ケイ酸アルミニウムなどの賦形剤、結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、希釈剤、保存剤、着色剤、香料、矯味剤、安定化剤、保湿剤、防腐剤、又は酸化防止剤等を用いて、常法に従って製造することができる。 The pharmaceutical composition includes, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitt, carboxymethyl cellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean residue, sucrose, fatty acid ester, talc, stearic acid. Excipients such as magnesium, polyethylene glycol, magnesium silicate, anhydrous silicate, or synthetic aluminum silicate, binders, disintegrants, surfactants, talc, fluidity promoters, diluents, preservatives, coloring It can be produced according to a conventional method using an agent, a fragrance, a flavoring agent, a stabilizer, a moisturizing agent, a preservative, an antioxidant or the like.
　非経口投与方法としては、注射（皮下、静脈内等）、又は直腸投与等が例示される。これらのなかで、注射剤が最も好適に用いられる。例えば、注射剤の調製においては、有効成分の他に、例えば、生理食塩水若しくはリンゲル液等の水溶性溶剤、植物油若しくは脂肪酸エステル等の非水溶性溶剤、ブドウ糖若しくは塩化ナトリウム等の等張化剤、溶解補助剤、安定化剤、防腐剤、懸濁化剤、又は乳化剤などを任意に用いることができる。 Examples of parenteral administration methods include injection (subcutaneous, intravenous, etc.), rectal administration, and the like. Of these, injections are most preferably used. For example, in the preparation of injections, in addition to the active ingredient, for example, a water-soluble solvent such as physiological saline or Ringer's solution, a water-insoluble solvent such as vegetable oil or fatty acid ester, an isotonic agent such as glucose or sodium chloride, etc. A solubilizing agent, a stabilizer, a preservative, a suspending agent, an emulsifier and the like can be arbitrarily used.
　また、投与形態も医薬品に限定されるものではなく、種々の形態、例えば、機能性食品や健康食品（飲料を含む）、又は動物に飼料として飲食物の形で与えることも可能である。 Further, the administration form is not limited to pharmaceutical products, and various forms such as functional foods, health foods (including beverages), or animals can be given in the form of food and drink as feed.
　以下、実施例によって本発明を具体的に説明するが、これらは本発明の範囲を限定するものではない。 Hereinafter, the present invention will be specifically described with reference to Examples, but these do not limit the scope of the present invention.
《実施例１》
　本実施例では、リナグリプチンの結晶形態（１）を作製した。１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン（リナグリプチン）４０ｇ（８５ｍｍｏｌ）とメタノール１００ｇとを混合し、４０～５０℃まで加熱して溶解した。その後、熱時ろ過し、メタノール２０ｇで洗浄した。濾液を４０℃まで冷却し、種結晶を添加した。結晶析出を確認後、４０℃で１時間撹拌した。懸濁液を０～５℃まで冷却して、１時間撹拌した。結晶をろ過し、メタノール６０ｇで洗浄した。湿結晶を３０～６０℃で減圧乾燥させることによって、白色のリナグリプチン結晶を３５ｇ（７４ｍｍｏｌ）収得した。 << Example 1 >>
In this example, the crystal form (1) of linagliptin was prepared. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -40 g (85 mmol) of xanthine (linagliptin) and 100 g of methanol were mixed and heated to 40 to 50 ° C. to dissolve. Then, it was filtered hot and washed with 20 g of methanol. The filtrate was cooled to 40 ° C. and seed crystals were added. After confirming the 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 to 60 ° C., 35 g (74 mmol) of white linagliptin crystals were obtained.
《実施例２》
　本実施例では、リナグリプチンの結晶形態（１）を、実施例１と異なる工程で作製した。１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン（リナグリプチン）３３ｇ（７０ｍｍｏｌ）とメタノール８２．５ｇを混合し、４０～５０℃まで加熱して溶解した。その後、熱時ろ過し、メタノール１６．５ｇで洗浄した。濾液を４０℃まで冷却し、tert.-ブチルメチルエーテル１９８ｇを滴下した。結晶析出を確認後、４０℃で３０分間撹拌した。懸濁液を０～５℃まで冷却して１時間撹拌した。結晶をろ過し、メタノール２２ｇとtert.-ブチルメチルエーテル４４ｇとの混合液で洗浄した。湿結晶を３０～６０℃で減圧乾燥させることによって、白色のリナグリプチン結晶を３１ｇ（６６ｍｍｏｌ）収得した。 << Example 2 >>
In this example, the crystal form (1) of linagliptin was prepared by a process different from that of Example 1. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 33 g (70 mmol) and methanol 82.5 g were mixed and heated to 40-50 ° C to dissolve. Then, it was filtered hot and washed with 16.5 g of methanol. The filtrate was cooled to 40 ° C. and 198 g of tert.-butylmethyl ether was added dropwise. After confirming the 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.-butylmethyl ether. By drying the wet crystals under reduced pressure at 30 to 60 ° C., 31 g (66 mmol) of white linagliptin crystals were obtained.
《粉末Ｘ線回折測定》
　前記実施例１又は実施例２で得られた結晶を、一般実験室で、室温、湿度５０％以上で一昼夜保管後に、以下の条件で粉末Ｘ線回折の測定を行った。
装置：ＢＲＵＫＥＲ製　Ｄ２　ＰＨＡＳＥＲ　２ｎｄ　Ｇｅｎ
ターゲット：ＣｕＫα
走査範囲：３．０～４０．０°
ステップ幅：０．０２°
時間：０．４０秒
　表１及び図１に実施例１で得られた結晶の粉末Ｘ線回折測定を、表２に実施例２で得られた結晶の粉末Ｘ線回折測定を示す。 << Powder X-ray diffraction measurement >>
The crystals obtained in Example 1 or Example 2 were stored in a general laboratory at room temperature and humidity of 50% or more for a whole day and night, and then powder X-ray diffraction was measured 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 of the crystal obtained in Example 1, and Table 2 shows the powder X-ray diffraction measurement of the crystal obtained in Example 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　表１、表２及び図１に記載のように、６．９°に最も大きなピークが得られ、２０．８°、７．６°、９．３°、及び１４．５°にも比較的大きなピークが見られた。また、６．９°の肩付近の７．３°にもピークがあり、更に１７．７°にもピークが観察され同一の結晶形態であった。
　本願発明の結晶形態（１）の粉末Ｘ線回折は安定であり、２５℃、６０％ＲＨ、又は４０℃、７５％ＲＨで６カ月保存しても粉末Ｘ線回折のピークの変化は見られなかった。 As shown in Table 1, Table 2 and FIG. 1, the largest peak was obtained at 6.9 ° and relatively at 20.8 °, 7.6 °, 9.3 °, and 14.5 °. A big peak was seen. In addition, there was a peak at 7.3 ° near the shoulder at 6.9 °, and a peak was also observed at 17.7 °, showing the same crystal morphology.
The powder X-ray diffraction of the crystal form (1) of the present invention is stable, and a change in the peak of the powder X-ray diffraction is observed even after storage at 25 ° C., 60% RH, or 40 ° C., 75% RH for 6 months. There wasn't.
《実施例３》
　本実施例では、リナグリプチンの結晶形態（２）を作製した。１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン（リナグリプチン）１０ｇ（２１ｍｍｏｌ）とメタノール３０ｇを混合し、４０～５０℃まで加熱して溶解した。その後、４０℃まで冷却し、種結晶を添加した。結晶析出を確認後、４０℃で１時間撹拌した。懸濁液を０～５℃まで冷却して、１時間撹拌した。結晶をろ過し、メタノール１５ｇで洗浄した。湿結晶を３０～６０℃で減圧乾燥させることによって、白色のリナグリプチン結晶を８．６ｇ（１８ｍｍｏｌ）収得した。
《粉末Ｘ線回折測定》
　得られた結晶を直ちに、以下の条件で粉末Ｘ線回折の測定を行った。
装置：ＢＲＵＫＥＲ製　Ｄ２　ＰＨＡＳＥＲ　２ｎｄ　Ｇｅｎ
ターゲット：ＣｕＫα
走査範囲：３．０～４０．０°
ステップ幅：０．０２°
時間：０．４０秒
　表３及び図２に粉末Ｘ線回折測定を示す。 << Example 3 >>
In this example, the crystal form (2) of linagliptin was prepared. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 10 g (21 mmol) and methanol 30 g were mixed and heated to 40-50 ° C to dissolve. Then, it cooled to 40 degreeC and the seed crystal was added. After confirming the 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 to 60 ° C., 8.6 g (18 mmol) of white linagliptin crystals were obtained.
<< Powder X-ray diffraction measurement >>
The obtained crystals were immediately measured for powder X-ray diffraction 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 powder X-ray diffraction measurements.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
《実施例４》
　本実施例では、リナグリプチンの結晶形態（２）を作製した。１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン（リナグリプチン）１０ｇ（２１ｍｍｏｌ）とメタノール３０ｇを混合し、４０～５０℃まで加熱して溶解した。その後、４０℃まで冷却し、種結晶を添加した。結晶析出を確認後、４０℃で１時間３０分撹拌した。懸濁液を０～５℃まで冷却して、１時間撹拌した。結晶をろ過し、メタノール１５ｇで洗浄した。湿結晶を３０～６０℃で減圧乾燥させることによって、白色のリナグリプチン結晶を８．６ｇ（１８ｍｍｏｌ）収得した。
《粉末Ｘ線回折測定》
　得られた結晶を、直ちに以下の条件で粉末Ｘ線回折の測定を行った。
装置：ＢＲＵＫＥＲ製　Ｄ２　ＰＨＡＳＥＲ　２ｎｄ　Ｇｅｎ
ターゲット：ＣｕＫα
走査範囲：３．０～４０．０°
ステップ幅：０．０２°
時間：０．４０秒
　表４に粉末Ｘ線回折測定を示す。本願発明の結晶形態（２）の粉末Ｘ線回折は、吸湿のない環境では安定であり、粉末Ｘ線回折のピークの変化は見られなかった。 << Example 4 >>
In this example, the crystal form (2) of linagliptin was prepared. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 10 g (21 mmol) and methanol 30 g were mixed and heated to 40-50 ° C to dissolve. Then, it cooled to 40 degreeC and the seed crystal was added. After confirming the 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 to 60 ° C., 8.6 g (18 mmol) of white linagliptin crystals were obtained.
<< Powder X-ray diffraction measurement >>
The obtained crystals were immediately measured for powder X-ray diffraction 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 measurement. The powder X-ray diffraction of the crystal form (2) of the present invention was stable in an environment without moisture absorption, and no change in the peak of the powder X-ray diffraction was observed.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
《安定性試験》
　実施例１で得られたリナグリプチンの結晶形態（１）及び実施例３で得られたリナグリプチンの結晶形態（２）の保存安定性を検討した。
　結晶形態（１）は、表５に記載の３つの保存条件で保管後に、ＨＰＬＣでリナグリプチンの純度を測定した。結晶形態（２）は、表６に記載の保存条件で保管後に、ＨＰＬＣでリナグリプチンの純度を測定した。 《Stability test》
The storage stability of the crystal form (1) of linagliptin obtained in Example 1 and the crystal form (2) of linagliptin obtained in Example 3 was examined.
The crystal form (1) was stored under the three storage conditions shown in Table 5, and then the purity of linagliptin was measured by HPLC. For the crystal form (2), the purity of linagliptin was measured by HPLC after storage under the storage conditions shown in Table 6.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　表５及び６に示すように、本発明の結晶形態（１）及び（２）は、優れた保存安定性を示した。 As shown in Tables 5 and 6, the crystal forms (1) and (2) of the present invention showed excellent storage stability.
《安定性加速試験及び苛酷試験》
　実施例１で得られたリナグリプチンの結晶形態（１）及び特許文献１に記載の製造方法で得られた結晶形態Ｃ（多形体Ｃ）について、保存安定性の加速試験（40℃、75%RH、二重のポリエチレン袋）及び苛酷試験（40℃、75%RH、無包装）を行った。具体的には、ＨＰＬＣで、リテンションタイム１１．７４（分）及びリテンションタイム２０．０２（分）にみられる不純物（それぞれ、不純物１及び２と称する）の測定を行った。 << Stability Accelerated Test and Severe Test >>
Accelerated storage stability test (40 ° C, 75% RH) of the crystal form (1) of linagliptin obtained in Example 1 and the crystal form C (polymorph C) obtained by the production method described in Patent Document 1 , Double polyethylene bag) and rigorous test (40 ° C, 75% RH, unpacked). Specifically, the impurities (referred to as impurities 1 and 2, respectively) found in the retention time of 11.74 (minutes) and the retention time of 20.02 (minutes) were measured by HPLC.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　表７に示すように、結晶形態Ｃは、加速試験及び苛酷試験ともに、不純物１は二週間から検出され、不純物２は３カ月から検出され、いずれも６カ月で増加していた。一方、本発明の結晶形態（１）では、加速試験で不純物１が６カ月、苛酷試験で不純物１及び２が６カ月で検出されたのみであり、安定であった。 As shown in Table 7, in the crystal form C, the impurity 1 was detected from 2 weeks and the impurity 2 was detected from 3 months in both the accelerated test and the severe test, and both increased in 6 months. On the other hand, in the crystal form (1) of the present invention, impurities 1 were detected only in 6 months in the accelerated test and impurities 1 and 2 were detected in 6 months in the severe test, and they were stable.
《溶解性試験》
　実施例１で得られたリナグリプチンの結晶形態（１）及び特許文献１に記載の製造方法で得られた結晶形態Ａ（多形体Ａ）について、水への溶解度を測定した。
　０．１ｇの結晶形態（１）又は結晶形態Ａのリナグリプチンを４０ｍＬの水に添加し、３７．０±０．５℃、又は２０．０±０．５℃、２００ｒｐｍで攪拌して、１０分、３０分、及び１時間後の溶解度を測定した。 《Solubility test》
The solubility of the crystal form (1) of linagliptin obtained in Example 1 and the crystal form A (polymorph A) obtained by the production method described in Patent Document 1 in water was measured.
Add 0.1 g of crystal form (1) or linagliptin of crystal form A to 40 mL of water and stir at 37.0 ± 0.5 ° C, or 20.0 ± 0.5 ° C, 200 rpm for 10 minutes. , 30 minutes, and 1 hour later were measured for solubility.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　表８に示すように、結晶形態（１）は、結晶形態Ａと比較して、優れた水への溶解性を示した。 As shown in Table 8, the crystal form (1) showed excellent solubility in water as compared with the crystal form A.
《かさ密度》
　実施例１で得られたリナグリプチンの結晶形態（１）、及び特許文献１に記載の製造方法で得られた結晶形態Ａ（多形体Ａ）及び結晶形態Ｃ（多形体Ｃ）のかさ密度を日本薬局方に記載の方法に従って測定した。 《Bulk density》
The bulk density of the crystal form (1) of linagliptin obtained in Example 1 and the crystal form A (polymorph A) and the crystal form C (polymorph C) obtained by the production method described in Patent Document 1 are obtained in Japan. It was measured according to the method described in the Pharmacopoeia.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
　本発明のリナグリプチンの結晶形態は、２型糖尿病の治療用医薬組成物の有効成分として用いることができる。 The crystalline form of linagliptin of the present invention can be used as an active ingredient of a pharmaceutical composition for treating type 2 diabetes.

Claims (12)

  1. 　Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°からなる群から選択される少なくとも３つのピークを示す１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態。 In powder X-ray diffraction (diffraction angle 2θ) by Cu-Kα irradiation, 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14.5 ° 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl- showing at least three peaks selected from the group consisting of ± 0.2 ° and 20.8 ° ± 0.2 ° Crystal form of 7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine.
  2. 　前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°からなる群から選択される少なくとも４つのピークを示す請求項１に記載の結晶形態。 The crystal morphology is 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14.5 ° in powder X-ray diffraction (diffraction angle 2θ). The crystal form according to claim 1, which shows at least four peaks selected from the group consisting of ± 0.2 ° and 20.8 ° ± 0.2 °.
  3. 　前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、７．６°±０．２°、９．３°±０．２°、１４．５°±０．２°、及び２０．８°±０．２°のピークを示す請求項１又は２に記載の結晶形態。 The crystal morphology is 6.9 ° ± 0.2 °, 7.6 ° ± 0.2 °, 9.3 ° ± 0.2 °, 14.5 ° in powder X-ray diffraction (diffraction angle 2θ). The crystal form according to claim 1 or 2, which shows peaks of ± 0.2 ° and 20.8 ° ± 0.2 °.
  4. 　図１で示される粉末Ｘ線回折パターンと実質的に同じ粉末Ｘ線回折パターンを有する、請求項１～３のいずれか一項に記載の結晶形態。 The crystal form according to any one of claims 1 to 3, which has substantially the same powder X-ray diffraction pattern as the powder X-ray diffraction pattern shown in FIG. 1.
  5. 　Ｃｕ－Ｋα照射による粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°からなる群から選択される少なくとも４つのピークを示す１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態。 In powder X-ray diffraction (diffraction angle 2θ) by Cu-Kα irradiation, 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17.9 ° 1-[(4-Methyl-quinazoline-2) showing at least 4 peaks selected from the group consisting of ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 ° -Il) Methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthin crystal form.
  6. 　前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°からなる群から選択される少なくとも５つのピークを示す請求項５に記載の結晶形態。 The crystal morphology is 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17.9 ° in powder X-ray diffraction (diffraction angle 2θ). The crystal form according to claim 5, which shows at least 5 peaks selected from the group consisting of ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 °.
  7. 　前記結晶形態が、粉末Ｘ線回折（回折角度２θ）において、６．９°±０．２°、１０．４°±０．２°、１５．４°±０．２°、１７．９°±０．２°、２０．８°±０．２°、及び２３．８°±０．２°のピークを示す請求項５又は６に記載の結晶形態。 The crystal morphology is 6.9 ° ± 0.2 °, 10.4 ° ± 0.2 °, 15.4 ° ± 0.2 °, 17.9 ° in powder X-ray diffraction (diffraction angle 2θ). The crystal form according to claim 5 or 6, which shows peaks of ± 0.2 °, 20.8 ° ± 0.2 °, and 23.8 ° ± 0.2 °.
  8. 　図２で示される粉末Ｘ線回折パターンと実質的に同じ粉末Ｘ線回折パターンを有する、請求項５～７のいずれか一項に記載の結晶形態。 The crystal form according to any one of claims 5 to 7, which has substantially the same powder X-ray diffraction pattern as the powder X-ray diffraction pattern shown in FIG. 2.
  9. 　請求項１～８のいずれか一項に記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態を有効成分として含む、糖尿病治療用医薬組成物。 1- [(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3) according to any one of claims 1 to 8. -(R) -Amino-piperidine-1-yl) -A pharmaceutical composition for treating diabetes, which comprises a crystal form of xanthine as an active ingredient.
  10. 　請求項１～８のいずれか一項に記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの結晶形態の糖尿病治療用医薬組成物の製造への使用。 1- [(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3) according to any one of claims 1 to 8. -(R) -Amino-piperidin-1-yl) -Xanthine in crystalline form for use in the manufacture of pharmaceutical compositions for the treatment of diabetes.
  11. 　請求項１～８のいずれか一項に記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチンの有効量を患者に投与する工程を含む、糖尿病の治療方法。 1- [(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3) according to any one of claims 1 to 8. A method for treating diabetes, comprising the step of administering to a patient an effective amount of-(R) -amino-piperidine-1-yl) -xanthine.
  12. 　糖尿病の治療方法における使用のための、請求項１～８のいずれか一項に記載の１－［（４－メチル－キナゾリン－２－イル）メチル］－３－メチル－７－（２－ブチン－１－イル）－８－（３－（Ｒ）－アミノ－ピペリジン－１－イル）－キサンチン。 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne) according to any one of claims 1 to 8 for use in a method for treating diabetes. -1-yl) -8- (3- (R) -amino-piperidine-1-yl) -xanthine.
PCT/JP2021/022157 2020-06-10 2021-06-10 Crystal morphology of 1-[(4-methyl-quinazoline-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-peperidine-1-yl)-xanthine WO2021251467A1 (en)

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