WO2016101432A1 - 一种卡格列净晶型i及其制备方法 - Google Patents

一种卡格列净晶型i及其制备方法 Download PDF

Info

Publication number
WO2016101432A1
WO2016101432A1 PCT/CN2015/075180 CN2015075180W WO2016101432A1 WO 2016101432 A1 WO2016101432 A1 WO 2016101432A1 CN 2015075180 W CN2015075180 W CN 2015075180W WO 2016101432 A1 WO2016101432 A1 WO 2016101432A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
water
ray powder
powder diffraction
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/075180
Other languages
English (en)
French (fr)
Inventor
王菲
张检
林蒙
唐远富
陈皓
雷皇书
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chongqing Pharmaceutical Research Institute Co Ltd
Original Assignee
Chongqing Pharmaceutical Research Institute Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chongqing Pharmaceutical Research Institute Co Ltd filed Critical Chongqing Pharmaceutical Research Institute Co Ltd
Priority to CA2971752A priority Critical patent/CA2971752A1/en
Priority to US15/538,965 priority patent/US20170342061A1/en
Priority to AU2015372234A priority patent/AU2015372234B2/en
Priority to EP15871510.2A priority patent/EP3239149B1/en
Priority to JP2017534731A priority patent/JP2018500368A/ja
Publication of WO2016101432A1 publication Critical patent/WO2016101432A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a new crystal form of cavigliflozin, namely, cardigridine crystal form I and a preparation method thereof.
  • Canagliflozin chemical name: 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] Benzene, having the structure shown in Formula I, can be prepared by the method disclosed in CN10180131.
  • Cagliflozin is a selective type 2 sodium glucose cotransporter (SGLT2) inhibitor developed by Johnson & Johnson. On March 29, 2013, the US Food and Drug Administration (FDA) approved its use in diet control and exercise to improve glycemic control in adult patients with type 2 diabetes.
  • SGLT2 selective type 2 sodium glucose cotransporter
  • FDA US Food and Drug Administration
  • Cagliflozin is a poorly water-soluble compound, which is generally used in solid form in the formulation, so the study of its crystal form is of great significance.
  • Patent CN101573368 discloses a chelate-based hemihydrate crystal form having characteristic peaks of 2 ⁇ values of 4.36°, 13.54°, 16.00°, 19.32° and 20.80° in an X-ray powder diffraction pattern of a CuK ⁇ source.
  • the crystal form is obtained by curing in an ethyl acetate/diethyl ether/water or acetone/water system.
  • Patent CN101801371 discloses another crystal form having a characteristic peak of 2 ⁇ value of 10.7°, 15.5°, 17.3°, 18.8° and 20.3° in an X-ray powder diffraction pattern of a CuK ⁇ source; the crystal form is passed through acetic acid Emulsified in ethyl ester / n-heptane / water system.
  • Patent WO2013064909 discloses the co-crystals of cardinol and L-valine, D-valine, L-phenylalanine and the amorphous form of calpaquin.
  • Patent CN103554092 discloses a crystal form B of capretazin having a characteristic diffraction peak of 2 ⁇ values such as 6.3°, 9.4° and 12.6° in an X-ray powder diffraction pattern of a CuK ⁇ source; the crystal form is obtained by The column is dissolved in a mixed solvent of water and an organic solvent, and is slowly volatilized at room temperature.
  • Patent CN103588762 discloses a crystal form C of capretastate having a characteristic diffraction peak of 2 ⁇ values such as 6.5°, 9.8° and 16.4° in an X-ray powder diffraction pattern of a CuK ⁇ source; the crystal form is obtained by The column is dissolved in a mixed solvent of water and an organic solvent, and is slowly volatilized at room temperature.
  • the patent also discloses a cardigliptin crystal form D having characteristic peaks of 2 ⁇ values of 6.8°, 13.6° and 20.5° in an X-ray powder diffraction pattern of a CuK ⁇ source; the crystal form is obtained by The prepared Form C is obtained by heating to 50 to 90 °C.
  • Patent CN103641822 discloses another hemihydrate crystal form of cardiglian, which has 2 ⁇ values of 3.86°, 15.46°, 17.30°, 18.80°, 19.10° and 20.26° in the X-ray powder diffraction pattern of the CuK ⁇ source. Characteristic diffraction peak; the crystal form is obtained by dissolving cardoline in a good solvent and then adding a mixed solvent of a non-good solvent and water.
  • Patent CN103980261 discloses a crystal form A of calglipide having 3.7°, 7.7°, 7.9°, 11.5°, 13.1°, 13.5°, 14.3°, 15.5 in the X-ray powder diffraction pattern of the CuK ⁇ source. Characteristic diffraction peaks of 2 ⁇ values such as 17.3°, 18.8°, 19.3°, 20.3°, 22.5°, 22.7°, 23.2°, and 23.4°; the crystal form is prepared by dissolving caldogrel in an alcohol solvent to prepare 0.05 The suspension solution of ⁇ 0.5 g/ml is obtained by dissolving at 15 to 43 ° C and then adding 3 to 10 times of a dissolution agent.
  • Patent CN103980262 discloses another crystal form B of capretamide having 3.4°, 6.6°, 12.6°, 13.2°, 15.3°, 15.6°, 16.5°, 19.4 in the X-ray powder diffraction pattern of the CuK ⁇ source. Characteristic diffraction peaks of 2 ⁇ values such as 19.8° and 23.7°; the crystal form is obtained by dissolving caldamine in an alcohol solvent, preparing a solution of 0.1 to 0.5 g/ml, and evaporating the solvent at 48 to 70 °C.
  • Patent CN103936725 discloses another crystal form C of capretamide having 3.4°, 6.5°, 12.7°, 15.8°, 19.8°, 24.3°, 24.8° and 29.1 in the X-ray powder diffraction pattern of the CuK ⁇ source. ° 2 ⁇ value characteristic diffraction peak; the crystal form is prepared by dissolving the cardoline in a good organic solvent to prepare a solution of 0.05-0.3 g/ml, and dissolving and adding a poor solvent to cure at -20 to 10 ° C. .
  • Patent WO2014180872 discloses another crystal form of kaffeta, which has characteristic peaks of 2 ⁇ values of 5.4°, 6.7°, 13.2°, 16.1°, 19.6° and 24.1° in the X-ray powder diffraction pattern of the CuK ⁇ source.
  • the crystal form is obtained by converting the amorphous form of the cardinol in water.
  • the present inventors have prepared a new crystal form of cagliflozin in the process of studying the crystal form of the cardiglipin.
  • the crystal form is simple in preparation, stable in physical and chemical properties, and easy to store, and is favorable for preparation of various preparations.
  • the object of the present invention is to provide a new crystal form of carbendazim which is simple in preparation process and excellent in physical and chemical stability, and is suitable for the manufacture and industrial production of various preparations.
  • the new crystal form of carbendazim provided by the present invention is defined herein as card Glycine Form I.
  • the X-ray powder diffraction pattern of the cardigel crystal form I of the present invention has a 2 ⁇ value of 4.4 ⁇ 0.2°, 8.4 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.0 ⁇ 0.2°, 22.8 ⁇ 0.2.
  • the position of ° corresponds to a characteristic diffraction peak.
  • the above-described cardiglin crystal form I of the present invention further includes an X-ray powder diffraction pattern having a 2 ⁇ value of 12.1 ⁇ 0.2°, 12.6 ⁇ 0.2°, 15.3 ⁇ 0.2°, 19.3 ⁇ 0.2°, and 20.4 ⁇ 0.2°.
  • the positions of 22.2 ⁇ 0.2 °, 23.0 ⁇ 0.2 °, 24.6 ⁇ 0.2 °, and 26.6 ⁇ 0.2 ° correspond to characteristic diffraction peaks.
  • the Klebylene Form I of the present invention has X-ray powder diffraction having a characteristic diffraction peak as shown in FIG.
  • the cardiophene crystal form I of the present invention has a DSC scan pattern having an endothermic peak between 90 and 95 ° C, especially at about 93 ° C; and a TGA scan pattern having a TGA scan of about 3.97 when heated to 180 ° C. % weight loss.
  • the card Glycine Form I of the present invention has a DSC-TGA scan pattern having the characteristics shown in FIG.
  • the new crystal form of kalepside provided by the invention has a characteristic absorption peak at about 1647 cm -1 .
  • the inventive infrared absorption pattern of the present invention has a feature as shown in FIG.
  • the X-ray powder diffraction test of the cardinal crystal form I of the present invention is a CuK ⁇ source of an Xinge XRD-6000 X-ray diffractometer under the ambient temperature and ambient humidity. The measurement is completed. During the test, due to various factors such as the particle size of the test sample, the processing method of the sample during the test, the instrument, the test parameters, the test operation, etc., the peak of the X-ray powder diffraction pattern measured by the same crystal form There will be some difference in position or peak intensity. The experimental error of the diffraction peak 2 ⁇ value in the X-ray powder diffraction pattern may be ⁇ 0.2°.
  • the "ambient temperature” is generally 0 to 40 ° C; the “ambient humidity” is generally 30% to 80% relative humidity.
  • the DSC-TGA analysis conditions of the card Glycine Form I of the present invention were tested by the Swiss Mettler 1100 LF type instrument under ambient temperature and ambient humidity.
  • the mixture was purged with high-purity Ar gas at a flow rate of 50 ml/min, and programmed at a rate of 10 ° C/min, and the temperature was raised from room temperature to 300 ° C for testing.
  • the "ambient temperature” is generally 0 to 40 ° C; the “ambient humidity” is generally 30% to 80% relative humidity.
  • the IR spectrum analysis of the cardinol crystal form I of the present invention was carried out by a Nicolet Atavar FT-IR330 from Nicolet, USA, at a relative humidity of generally less than 80% and a temperature of generally 15 to 30 °C.
  • the test was carried out by KBr, and the spectrophotometer was corrected with polystyrene (wavelength).
  • the measured peak position or peak intensity of the IR spectrum will be different. .
  • the experimental error of the characteristic absorption peak in the IR spectrum can be ⁇ 2 cm -1 .
  • a method of preparing a cardiglio form I of the present invention comprises the steps of:
  • cardinol is dissolved in a mixed solvent of a suitable good solvent and water to obtain a cardinide solution, wherein the dissolution temperature is 30 to 100 ° C, preferably 50 to 80 ° C;
  • the separated solid is dried, and the drying temperature is generally 30 to 80 ° C, preferably 40 to 50 ° C.
  • the drying may be dry under normal pressure, or may be dried under reduced pressure, and vacuum degree under reduced pressure. It is usually 300 to 760 mmHg, preferably 650 to 760 mmHg.
  • the suitable solvent in the method of the present invention in step 1), comprises methanol, ethanol, isopropanol, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, dioxane, etc. or mixtures thereof, preferably methanol, ethanol, isopropanol or a mixture thereof.
  • the method of the present invention has a volume ratio of good solvent to water of from 1:1 to 3.
  • the weight-to-volume ratio of cagliflozin to good solvent is 1:3-8g/ml
  • a method of preparing a cardinide Form I of the present invention comprises the steps of:
  • cardinol is dissolved in a mixed solvent of a suitable good solvent and water to obtain a cardinide solution, wherein the dissolution temperature is 50 to 80 ° C, and the suitable good solvent is selected from the group consisting of methanol, ethanol and isopropyl alcohol. alcohol;
  • the separated solid is dried under reduced pressure at a drying temperature of 30 to 80 ° C, and a vacuum degree of 650 to 760 mmHg under reduced pressure.
  • the weight-to-volume ratio of cavigliflozin to good solvent is from 1:3 to 8 g/ml.
  • the curing of the cardinol is generally carried out under stirring.
  • the cardinal crystal form I of the present invention has good stability and is advantageous for preparation of various preparations.
  • the preparation process of the card Glycine crystal form I of the invention is simple, can be completed by ordinary equipment and mild conditions, and is suitable for industrial production.
  • Fig. 1 is an X-ray diffraction chart of the form of Form I of the present invention.
  • Figure 2 is a DSC-TGA diagram of the card Glycine Form I of the present invention.
  • Figure 3 is an infrared spectrum of the cardiglio form I of the present invention.
  • the X-ray powder diffraction pattern of the present invention was collected on a Shimadzu XRD-6000 X-ray diffractometer.
  • the parameters of the X-ray powder diffraction analysis method of the present invention are specifically as follows:
  • the DSC-TGA pattern of the card Glycine Form I of the present invention was taken on a Swiss Mettler 1100 LF instrument.
  • the parameters of the DSC-TGA analysis method described in the present invention are as follows:
  • the IR spectrum (KBr pellet) of the cardinol crystal form I of the present invention was collected on a Fourier transform infrared spectrometer (Nicolet Atavar FT-IR330) of Nicolet, USA.
  • Example 1 100 g of calpaparin dissolved in a mixed solvent of 300 ml of methanol and 100 ml of water at 50 to 55 ° C, and the temperature was lowered to 30 to 35 ° C, 200 ml of water was added dropwise with stirring, and a large amount of solid was precipitated after the addition; The filter cake was dried under reduced pressure at 700 to 760 mmHg at 40 to 50 ° C to obtain 96 g of cagliflozin. HPLC: 99.89%.
  • the results of testing X-ray powder diffraction are shown in Figure 1; the results of testing DSC-TGA are shown in Figure 2; the results of testing infrared spectroscopy are shown in Figure 3.
  • calpaparin 80g is dissolved in a mixed solvent of 99 ml of ethanol and 150 ml of water at 65-70 ° C, mixed in a solvent, and cooled to between 35 and 40 ° C.
  • 550 ml of water is added dropwise with stirring, and after the addition is completed, A large amount of solid precipitated; cooled to room temperature, filtered, and the filter cake was dried under reduced pressure at 650-760 mmHg at 45-50 ° C to obtain 67 g of cagliflozin.
  • HPLC 99.88%.
  • X-ray powder diffraction analysis was carried out as a cardinal crystal form I.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明公开了一种卡格列净晶型Ⅰ，该晶型的X-射线粉末衍射图谱在2θ值为4.4±0.2°、8.4±0.2°、16.8±0.2°、17.5±0.2°、18.0±0.2°、22.8±0.2°的位置有特征衍射峰。该晶型理化性质稳定，适合其各种制剂的制造。

Description

一种卡格列净晶型I及其制备方法 技术领域
本发明属于药物化学领域，具体涉及卡格列净的一种新晶型即卡格列净晶型I及其制备方法。
背景技术
卡格列净(Canagliflozin)，化学名为：1-(β-D-吡喃葡萄糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯，结构如式Ⅰ所示，其可通过CN101801371公开的方法制备。
Figure PCTCN2015075180-appb-000001
卡格列净是美国Johnson&Johnson公司研发的一种选择性2型钠葡萄糖协同转运蛋白(SGLT2)抑制剂。2013年3月29日，美国食品和药品监督管理局(FDA)批准其配合饮食控制和运动，用于改善2型糖尿病成年患者的血糖控制。
卡格列净属水难溶性化合物，在制剂中一般以固体形式使用，因此对其晶型的研究具有十分重要的意义。
专利CN101573368公开了一种卡格列净的半水合物晶型，其在CuKα源的X-射线粉末衍射图谱中具有4.36°、13.54°、16.00°、19.32°和20.80°等2θ值特征衍射峰；该晶型通过在乙酸乙酯/二乙醚/水或者丙酮/水体系中固化而得。
专利CN101801371公开了另一种晶型，其在CuKα源的X-射线粉末衍射图谱中具有10.9°、15.5°、17.3°、18.8°和20.3°等2θ值特征衍射峰；该晶型通过在乙酸乙酯/正庚烷/水体系中固化而得。
专利WO2013064909公开了卡格列净与L-脯氨酸，D-脯氨酸、L-苯丙氨酸的共晶及卡格列净的无定型形式。
专利CN103554092公开了卡格列净一种晶型B，其在CuKα源的X-射线粉末衍射图谱中具有6.3°、9.4°和12.6°等2θ值特征衍射峰；该晶型是通过将卡格列净溶于水和有机溶剂的混合溶剂后室温缓慢挥发而得。
专利CN103588762公开了卡格列净一种晶型C，其在CuKα源的X-射线粉末衍射图谱中具有6.5°、9.8°和16.4°等2θ值特征衍射峰；该晶型是通过将卡格列净溶于水和有机溶剂的混合溶剂后室温缓慢挥发而得。该专利还公开了一种卡格列净晶型D,其在CuKα源的X-射线粉末衍射图谱中具有6.8°、13.6°和20.5°等2θ值特征衍射峰；该晶型是通过将其制备的晶型C加热至50～90℃而得。
专利CN103641822公开了卡格列净另一种半水合物晶型，其在CuKα源的X-射线粉末衍射图谱中具有3.86°、15.46°、17.30°、18.80°、19.10°和20.26°等2θ值特征衍射峰；该晶型是通过将卡格列净溶于良溶剂中，再添加非良溶剂和水的混合溶剂固化而得。
专利CN103980261公开了卡格列净一种晶型A，其在CuKα源的X-射线粉末衍射图谱中具有3.7°、7.7°、7.9°、11.5°、13.1°、13.5°、14.3°、15.5、17.3°、18.8°、19.3°、20.3°、22.5°、22.7°、23.2°和23.4°等2θ值特征衍射峰；该晶型是通过将卡格列净溶于醇类溶剂中，配制成0.05～0.5g/ml的悬浮溶液，15～43℃溶解后再添加3～10倍溶析剂固化而得。
专利CN103980262公开了卡格列净另一种晶型B，其在CuKα源的X-射线粉末衍射图谱中具有3.4°、6.6°、12.6°、13.2°、15.3°、15.6°、16.5°、19.4、19.8°和23.7°等2θ值特征衍射峰；该晶型是通过将卡格列净溶于醇类溶剂中，配制成0.1～0.5g/ml的溶液，48～70℃蒸发溶剂而得。
专利CN103936725公开了卡格列净另一种晶型C，其在CuKα源的X-射线粉末衍射图谱中具有3.4°、6.5°、12.7°、15.8°、19.8°、24.3°、24.8°和29.1°等2θ值特征衍射峰；该晶型是通过将卡格列净溶于有机良溶剂中，配制成0.05～0.3g/ml的溶液，溶解后加入不良溶剂在-20～10℃固化而得。
专利WO2014180872公开了卡格列净另外一种晶型，其在CuKα源的X-射线粉末衍射图谱中具有5.4°、6.7°、13.2°、16.1°、19.6°和24.1°等2θ值特征衍射峰；该晶型是通过将卡格列净的无定型形式在水中转化得到。
本发明人在研究卡格列净晶型的过程中，制备出卡格列净的一种新晶型，该晶型制备简单，物理化学性质稳定，容易保存，有利于制成各种制剂。
发明内容
本发明的目的在于提供一种卡格列净的新晶型，该晶型制备工艺简便、物理化学稳定性优良，适用于多种制剂的制造和工业化生产。
本发明提供的卡格列净新晶型，在本文本中被定义为卡格列净晶型I。
本发明的卡格列净晶型I，其X-射线粉末衍射图谱在2θ值为4.4±0.2°、8.4±0.2°、16.8±0.2°、17.5±0.2°、18.0±0.2°、22.8±0.2°的位置对应有特征衍射峰。
上述本发明的卡格列净晶型I，还进一步包括其X-射线粉末衍射图谱在2θ值为12.1±0.2°、12.6±0.2°、15.3±0.2°、19.3±0.2°、20.4±0.2°、22.2±0.2°、23.0±0.2°、24.6±0.2°和26.6±0.2°的位置对应有特征衍射峰。
在一实施方案中，本发明的卡格列净晶型I，其X-射线粉末衍射具有如图1所示的特征衍射峰。
本发明的卡格列净晶型I，其DSC扫描图在90～95℃之间有一吸热峰，特别是在约93℃达到峰值；其TGA扫描图在加热至180℃时，具有约3.97％的失重。
本发明的卡格列净晶型I，其DSC-TGA扫描图具有如图2所示的特征。
本发明提供的卡格列净新晶型，其红外吸收约在1647cm-1有特征吸收峰。
在一实施方案中，本发明的卡格列净新晶型，其红外吸收扫描图具有如图3所示的特征。
本发明的卡格列净晶型Ⅰ的X-射线粉末衍射测试是在环境温度及环境湿度下，经日本岛津XRD-6000型X-射线衍射仪的CuKα源
Figure PCTCN2015075180-appb-000002
测定完成的。测试过程中，由于受到多种因素如测试样品的粒度、测试时样品的处理方法、仪器、测试参数、测试操作等的影响，同一种晶型所测得的X-射线粉末衍射图谱的出峰位置或峰强度会有一定的差异。X-射线粉末衍射图谱中衍射峰2θ值的实验误差可为±0.2°。“环境温度”一般是0～40℃；“环境湿度”一般是30％～ 80％的相对湿度。
本发明的卡格列净晶型Ⅰ的DSC-TGA分析条件是在环境温度及环境湿度下，经瑞士Mettler 1100LF型仪器测试完成。以高纯Ar气以50ml/min的流速吹扫，以10℃/min的速度进行程序升温，升温范围为室温至300℃进行测试。“环境温度”一般是0～40℃；“环境湿度”一般是30％～80％的相对湿度。
本发明的卡格列净晶型Ⅰ的IR光谱分析是经美国Nicolet公司的傅立叶变换红外光谱仪(Nicolet Atavar FT-IR330)在相对湿度一般小于80％,温度一般是15～30℃下测试。测试时用KBr进行压片，分光光度计用聚苯乙烯进行校正(波长)。测试过程中，由于受到多种因素(如研磨的颗粒大小、压片程度、以及空气中的相对湿度等)的影响，所测得的IR光谱图谱的出峰位置或峰强度会有一定的差异。IR光谱图谱中的特征吸收峰值的实验误差可为±2cm-1。
本发明的目的还提供了一种制备卡格列净晶型Ⅰ的方法，该方法包括将卡格列净在良溶剂与水的混合溶剂中加热溶解，然后加水使其固化。
在一具体实施方案中，本发明的一种制备卡格列净晶型Ⅰ的方法，包括以下步骤：
1)将卡格列净用适宜良溶剂与水的混合溶剂溶解，得到卡格列净溶液，其中，溶解温度为30～100℃，优选50～80℃；
2)然后将卡格列净溶液的温度降至20～60℃，优选30～50℃，加入水使卡格列净固化；
3)将析出的固体进行过滤或离心分离；
4)任选的，将分离得到的固体进行干燥，干燥温度一般为30～80℃，优选40～50℃，所述干燥可以是常压干燥，也可以是减压干燥，减压时真空度一般是300～760mmHg，优选650～760mmHg。
在上述具体实施方案中，本发明的方法，步骤1)中所说适宜的良溶剂包括甲醇、乙醇、异丙醇、丙酮、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜、N,N-二甲基乙酰胺、二氧六环等或它们的混合物，优选甲醇、乙醇、异丙醇或它们的混合物。
在上述具体实施方案中，本发明的方法，良溶剂与水的体积比为1：1-3。卡格列净与良溶剂的重量体积比为1：3-8g/ml
在一优选具体实施方案中，本发明的一种制备卡格列净晶型Ⅰ的方法，包括以下步骤：
1)将卡格列净用适宜的良溶剂与水的混合溶剂溶解，得到卡格列净溶液，其中，溶解温度为50～80℃，所述适宜的良溶剂选自甲醇、乙醇和异丙醇；
2)然后将卡格列净溶液的温度降至30～50℃，加入水使卡格列净固化；
3)将析出的固体进行过滤或离心分离；
4)任选的，将分离得到的固体进行减压干燥，干燥温度为30～80℃，减压时真空度为650～760mmHg，
其中，所述适宜的良溶剂与水的体积比为1：1-3。
在上述优选具体实施方案中，卡格列净与良溶剂的重量体积比为1：3-8g/ml。
在上述实施方案中，本发明的方法，卡格列净的固化一般是在搅拌条件下完成。
为了说明本发明卡格列净晶型Ⅰ的稳定性，选取了实施例1制得的卡格列净晶型Ⅰ进行了稳定性研究，结果如下表。
表 卡格列净晶型Ⅰ的稳定性测试结果
Figure PCTCN2015075180-appb-000003
由上表可以看出，本发明的卡格列净晶型I，稳定性较好，有利于制成各种制剂。
本发明的卡格列净晶型Ⅰ制备工艺简便，采用普通设备及温和条件就能完成，适于工业化生产。
附图说明
图1是本发明的卡格列净晶型Ⅰ的X-射线衍射图。
图2是本发明的卡格列净晶型Ⅰ的DSC-TGA图。
图3是本发明的卡格列净晶型Ⅰ的红外光谱图。
具体实施方式
下面将结合实施例对本发明作进一步说明，可以使本领域的技术人员更全面的理解本发明的实质，但不以任何方式限制本发明的范围。
本发明所述的X射线粉末衍射图是在日本岛津XRD-6000型X-射线衍射仪上采集。本发明所述的X射线粉末衍射分析方法的参数具体如下：
X射线反射参数：CuKα
CuKα源
Figure PCTCN2015075180-appb-000004
电压：40千伏特(KV)
电流：30毫安培(mA)
发散狭缝：自动
扫描模式：连续
扫描范围：2～45度
取样步长：0.02度
扫描速度：2度/分钟
本发明的卡格列净晶型Ⅰ的DSC-TGA图是在瑞士Mettler 1100LF型仪器上采集。本发明所述的DSC-TGA分析方法的参数具体如下：
温度范围：室温～300℃
扫描速率：10℃/min
保护气体：Ar气50ml/min
本发明的卡格列净晶型Ⅰ的IR光谱图(KBr压片)是在美国Nicolet公司的傅立叶变换红外光谱仪(Nicolet Atavar FT-IR330)上采集。
实施例1100g卡格列净在50～55℃溶于300ml甲醇与100ml水的混合溶剂中，降温至30～35℃之间，搅拌下滴加入200ml水，滴加完后，大量固体析出；过滤，滤饼在700～760mmHg，40～50℃下减压干燥得卡格列净96g，HPLC:99.89％。测试X-射线粉末衍射结果见图1；测试DSC-TGA结果见图2；测试红外光谱结果见图3。
实施例2卡格列净晶型Ⅰ的制备
80g卡格列净在65～70℃溶于9溶于350ml乙醇与150ml水的混合溶剂中，混合溶剂中，降温至35～40℃之间，搅拌下滴加入550ml水，滴加完后，大量固体析出；冷至室温，过滤，滤饼在650～760mmHg，45～50℃下减压干燥得卡格列净67g，HPLC:99.88％。经X-射线粉末衍射分析为卡格列净晶型Ⅰ。
实施例3卡格列净晶型Ⅰ的制备
100g卡格列净在70～80℃溶于800ml异丙醇与300ml水的混合溶剂中，降温至40～50℃之间，搅拌下滴加入2100ml水，滴加完后，大量固体析出；冷至室温，过滤，滤饼在680～760mmHg，45～50℃下减压干燥得卡格列净92g，HPLC:99.92％。经X-射线粉末衍射分析为卡格列净晶型Ⅰ。

Claims (10)

  1. 一种卡格列净晶型Ⅰ，其X-射线粉末衍射图谱在2θ值为4.4±0.2°、8.4±0.2°、16.8±0.2°、17.5±0.2°、18.0±0.2°、22.8±0.2°的位置有特征衍射峰。
  2. 根据权利要求1所述的晶型Ⅰ，其X-射线粉末衍射图谱还进一步包括在2θ为12.1±0.2°、12.6±0.2°、15.3±0.2°、19.3±0.2°、20.4±0.2°、22.2±0.2°、23.0±0.2°、24.6±0.2°和26.6±0.2°的位置有特征衍射峰。
  3. 根据权利要求1或2所述的晶型Ⅰ，其X-射线粉末衍射图谱实质上具有如图1的特征衍射峰。
  4. 根据权利要求1或2所述的晶型Ⅰ，其DSC扫描图在90～95℃之间有一吸热峰。
  5. 一种制备权利要求1的卡格列净晶型Ⅰ的方法，包括将卡格列净于适宜的良溶剂与水的混合溶剂中加热溶解中，再加入水使其固化。
  6. 根据权利要求5所述的方法，具体包括以下步骤：
    1)将卡格列净用适宜良溶剂与水的混合溶剂溶解，得到卡格列净溶液，其中，溶解温度为30～100℃；
    2)将卡格列净溶液降温至20～60℃，加水使卡格列净固化；
    3)将析出的固体进行过滤或离心分离；
    4)任选的，将分离得到的固体在常压或减压条件下进行干燥，干燥温度为30～80℃。
  7. 根据权利要求6所述的方法，步骤1)的溶解温度为50～80℃，步骤2)的温度为30～50℃，步骤4)的干燥温度为40～50℃。
  8. 根据权利要求5或6所述的方法，所述适宜的良溶剂包括甲醇、乙醇、异丙醇、丙酮、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜、N,N-二甲基乙酰胺、二氧六环或它们的混合物。
  9. 根据权利要求8所述的方法，所述适宜的良溶剂为甲醇、乙醇、异丙醇或它们的混合物。
  10. 根据权利要求5或6所述的方法，所述适宜的良溶剂与水的体积比为1：1-3。
PCT/CN2015/075180 2014-12-25 2015-03-27 一种卡格列净晶型i及其制备方法 Ceased WO2016101432A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA2971752A CA2971752A1 (en) 2014-12-25 2015-03-27 Crystal form i of canagliflozin and preparation method thereof
US15/538,965 US20170342061A1 (en) 2014-12-25 2015-03-27 Crystal form i of canagliflozin and preparation method thereof
AU2015372234A AU2015372234B2 (en) 2014-12-25 2015-03-27 Crystal form l of Canagliflozin and preparation method thereof
EP15871510.2A EP3239149B1 (en) 2014-12-25 2015-03-27 Crystal form i of canagliflozin and preparation method thereof
JP2017534731A JP2018500368A (ja) 2014-12-25 2015-03-27 カナグリフロジンの結晶形ｉ及びその製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410820560.1 2014-12-25
CN201410820560.1A CN104530023A (zh) 2014-12-25 2014-12-25 一种卡格列净晶型i及其制备方法

Publications (1)

Publication Number Publication Date
WO2016101432A1 true WO2016101432A1 (zh) 2016-06-30

Family

ID=52845694

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/075180 Ceased WO2016101432A1 (zh) 2014-12-25 2015-03-27 一种卡格列净晶型i及其制备方法

Country Status (7)

Country Link
US (1) US20170342061A1 (zh)
EP (1) EP3239149B1 (zh)
JP (1) JP2018500368A (zh)
CN (2) CN108003149A (zh)
AU (1) AU2015372234B2 (zh)
CA (1) CA2971752A1 (zh)
WO (1) WO2016101432A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119780366A (zh) * 2025-03-11 2025-04-08 中国食品药品检定研究院 混晶类多晶型药物的表观晶型与杂质形成相关关系分析方法

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530024B (zh) * 2015-02-04 2017-08-08 上海迪赛诺药业有限公司 1‑(β‑D‑吡喃葡糖基)‑4‑甲基‑3‑[5‑(4‑氟苯基)‑2‑噻吩基甲基]苯的晶型及其制备方法
CN105001214A (zh) * 2015-04-20 2015-10-28 华润赛科药业有限责任公司 一种卡格列净晶型f及其制备方法
CZ2015824A3 (cs) * 2015-11-20 2017-05-31 Zentiva, K.S. Krystalická forma Canagliflozinu a způsob její přípravy
CN105541818A (zh) * 2016-03-04 2016-05-04 浙江华海药业股份有限公司 一种卡格列净水合物新晶型及其制备方法
CN107311993A (zh) * 2017-08-09 2017-11-03 江苏德源药业股份有限公司 一种卡格列净的晶型ii及其制备方法
CN111487266B (zh) * 2020-04-30 2023-10-13 江苏德源药业股份有限公司 卡格列净半水合物药用晶型中一水合物晶型定量测定方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101573368A (zh) * 2006-12-04 2009-11-04 田边三菱制药株式会社 结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物
CN101801371A (zh) * 2007-09-10 2010-08-11 詹森药业有限公司 可用作sglt抑制剂的化合物的制备方法
CN103554092A (zh) * 2013-11-11 2014-02-05 苏州晶云药物科技有限公司 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的新晶型B及其制备方法
CN103588762A (zh) * 2013-11-27 2014-02-19 苏州晶云药物科技有限公司 坎格列净的新晶型及其制备方法
CN103641822A (zh) * 2013-10-21 2014-03-19 江苏奥赛康药业股份有限公司 一种卡格列净化合物及其药物组合物
CN103896930A (zh) * 2014-04-02 2014-07-02 安徽联创药物化学有限公司 卡格列净半水合物药用晶型的制备方法
CN103936725A (zh) * 2014-04-01 2014-07-23 天津大学 卡格列净的c晶型及其结晶制备方法
CN103980262A (zh) * 2014-04-01 2014-08-13 天津大学 卡格列净的b晶型及其结晶制备方法
WO2014180872A1 (en) * 2013-05-08 2014-11-13 Lek Pharmaceuticals D.D. NOVEL CRYSTALLINE HYDRATES OF 1-(ß-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL]BENZENE

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2451797B1 (en) * 2009-07-10 2013-04-03 Janssen Pharmaceutica, N.V. CRYSTALLISATION PROCESS FOR 1-(ß-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL]BENZENE
HUE031375T2 (en) * 2009-10-14 2017-07-28 Janssen Pharmaceutica Nv Process for the preparation of compounds useful as inhibitors of sglt2
BR112014010574A2 (pt) * 2011-10-31 2017-05-02 Scinopharm Taiwan Ltd formas cristalinas e não cristalinas de inibidores sglt2
US20160083374A1 (en) * 2013-05-30 2016-03-24 Cadila Healthcare Limited Amorphous form of canagliflozin and process for preparing thereof
CN103655539B (zh) * 2013-12-13 2019-09-13 重庆医药工业研究院有限责任公司 一种卡格列净的口服固体制剂及其制备方法
CN103980261B (zh) * 2014-04-01 2016-06-29 天津大学 卡格列净的a晶型及其结晶制备方法
CN104230907B (zh) * 2014-08-07 2017-05-10 王军 晶体制备方法及其用途

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101573368A (zh) * 2006-12-04 2009-11-04 田边三菱制药株式会社 结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物
CN101801371A (zh) * 2007-09-10 2010-08-11 詹森药业有限公司 可用作sglt抑制剂的化合物的制备方法
WO2014180872A1 (en) * 2013-05-08 2014-11-13 Lek Pharmaceuticals D.D. NOVEL CRYSTALLINE HYDRATES OF 1-(ß-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL]BENZENE
CN103641822A (zh) * 2013-10-21 2014-03-19 江苏奥赛康药业股份有限公司 一种卡格列净化合物及其药物组合物
CN103554092A (zh) * 2013-11-11 2014-02-05 苏州晶云药物科技有限公司 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的新晶型B及其制备方法
CN103588762A (zh) * 2013-11-27 2014-02-19 苏州晶云药物科技有限公司 坎格列净的新晶型及其制备方法
CN103936725A (zh) * 2014-04-01 2014-07-23 天津大学 卡格列净的c晶型及其结晶制备方法
CN103980262A (zh) * 2014-04-01 2014-08-13 天津大学 卡格列净的b晶型及其结晶制备方法
CN103896930A (zh) * 2014-04-02 2014-07-02 安徽联创药物化学有限公司 卡格列净半水合物药用晶型的制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119780366A (zh) * 2025-03-11 2025-04-08 中国食品药品检定研究院 混晶类多晶型药物的表观晶型与杂质形成相关关系分析方法

Also Published As

Publication number Publication date
US20170342061A1 (en) 2017-11-30
JP2018500368A (ja) 2018-01-11
AU2015372234B2 (en) 2019-02-14
EP3239149A4 (en) 2018-05-30
AU2015372234A1 (en) 2017-07-13
CA2971752A1 (en) 2016-06-30
EP3239149A1 (en) 2017-11-01
CN104530023A (zh) 2015-04-22
CN108003149A (zh) 2018-05-08
EP3239149B1 (en) 2021-01-27

Similar Documents

Publication Publication Date Title
WO2016101432A1 (zh) 一种卡格列净晶型i及其制备方法
CN104130302A (zh) 一种核苷药物的晶型及其制备方法
CN101139325B (zh) 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸晶型及其制备方法
CN106397298B (zh) 含吲哚布芬的药物组合物和用途
CN103965116B (zh) 半5-氟胞嘧啶盐、其制备方法及应用
CN103980226A (zh) 盐酸阿考替胺水合物晶型及其制备方法
JP6929769B2 (ja) ６−アリールアミノピリドンカルボキサミド化合物の結晶、およびその製造方法
WO2018137502A1 (zh) 一种丹酚酸a的晶型及其制备方法
CN103833733B (zh) 一种替尼类药物新晶型
CN107188800B (zh) 具有晶型a形式的甜菊醇晶体、其制备方法及应用
CN105601500B (zh) 洛索洛芬钠倍半水合物晶型及其制备方法
CN102321048A (zh) 糖精瑞格列奈无定形物
CN102321141B (zh) 一种17α-乙酰氧基-11β-（4-N,N-二甲氨基苯基）-19-去甲孕甾-4，9-二烯-3,20-二酮的无定形物及其制备方法
CN113336718A (zh) 依帕司他-二甲双胍盐及其制备方法和应用
CN114796331A (zh) 一种制备枳壳总黄酮的方法
CN107216314A (zh) 一种盐酸替匹嘧啶的晶型及其制备方法
CN101747272B (zh) 布南色林晶型b及其制备方法
CN102351835A (zh) 芒果苷元晶型及其组合物、制备方法与应用
CN116143616B (zh) 丹参素钠ⅱ晶型及其制备方法
CN118141941B (zh) 含醋酸阿比特龙的药物组合物及其制备方法
CN102584743A (zh) 对二甲氨基吡啶瑞格列奈共晶
CN101812035B (zh) 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸晶型及其制备方法
CN104311447B (zh) 对乙酰氨基酚新晶型、其制备方法及复方氨酚烷胺制剂
CN115745913B (zh) 曲法罗汀多晶型及其制备方法
CN113277962B (zh) 依帕司他-二甲双胍盐水合物及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15871510

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2971752

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2017534731

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15538965

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2015871510

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2015372234

Country of ref document: AU

Date of ref document: 20150327

Kind code of ref document: A