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WO2015176677A1 - Formes cristallines et amorphisme de composé d'oxazolidinone - Google Patents

Formes cristallines et amorphisme de composé d'oxazolidinone Download PDF

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Publication number
WO2015176677A1
WO2015176677A1 PCT/CN2015/079522 CN2015079522W WO2015176677A1 WO 2015176677 A1 WO2015176677 A1 WO 2015176677A1 CN 2015079522 W CN2015079522 W CN 2015079522W WO 2015176677 A1 WO2015176677 A1 WO 2015176677A1
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Prior art keywords
crystalline form
amorphism
crystalline
xrpd
ray powder
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English (en)
Inventor
Liang Chen
Xiaojun Wang
Yinglin ZUO
Yingjun Zhang
Jiancun Zhang
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 present invention relates to the crystalline forms and amorphism of oxazolidinone compound, and a pharmaceutical composition containing the crystalline form or amorphism or a combination thereof.
  • the crystalline forms, amorphism or the pharmaceutical composition disclosed herein can be used for the manufacture of a blood coagulation factor Xa inhibitor and/or in the treatment of thromboembolism diseases.
  • the present invention also relates to a method of preparing form I.
  • Blood coagulation factor Xa is a serine protease, which can transform the prothrombin to thrombin. Blood coagulation factor Xa has a great clinical-value in anticoagulation as a target and plays an important role of controlling thrombin formation and coagulation cascade activation. Blood coagulation factor Xa mainly catalyzes the transformation of II factor to IIa factor in the interaction of intrinsic coagulation pathway and extrinsic coagulation pathway. One blood coagulation factor Xa inhibitor has the physiological effects of inhibiting 138 prothrombin molecules, because the biological signal amplification exists in the coagulation process.
  • blood coagulation factor Xa An effective and specific inhibitor of blood coagulation factor Xa could be a potential and valuable therapeutic agent to treat thromboembolism diseases in a patient.
  • Patent PCT WO 2014110971 (patent family: CN 103936763A) (incorporated herein by reference) published on July 24, 2014, disclosed an oxazolidinone compound of 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino-4-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide and its preparation method, and its structure represented by Formula (I) is as shown below.
  • This compound has a good FXa inhibition activity, and can be used as anticoagulant drug for the treatment of thromboembolic-related disorders.
  • the crystal form of compound of Formula (I) and preparation thereof were not disclosed in patent WO 2014110971.
  • Polymorphism of pharmaceuticals is a common phenomenon in drug research, which is a very important factor affecting the quality of drugs. Different crystalline forms of the same drug have significantly differences in appearance, solubility, melting point, dissolution rate, bio-availability, and so on, and which also have different influences on stability, bioavailability and curative effect of drugs. Hence, the person skilled in the art may consider the polymorphism of this compound in the drug research.
  • Amorphism is a form of polymorphism, and a non-crystaline form.
  • the amorphous drug is different from the normal crystalline drug in physicochemical properties and clinical efficacy. Therefore, also it has important significance that exploring the amorphous substance in depth in the polymorphism research of solid drug.
  • the present invention refers to crystalline forms and amorphism of the compound having 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino-4-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide (Formula (I) ) , specially refers to form I, form II, form III, form IV, form V and amorphism of the compound of Formula (I) .
  • the present invention also refers to a pharmaceutical composition containing the crystalline form or amorphism disclosed herein or a combination thereof, and uses of the crystalline forms, amorphism or the pharmaceutical composition disclosed herein for the manufacture of a blood coagulation factor Xa inhibitor and/or in the treatment of thromboembolism diseases in a patient.
  • the present invention further refers to two preparation methods of crystalline form I of the compound of Formula (I) .
  • crystalline form I was formed from the compound of Formula (I) through a reverse anti-solvent addition method; this method has low yields, and which is unsuitable for amplified production.
  • crystalline form I was formed from amorphism of the compound of Formula (I) through a rotating crystal method by heating; this method has simple and practicable operations, good reproducibility, manageable process, stable technological process, and high yields, high purity of prepared crystalline form I, which is suitable for industrial production.
  • crystalline forms of the compound (I) comprising form I, form II, form III, form IV or form V.
  • the crystalline form disclosed herein is form I having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 5.41° ⁇ 0.2°, 11.06° ⁇ 0.2°, 18.93° ⁇ 0.2°, 19.39° ⁇ 0.2°, 19.57° ⁇ 0.2°, 21.05° ⁇ 0.2°, 21.72° ⁇ 0.2°, 23.85° ⁇ 0.2°, 24.68° ⁇ 0.2°, 30.21° ⁇ 0.2° and 34.27° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form I having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 5.41° ⁇ 0.2°, 11.06° ⁇ 0.2°, 16.26° ⁇ 0.2°, 16.95° ⁇ 0.2°, 18.01° ⁇ 0.2°, 18.69° ⁇ 0.2°, 18.93° ⁇ 0.2°, 19.39° ⁇ 0.2°, 19.57° ⁇ 0.2°, 20.75° ⁇ 0.2°, 21.05° ⁇ 0.2°, 21.72° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.85° ⁇ 0.2°, 24.68° ⁇ 0.2°, 27.08° ⁇ 0.2°, 27.25° ⁇ 0.2°, 28.96° ⁇ 0.2°, 30.21° ⁇ 0.2°, 31.61° ⁇ 0.2°, 32.10° ⁇ 0.2°, 32.86° ⁇ 0.2°, 34.27° ⁇ 0.2° and 39.34° ⁇ 0.2°.
  • XRPD X-
  • the crystalline form disclosed herein is form I having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 5.41° ⁇ 0.2°, 11.06° ⁇ 0.2°, 12.64° ⁇ 0.2°, 16.26° ⁇ 0.2°, 16.66° ⁇ 0.2°, 16.95° ⁇ 0.2°, 18.01° ⁇ 0.2°, 18.69° ⁇ 0.2°, 18.93° ⁇ 0.2°, 19.39° ⁇ 0.2°, 19.57° ⁇ 0.2°, 20.13° ⁇ 0.2°, 20.75° ⁇ 0.2°, 21.05° ⁇ 0.2°, 21.72° ⁇ 0.2°, 22.23° ⁇ 0.2°, 22.96° ⁇ 0.2°, 23.39° ⁇ 0.2°, 23.85° ⁇ 0.2°, 24.68° ⁇ 0.2°, 24.96° ⁇ 0.2°, 25.74° ⁇ 0.2°, 26.36° ⁇ 0.2°, 27.08° ⁇ 0.2°, 27.25° ⁇ 0.2°
  • the crystalline form disclosed herein is form I having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form I having a differential scanning calorimetry thermogram comprising an endothermic peak at 204.81 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form I having a differential scanning calorimetry thermogram substantially the same as shown in Figure 2.
  • the crystalline form disclosed herein is form I having a Raman spectrogram comprising absorption peaks at 163 cm -1 , 246 cm -1 , 280 cm -1 , 389 cm -1 , 516 cm -1 , 582 cm -1 , 672 cm -1 , 690 cm -1 , 715 cm -1 , 730 cm -1 , 796 cm -1 , 971 cm -1 , 1035 cm -1 , 1084 cm -1 , 1117 cm -1 , 1296 cm -1 , 1325 cm -1 , 1428 cm -1 , 1556 cm -1 , 1609 cm -1 , 1666 cm -1 , 2958 cm -1 and 2991 cm -1 , and the error margin is ⁇ 2 cm -1 .
  • the crystalline form disclosed herein is form I having a Raman spectrogram substantially the same as shown in Figure 3.
  • the crystalline form disclosed herein is form I having a Fourier transform infrared spectrogram comprising absorption peaks at 418 cm -1 , 455 cm -1 , 480 cm -1 , 498 cm -1 , 516 cm -1 , 555 cm -1 , 568 cm -1 , 582 cm -1 , 605 cm -1 , 637 cm -1 , 687 cm -1 , 715 cm -1 , 739 cm -1 , 809 cm -1 , 883 cm -1 , 909 cm -1 , 937 cm -1 , 965 cm -1 , 996 cm -1 , 1025 cm -1 , 1048 cm -1 , 1087 cm -1 , 1115 cm -1 , 1153 cm -1 , 1188 cm -1 , 1217 cm -1 , 1237 cm -1 , 1290 cm -1 , 1324 cm -1 , 1344 cm -1 , 1385 cm -1 , 1427
  • the crystalline form disclosed herein is form I having a Fourier transform infrared spectrogram substantially the same as shown in Figure 4.
  • a pharmaceutical composition comprising form I disclosed herein;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • form I or the pharmaceutical composition containing form I disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases.
  • form I or the pharmaceutical composition containing I disclosed herein in the manufacture of a medicament for inhibiting the activity of blood coagulation factor Xa.
  • provided herein is a method of preventing, managing, treating or lessening thromboembolism diseases in a patient comprising administering to the patient a therapeutically effective amount of form I or the pharmaceutical composition containing form I disclosed herein.
  • provided herein is a method of inhibiting the activity of blood coagulation factor Xa comprising administering a therapeutically effective amount of form I or the pharmaceutical composition containing form I disclosed herein.
  • form I or the pharmaceutical composition containing I disclosed herein for use in preventing, managing, treating or lessening thromboembolism diseases in a patient.
  • the crystalline form disclosed herein is form II having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 9.39° ⁇ 0.2°, 19.00° ⁇ 0.2°, 19.96° ⁇ 0.2°, 21.98° ⁇ 0.2°, 24.73° ⁇ 0.2°, 27.23° ⁇ 0.2°, 27.56° ⁇ 0.2°, 28.18° ⁇ 0.2° and 37.84° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form II having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 9.39° ⁇ 0.2°, 14.65° ⁇ 0.2°, 15.85° ⁇ 0.2°, 16.90° ⁇ 0.2°, 19.00° ⁇ 0.2°, 19.96° ⁇ 0.2°, 20.99° ⁇ 0.2°, 21.98° ⁇ 0.2°, 23.07° ⁇ 0.2°, 24.73° ⁇ 0.2°, 27.23° ⁇ 0.2°, 27.56° ⁇ 0.2°, 28.18° ⁇ 0.2°, 30.36° ⁇ 0.2°, 30.86° ⁇ 0.2°, 33.43° ⁇ 0.2°, 34.68° ⁇ 0.2°, 35.22° ⁇ 0.2°, 36.24° ⁇ 0.2° and 37.84° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form II having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 9.39° ⁇ 0.2°, 12.70° ⁇ 0.2°, 14.65° ⁇ 0.2°, 15.41° ⁇ 0.2°, 15.85° ⁇ 0.2°, 16.90° ⁇ 0.2°, 19.00° ⁇ 0.2°, 19.96° ⁇ 0.2°, 20.99° ⁇ 0.2°, 21.98° ⁇ 0.2°, 22.45° ⁇ 0.2°, 23.07° ⁇ 0.2°, 23.32° ⁇ 0.2°, 24.73° ⁇ 0.2°, 25.42° ⁇ 0.2°, 27.23° ⁇ 0.2°, 27.56° ⁇ 0.2°, 28.18° ⁇ 0.2°, 29.94° ⁇ 0.2°, 30.36° ⁇ 0.2°, 30.86° ⁇ 0.2°, 31.36° ⁇ 0.2°, 33.
  • the crystalline form disclosed herein is form II having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 5.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form II having a differential scanning calorimetry thermogram comprising an endothermic peak at 194.90 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form II having a differential scanning calorimetry thermogram substantially the same as shown in Figure 6.
  • the crystalline form disclosed herein is form II having a Raman spectrogram comprising absorption peaks at 174 cm -1 , 198 cm -1 , 270 cm -1 , 336 cm -1 , 401 cm -1 , 448 cm -1 , 524 cm -1 , 559 cm -1 , 669 cm -1 , 696 cm -1 , 729 cm -1 , 797 cm -1 , 880 cm -1 , 1078 cm -1 , 1092 cm -1 , 1234 cm -1 , 1294 cm -1 , 1328 cm -1 , 1390 cm -1 , 1428 cm -1 , 1478 cm -1 , 1562 cm -1 , 1605 cm -1 , 1642 cm -1 , 1770 cm -1 , 2877 cm -1 , 2926 cm -1 , 2955 cm -1 , 2987 cm -1 and 3089 cm -1 , and the error margin is ⁇ 2 cm -1 .
  • the crystalline form disclosed herein is form II having a Raman spectrogram substantially the same as shown in Figure 7.
  • the crystalline form disclosed herein is form II having a Fourier transform infrared spectrogram comprising absorption peaks at 421 cm -1 , 481 cm -1 , 497 cm -1 , 512 cm -1 , 558 cm -1 , 584 cm -1 , 607 cm -1 , 637 cm -1 , 682 cm -1 , 727 cm -1 , 749 cm -1 , 798 cm -1 , 829 cm -1 , 881 cm -1 , 938 cm -1 , 962 cm -1 , 985 cm -1 , 999 cm -1 , 1014 cm -1 , 1027 cm -1 , 1058 cm -1 , 1098 cm -1 , 1129 cm -1 , 1157 cm -1 , 1184 cm -1 , 1204 cm -1 , 1237 cm -1 , 1291 cm -1 , 1328 cm -1 , 1348 cm -1 , 1372 cm -1 , 1391
  • the crystalline form disclosed herein is form II having a Fourier transform infrared spectrogram substantially the same as shown in Figure 8.
  • a pharmaceutical composition comprising form II disclosed herein;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • form II or the pharmaceutical composition containing form II disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases.
  • form II or the pharmaceutical composition containing II disclosed herein in the manufacture of a medicament for inhibiting the activity of blood coagulation factor Xa.
  • provided herein is a method of preventing, managing, treating or lessening thromboembolism diseases in a patient comprising administering to the patient a therapeutically effective amount of form II or the pharmaceutical composition containing form II disclosed herein.
  • provided herein is a method of inhibiting the activity of blood coagulation factor Xa comprising administering a therapeutically effective amount of form II or the pharmaceutical composition containing form II disclosed herein.
  • form II or the pharmaceutical composition containing form II disclosed herein for use in preventing, managing, treating or lessening thromboembolism diseases in a patient.
  • form II or the pharmaceutical composition containing form II disclosed herein for use in inhibiting the activity of blood coagulation factor Xa is provided herein.
  • the crystalline form disclosed herein is form III having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 12.14° ⁇ 0.2°, 15.22° ⁇ 0.2°, 17.97° ⁇ 0.2°, 19.75° ⁇ 0.2°, 20.89° ⁇ 0.2°, 24.87° ⁇ 0.2°, 26.12° ⁇ 0.2°, 28.67° ⁇ 0.2°, 29.06° ⁇ 0.2°, 29.97° ⁇ 0.2° and 34.49° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form III having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 8.94° ⁇ 0.2°, 12.14° ⁇ 0.2°, 15.22° ⁇ 0.2°, 16.13° ⁇ 0.2°, 17.97° ⁇ 0.2°, 19.00° ⁇ 0.2°, 19.75° ⁇ 0.2°, 20.49° ⁇ 0.2°, 20.89° ⁇ 0.2°, 22.40° ⁇ 0.2°, 23.43° ⁇ 0.2°, 23.83° ⁇ 0.2°, 24.45° ⁇ 0.2°, 24.87° ⁇ 0.2°, 25.05° ⁇ 0.2°, 25.77° ⁇ 0.2°, 26.12° ⁇ 0.2°, 28.67° ⁇ 0.2°, 29.06° ⁇ 0.2°, 29.52° ⁇ 0.2°, 29.73° ⁇ 0.2°, 29.97° ⁇ 0.2°, 33.
  • the crystalline form disclosed herein is form III having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 4.73° ⁇ 0.2°, 8.94° ⁇ 0.2°, 9.46° ⁇ 0.2°, 12.14° ⁇ 0.2°, 14.23° ⁇ 0.2°, 15.22° ⁇ 0.2°, 16.13° ⁇ 0.2°, 17.39° ⁇ 0.2°, 17.97° ⁇ 0.2°, 19.00° ⁇ 0.2°, 19.75° ⁇ 0.2°, 20.49° ⁇ 0.2°, 20.89° ⁇ 0.2°, 22.40° ⁇ 0.2°, 23.43° ⁇ 0.2°, 23.83° ⁇ 0.2°, 24.45° ⁇ 0.2°, 24.87° ⁇ 0.2°, 25.05° ⁇ 0.2°, 25.77° ⁇ 0.2°, 26.12° ⁇ 0.2°, 27.10° ⁇ 0.2°, 28.67°
  • the crystalline form disclosed herein is form III having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 9.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form III having a differential scanning calorimetry thermogram comprising an endothermic peak at 125.24 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form III having a differential scanning calorimetry thermogram substantially the same as shown in Figure 10.
  • the crystalline form disclosed herein is form III having a Raman spectrogram comprising absorption peaks at 201 cm -1 , 245 cm -1 , 283 cm -1 , 367 cm -1 , 407 cm -1 , 450 cm -1 , 510 cm -1 , 525 cm -1 , 571 cm -1 , 639 cm -1 , 665 cm -1 , 693 cm -1 , 714 cm -1 , 742 cm -1 , 769 cm -1 , 802 cm -1 , 864 cm -1 , 903 cm -1 , 949 cm -1 , 974 cm -1 , 1005 cm -1 , 1034 cm -1 , 1080 cm -1 , 1099 cm -1 , 1231 cm -1 , 1272 cm -1 , 1291 cm -1 , 1309 cm -1 , 1328 cm -1 , 1388 cm -1 , 1426 cm -1 , 1507 cm -1 ,
  • the crystalline form disclosed herein is form III having a Raman spectrogram substantially the same as shown in Figure 11.
  • the crystalline form disclosed herein is form III having a Fourier transform infrared spectrogram comprising absorption peaks at 416 cm -1 , 430 cm -1 , 451 cm -1 , 469 cm -1 , 484 cm -1 , 498 cm -1 , 510 cm -1 , 525 cm -1 , 554 cm -1 , 570 cm -1 , 584 cm -1 , 616 cm -1 , 639 cm -1 , 665 cm -1 , 688 cm -1 , 713 cm -1 , 727 cm -1 , 755 cm -1 , 769 cm -1 , 801 cm -1 , 816 cm -1 , 833 cm -1 , 880 cm -1 , 904 cm -1 , 939 cm -1 , 953 cm -1 , 974 cm -1 , 996 cm -1 , 1022 cm -1 , 1034 cm -1 , 1064 cm -1 , 1079
  • the crystalline form disclosed herein is form III having a Fourier transform infrared spectrogram substantially the same as shown in Figure 12.
  • a pharmaceutical composition comprising form III disclosed herein;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • form III or the pharmaceutical composition containing form III disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases.
  • form III or the pharmaceutical composition containing form III disclosed herein in the manufacture of a medicament for inhibiting the activity of blood coagulation factor Xa.
  • provided herein is a method of preventing, managing, treating or lessening thromboembolism diseases in a patient comprising administering to the patient a therapeutically effective amount of form III or the pharmaceutical composition containing form III disclosed herein.
  • provided herein is a method of inhibiting the activity of blood coagulation factor Xa comprising administering a therapeutically effective amount of form III or the pharmaceutical composition containing form III disclosed herein.
  • form III or the pharmaceutical composition containing form III disclosed herein for use in preventing, managing, treating or lessening thromboembolism diseases in a patient.
  • the crystalline form disclosed herein is form IV having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 14.98° ⁇ 0.2°, 18.26° ⁇ 0.2°, 20.41° ⁇ 0.2°, 20.76° ⁇ 0.2°, 23.13° ⁇ 0.2°, 24.28° ⁇ 0.2°, 26.56° ⁇ 0.2° and 29.67° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form IV having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 8.84° ⁇ 0.2°, 14.98° ⁇ 0.2°, 17.76° ⁇ 0.2°, 18.26° ⁇ 0.2°, 18.97° ⁇ 0.2°, 20.41° ⁇ 0.2°, 20.76° ⁇ 0.2°, 22.64° ⁇ 0.2°, 23.13° ⁇ 0.2°, 24.28° ⁇ 0.2°, 24.56° ⁇ 0.2°, 26.56° ⁇ 0.2°, 29.39° ⁇ 0.2°, 29.67° ⁇ 0.2°, 33.64° ⁇ 0.2°, 34.30° ⁇ 0.2°, 34.59° ⁇ 0.2° and 37.00° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form IV having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 8.84° ⁇ 0.2°, 9.48° ⁇ 0.2°, 14.26° ⁇ 0.2°, 14.98° ⁇ 0.2°, 16.12° ⁇ 0.2°, 16.63° ⁇ 0.2°, 17.76° ⁇ 0.2°, 18.26° ⁇ 0.2°, 18.97° ⁇ 0.2°, 19.93° ⁇ 0.2°, 20.41° ⁇ 0.2°, 20.76° ⁇ 0.2°, 22.07° ⁇ 0.2°, 22.64° ⁇ 0.2°, 23.13° ⁇ 0.2°, 24.28° ⁇ 0.2°, 24.56° ⁇ 0.2°, 25.08° ⁇ 0.2°, 25.43° ⁇ 0.2°, 26.56° ⁇ 0.2°, 28.68° ⁇ 0.2°, 29.39° ⁇ 0.2°, 29.67
  • the crystalline form disclosed herein is form IV having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 13.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form IV having a differential scanning calorimetry thermogram comprising an endothermic peak at 116.97 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form IV, which transforms to form I at a temperature from about 150 °C to about 215 °C, and form IV has a differential scanning calorimetry thermogram comprising an endothermic peak at 203.20 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form IV having a differential scanning calorimetry thermogram comprising endothermic peaks at 116.97 °C ⁇ 3 °Cand 203.20 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form IV having a differential scanning calorimetry thermogram substantially the same as shown in Figure 14.
  • the crystalline form disclosed herein is form IV having a Raman spectrogram comprising absorption peaks at 202 cm -1 , 241 cm -1 , 283 cm -1 , 381 cm -1 , 510 cm -1 , 668 cm -1 , 692 cm -1 , 714 cm -1 , 742 cm -1 , 800 cm -1 , 1035 cm -1 , 1081 cm -1 , 1228 cm -1 , 1273 cm -1 , 1305 cm -1 , 1327 cm -1 , 1428 cm -1 , 1554 cm -1 , 1608 cm -1 , 1643 cm -1 , 1703 cm -1 , 1765 cm -1 , 2924 cm-1, 2987 cm -1 and 3085 cm -1 , and the error margin is ⁇ 2 cm -1 .
  • the crystalline form disclosed herein is form IV having a Raman spectrogram substantially the same as shown in Figure 15.
  • the crystalline form disclosed herein is form IV having a Fourier transform infrared spectrogram comprising absorption peaks at 421 cm -1 , 481 cm -1 , 496 cm -1 , 511 cm -1 , 558 cm -1 , 584 cm -1 , 606 cm -1 , 637 cm -1 , 681 cm -1 , 727 cm -1 , 749 cm -1 , 798 cm -1 , 829 cm -1 , 840 cm -1 , 880 cm -1 , 894 cm -1 , 938 cm -1 , 961 cm -1 , 985 cm -1 , 999 cm -1 , 1014 cm -1 , 1027 cm -1 , 1058 cm -1 , 1098 cm -1 , 1114 cm -1 , 1128 cm -1 , 1157 cm -1 , 1184 cm -1 , 1204 cm -1 , 1237 cm -1 , 1291 cm -1 , 1328
  • the crystalline form disclosed herein is form IV having a Fourier transform infrared spectrogram substantially the same as shown in Figure 16.
  • a pharmaceutical composition comprising form IV disclosed herein;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • form IV or the pharmaceutical composition containing form IV disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases.
  • form IV or the pharmaceutical composition containing form IV disclosed herein in the manufacture of a medicament for inhibiting the activity of blood coagulation factor Xa.
  • provided herein is a method of preventing, managing, treating or lessening thromboembolism diseases in a patient comprising administering to the patient a therapeutically effective amount of form IV or the pharmaceutical composition containing form IV disclosed herein.
  • provided herein is a method of inhibiting the activity of blood coagulation factor Xa comprising administering a therapeutically effective amount of form IV or the pharmaceutical composition containing form IV disclosed herein.
  • form IV or the pharmaceutical composition containing form IV disclosed herein for use in preventing, managing, treating or lessening thromboembolism diseases in a patient.
  • the crystalline form disclosed herein is form V having single-crystal structural parameters as shown in table 1:
  • crystal parameters such as unit cell dimensions are given in standard crystallographic notation, such that the standard uncertainty for a specific value is stated in bracket.
  • the crystalline form disclosed herein is form V having a single-crystal structure substantially the same as shown in Figure 21. It can be known from Figure 21 that, the form V is a crystalline form of the chloroform solvate of the compound of Formula (I) , and each unit cell contains two molecules of the compound of Formula (I) and two molecules of chloroform, i.e. in unit cell structure, the ratio of the compound of Formula (I) to chloroform is 1: 1.
  • the crystalline form disclosed herein is form V having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 8.97° ⁇ 0.2°, 14.16° ⁇ 0.2°, 19.18° ⁇ 0.2°, 19.92° ⁇ 0.2°, 20.20° ⁇ 0.2°, 22.53° ⁇ 0.2°, 24.73° ⁇ 0.2°, 27.13° ⁇ 0.2° and 31.75° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form V having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 8.97° ⁇ 0.2°, 14.16° ⁇ 0.2°, 17.58° ⁇ 0.2°, 17.98° ⁇ 0.2°, 19.18° ⁇ 0.2°, 19.92° ⁇ 0.2°, 20.20° ⁇ 0.2°, 20.40° ⁇ 0.2°, 22.53° ⁇ 0.2°, 24.73° ⁇ 0.2°, 26.39° ⁇ 0.2°, 27.13° ⁇ 0.2°, 28.77° ⁇ 0.2°, 31.75° ⁇ 0.2° and 33.21° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form V having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 ⁇ at 4.50° ⁇ 0.2°, 8.97° ⁇ 0.2°, 10.55° ⁇ 0.2°, 13.14° ⁇ 0.2°, 14.16° ⁇ 0.2°, 16.10° ⁇ 0.2°, 16.50° ⁇ 0.2°, 17.58° ⁇ 0.2°, 17.98° ⁇ 0.2°, 19.18° ⁇ 0.2°, 19.92° ⁇ 0.2°, 20.20° ⁇ 0.2°, 20.40° ⁇ 0.2°, 20.96° ⁇ 0.2°, 21.23° ⁇ 0.2°, 22.53° ⁇ 0.2°, 23.07° ⁇ 0.2°, 23.47° ⁇ 0.2°, 24.11° ⁇ 0.2°, 24.73° ⁇ 0.2°, 25.94° ⁇ 0.2°, 26.39° ⁇ 0.2°, 26.70°
  • the crystalline form disclosed herein is form V having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 22.
  • XRPD X-ray powder diffraction
  • the crystalline form disclosed herein is form V having a differential scanning calorimetry thermogram comprising an endothermic peak at 106.98 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form V, which transforms to form I and form II at a temperature from about 175 °C to about 210 °C, and the form V has a differential scanning calorimetry thermogram comprising endothermic peaks at 193.82 °C ⁇ 3 °Cand 203.62 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form V having a differential scanning calorimetry thermogram comprising endothermic peaks at 106.98 °C ⁇ 3 °C, 193.82 °C ⁇ 3 °C and 203.62 °C ⁇ 3 °C.
  • the crystalline form disclosed herein is form V having a differential scanning calorimetry thermogram substantially the same as shown in Figure 23.
  • the crystalline form disclosed herein is form V, which has a weight loss of 16.59%measured by thermogravimetric analysis in a temperature range from about 50 °C to about 150 °C; the error margin is ⁇ 0.1%.
  • the crystalline form disclosed herein is form V having a thermogravimetric analysis pattern substantially the same as shown in Figure 24.
  • a pharmaceutical composition comprising form V disclosed herein;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • form V or the pharmaceutical composition containing form V disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases.
  • form V or the pharmaceutical composition containing form V disclosed herein in the manufacture of a medicament for inhibiting the activity of blood coagulation factor Xa.
  • provided herein is a method of preventing, managing, treating or lessening thromboembolism diseases in a patient comprising administering to the patient a therapeutically effective amount of form V or the pharmaceutical composition containing form V disclosed herein.
  • provided herein is a method of inhibiting the activity of blood coagulation factor Xa comprising administering a therapeutically effective amount of the crystalline form V or the pharmaceutical composition containing form V disclosed herein.
  • form V or the pharmaceutical composition containing form V disclosed herein for use in preventing, managing, treating or lessening thromboembolism diseases in a patient.
  • form V or the pharmaceutical composition containing form V disclosed herein for use in inhibiting the activity of blood coagulation factor Xa is provided herein.
  • an amorphism of a compound having Formula (I) wherein the amorphism has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 17.
  • XRPD X-ray powder diffraction
  • the amorphism disclosed herein has a glass transition temperature of 107.44 °C ⁇ 3 °C.
  • the amorphism disclosed herein transforms to form I at a temperature from about 140 °C to about 215 °C, and the amorphism has a differential scanning calorimetry thermogram comprising an endothermic peak at 203.43 °C ⁇ 3 °C.
  • the amorphism disclosed herein has a differential scanning calorimetry thermogram substantially the same as shown in Figure 18.
  • the amorphism disclosed herein has a Raman spectrogram comprising absorption peaks at 181 cm -1 , 276 cm -1 , 392 cm -1 , 425 cm -1 , 512 cm -1 , 672 cm -1 , 694 cm -1 , 739 cm -1 , 795 cm -1 , 1080 cm -1 , 1120 cm -1 , 1298 cm -1 , 1328 cm -1 , 1427 cm -1 , 1549 cm -1 , 1612 cm-1, 2981 cm -1 and 3088 cm -1 , and wherein the error margin is ⁇ 2 cm -1 .
  • the amorphism disclosed herein has a Raman spectrogram substantially the same as shown in Figure 19.
  • the amorphism disclosed herein has a Fourier transform infrared spectrogram comprising absorption peaks at 419 cm -1 , 487 cm -1 , 516 cm -1 , 548 cm -1 , 581 cm -1 , 605 cm -1 , 636 cm -1 , 689 cm -1 , 720 cm -1 , 747 cm -1 , 816 cm -1 , 883 cm -1 , 939 cm -1 , 968 cm -1 , 998 cm -1 , 1023 cm -1 , 1060 cm -1 , 1099 cm -1 , 1121 cm -1 , 1156 cm -1 , 1191 cm -1 , 1216 cm -1 , 1245 cm -1 , 1291 cm -1 , 1327 cm -1 , 1347 cm -1 , 1390 cm -1 , 1427 cm -1 , 1478 cm -1 , 1514 cm -1 , 1551 cm -1 , 1585 cm
  • the amorphism disclosed herein has a Fourier transform infrared spectrogram substantially the same as shown in Figure 20.
  • the amorphism disclosed herein has a weight loss ratio of about 1.75%to about 4.10%measured by thermogravimetric analysis at a high temperature from about 50 °C to about 150 °C.
  • a pharmaceutical composition comprising the amorphism;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • amorphism or the pharmaceutical composition containing the amorphism disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases.
  • amorphism or the pharmaceutical composition containing the amorphism disclosed herein in the manufacture of a medicament for inhibiting the activity of blood coagulation factor Xa.
  • provided herein is a method of preventing, managing, treating or lessening thromboembolism diseases in a patient comprising administering to the patient a therapeutically effective amount of the amorphism or the pharmaceutical composition containing the amorphism disclosed herein.
  • provided herein is a method of inhibiting the activity of blood coagulation factor Xa comprising administering a therapeutically effective amount of the amorphism or the pharmaceutical composition containing the amorphism disclosed herein.
  • amorphism or the pharmaceutical composition disclosed herein containing the amorphism for use in preventing, managing, treating or lessening thromboembolism diseases in a patient.
  • amorphism or the pharmaceutical composition containing the amorphism disclosed herein for use in inhibiting the activity of blood coagulation factor Xa is provided herein.
  • a pharmaceutical composition comprising any one of the crystalline forms or the amorphism disclosed herein or a combination thereof; the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • provided herein is use of the crystalline forms or the amorphism or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases.
  • the thromboembolism diseases comprise myocardial infarction, stenocardia, reocclusion and restenosis after angioplasty or aortocoronary artery bypass surgery, stroke, transitory ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses.
  • provided herein is use of the crystalline forms or the amorphism or the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting the activity of blood coagulation factor Xa.
  • crystalline forms or the amorphism or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening thromboembolism diseases in a patient; the use comprises administering to the patient a therapeutically effective amount of the crystalline form or the amorphism or the pharmaceutical composition disclosed herein.
  • provided herein is a method for preparing the crystalline form I of a compound having formula (I) disclosed herein comprising transforming an amorphism of the compound of formula (I) to form I by heating.
  • the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out at a temperature from about 170 °C to about 200 °C; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out at a temperature from about 180 °C to about 190 °C; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out at a temperature of about 185 °C; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out at a temperature of about 180 °C; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out at a temperature of about 190 °C.
  • the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out for 2 to 24 hours; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out for 5 to 24 hours; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out for 5 to 12 hours; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out for 5 to 7.5 hours; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out for 5 hours; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by heating is carried out for 5.5 hours; In other embodiments, wherein the transforming an amorphism of the compound of formula (I) to the form I by
  • the heating is carried out under aerobic or anaerobic condition, and the anaerobic condition is vacuum or inert gas protection.
  • the heating is carried out by vacuum drying or blast drying.
  • the method of preparing the crystalline form I further comprises preparation of the amorphism of the compound of Formula (I) which comprising: step (a) dissolving completely the compound of Formula (I) in a solvent by heating; and step (b) preparing the amorphous form of compound of Formula (I) by spray drying of the solution obtained from step (a) .
  • the aims of the heating are to make the raw materials dissolve completely, save cost and improve yield; the heating temperature is related to the boiling point of the solvent that used and the amount of the solvent that used.
  • the method of preparing the amorphism disclosed herein wherein the solvent is methanol, ethanol, acetone, isopropanol, toluene, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, hexane or a combination thereof.
  • the method of preparing the amorphism disclosed herein wherein the solvent is ethanol, dichloromethane or a combination thereof.
  • the solvent is a mixture of ethanol and dichloromethane; in other embodiments, wherein the solvent is a mixture of ethanol and dichloromethane in a volume ratio of 1/4; in other embodiments, wherein the solvent is a mixture of ethanol and dichloromethane in a volume ratio of 1/2.4.
  • the method of preparing the amorphism disclosed herein wherein the amount of the solvent is according to the ratio of the total volume of the solvent to the quality of the compound of Formula (I) , which is ranged from 10 mL/1 g to 12 mL/1 g. In other embodiments, wherein the amount of the solvent is according to the ratio of the total volume of the solvent to the quality of the compound of Formula (I) , which is 10 mL/1 g.
  • the yield of the amorphism prepared through spray drying disclosed herein is affected by air inlet temperature and air outlet temperature of apparatus, system pressure in spray drying process, and other factors.
  • air inlet temperature, the air outlet temperature and the system pressure in spray drying process, etc are associated with the type of the apparatus, the solvent, and other factors.
  • the air inlet temperature in spray drying process at the beginning is 90 °C, and which is then gradually transferred to 100 °C when the apparatus operates smoothly, and the air outlet temperature is controlled between 45 °C and 55 °C; in other embodiments, wherein the air inlet temperature in spray drying process at the beginning is 80 °C, and which is then gradually transferred to 100 °C when the apparatus operates smoothly, and the air outlet temperature is controlled between 45 °C and 55 °C; in other embodiments, wherein the air inlet temperature in spray drying process is 100 °C, and the air outlet temperature is 54 °C; in other embodiments, wherein the air inlet temperature in spray drying process is 80 °C, and the air outlet temperature is 48 °C; in other embodiments, wherein the air inlet temperature in spray drying process is 90 °C, and the air outlet temperature is 51 °C; in other embodiments, wherein the air inlet temperature in spray drying process is 80 °C, and the air outlet temperature is 48 °C.
  • any solvent so long as it can dissolve the raw materials to some extent and does not affect the quality thereof, all are within the scope of the invention.
  • the present invention provides the preferred solvents used in each reaction step.
  • the present invention provides solubility test, stability test, hygroscopicity test and pharmacokinetics test of the crystalline form and amorphism described herein, and the results are as shown in tables 5 to 9, and figures 25 to 27.
  • solubility test results of form I, form II or amorphism are as shown in table 5.
  • the solubility of form I, form II or amorphism is better than that of the compound of Formula (I) prepared according to the reference, i.e. the solubility of form I, form II or amorphism is evidently improved, which is benefit for improving drug effect and reducing drug loading capacity.
  • the stability test results of form I, form II or amorphism are as shown in table 7 and table 8.
  • the appearances and purities of form I, form II or amorphism have no obvious variation under high temperature (60 °C) and/or high humidity (25°C, RH 90% ⁇ 5%) , and the quality of which is stable.
  • the crystalline form I, form II or amorphism of the present invention has a good stability, and which can better avoid changes in the bioavailability and drug effect in the process of drug storage or drug development.
  • the hygroscopicity test results of form I, form II or amorphism are as shown in table 9 and figures 25 to 27.
  • the hygroscopic features and definition of hygroscopic weight gain are summarized in table 2 (deriving from Chinese Pharmacopoeia 2010, appendix XIX J: Guideline on pharmaceutical hygroscopicity test, test conditions: 25°C ⁇ 1°C, Relative Humidity 80%) .
  • the crystalline form I has slight hygroscopicity; form II has almost no hygroscopicity; the amorphism has hygroscopicity, but there is no obvious increase in the weight on the hygroscopicity; i.e. form I, form II or amorphism is not easy to deliquesce under high humidity conditions, which is benefit for a long-term storage of drug.
  • the crystalline forms and amorphism of the invention are all have good biological activities, and also have good solubilities, high stabilities, which are suitable for pharmaceutical use.
  • crystalline form refers to a solid having a highly regular chemical structure, including, but not limited to, a single-component or multiple-component crystal, and/or a polymorph, a solvate, a hydrate, a clathrate, a co-crystal, a salt of a compound, solvates of salts, hydrates of salts. Crystalline forms of a substance can be obtained by a number of methods, as known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces such as, e.g., in nanopores or capillaries, crystallization on surfaces or templates such as, e.g., on polymers, crystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent-drop grinding.
  • additives such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent-drop grinding.
  • Amorphism or “amorphous form” refers to substance forming by particle (such as molecule, atom, ion) arranged in no periodic in three-dimensional space, which is characterized by a diffused X-ray powder diffraction pattern with no sharp peaks. Amorphism is a special physical form of solid substance, the ordered structural characteristics in a part of amorphous substance imply there are innumerable links between amorphous substance and crystal substance. Amorphous substance can be obtained through many methods as known in the art. These methods include, but are not limited to, rapid freezing method, anti-solvent flocculence, ball-milling method, spray drying method, freeze-drying method, wet granulating method and solid dispersion technique, and the like.
  • solvent means a substance, typically a liquid, that is capable of completely or partially dissolving another substance, typically a solid.
  • Solvents for the practice of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloromethane, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, to
  • anti-solvent means a fluid which promotes precipitation from the solvent of the product (or of a precursor for the product) .
  • the anti-solvent may comprise a cold gas, or a fluid which promotes the precipitation via a chemical reaction, or which decreases the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature or it may be a different liquid from the solvent.
  • solvate means having on a surface, in a lattice or on a surface and in a lattice, a solvent such as water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloromethane, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methylethylketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof etc.
  • a solvent such as water,
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or on the surface and in the lattice, is water. Hydrates may or may not have solvents other than water on the surface, in the lattice or on the surface and in the lattice of a substance.
  • Crystalline form or amorphism can be identified through multiple technological means, such as X-ray powder diffraction (XRPD) , infrared spectroscopy (IR) , melting point, differential scanning calorimetry (DSC) , thermogravimetry analysis (TGA) , nuclear magnetic resonance, raman spectroscopy, single-crystal X-ray diffraction, solution calorimetry, scanning electron microscope (SEM) , quantitative analysis, solubility, dissolution velocity, etc.
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetry analysis
  • SEM scanning electron microscope
  • XRPD X-ray powder diffraction
  • the measurement of 2 ⁇ in XRPD pattern could have some experimental error, for example the measurements of 2 ⁇ in XRPD pattern could be different because of different instruments and different samples. Therefore, the value of 2 ⁇ is not absolute. According to the state of the instrument for the experiment disclosed herein, the error margin in 2 ⁇ of the characteristic peaks is ⁇ 0.2°.
  • DSC Differential scanning calorimetry
  • sample and inert reference compound usually ⁇ -Al 2 O 3
  • the relative peak height of DSC thermogram depends on many factors related to sample preparation and geometry of the instrument, while the peak position is relatively insensitive to experiment details.
  • the crystalline form disclosed herein is characterized by a DSC thermogram having some peaks in certain positions, which is substantially the same as DSC thermogram provided in appended figures of the present invention.
  • the DSC thermogram could have some experimental error, for example the peak position and the peak value in DSC thermogram could exist a little difference because of different instruments and different samples. Therefore, the peak position and the peak value in DSC thermogram are not absolute. According to the state of the instrument for the experiment disclosed herein.
  • the error margin in the melting peaks is ⁇ 3 °C.
  • Glass transition is a transition of non-crystalline substance between elastomeric state and glassy state, which is an intrinsic quality of the substance; the temperature corresponding to glass transition is glass transition temperature (Tg) , which is an important physical property of non-crystalline substance. Glass transition is a phenomenon related with the molecular motion. Therefore, glass transition temperature (Tg) mainly depends on the substance structure, which is relatively insensitive to experimental details.
  • the glass transition temperature (Tg) of the amorphism disclosed herein is measured through differential scanning calorimetry (DSC) , which is characterized by having a glass transition temperature of 107.44 °C. According to the state of the instrument for the experiment disclosed herein, the error margin in the melting peaks is ⁇ 3 °C.
  • DSC Differential scanning calorimetry
  • the solid having same chemical composition usually form different crystal structural polymorph (or called modification) under different thermodynamic conditions, this phenomenon is called polymorphism.
  • the transformations among the modifications will occur when the temperature and pressure change, this phenomenon is called crystal transition.
  • the properties of crystalline form are largely changed such as mechanics, electronics, magnetic because of crystal transition.
  • the crystal transition process could be described in differential scanning calorimetry (DSC) thermogram when the transition temperature is in the measuring ranges, which is characterized by having exothermic peaks reflected this transformation and two or more endothermic peaks which respectively are characteristic endothermic peaks of different crystalline forms before and after the transformation in DSC thermogram.
  • DSC differential scanning calorimetry
  • Crystal transition could occur in the crystalline form or amorphism of the compound disclosed herein under appropriate conditions.
  • the crystalline form IV disclosed herein can transfer to the crystalline form I under high temperature (150 °C to 215 °C) , and there are endothermic peaks at 117.04 °C and 203.30 °C and exothermic peaks at temperatures from about 160 °C to about 200 °C in its DSC thermogram, wherein the endothermic peak at 203.30 °C is a characteristic endothermic peak of crystalline form I.
  • the crystalline form V disclosed herein can transfer to the crystalline form II and form I under high temperature (175 °C to 210 °C) , there are endothermic peaks at 106.98 °C, 193.82 °C and 203.62 °C and exothermic peaks at temperatures from about 196 °C to about 201 °C in its DSC thermogram, wherein the endothermic peaks at 193.82 °C and 203.62 °C are respectively a characteristic endothermic peak of crystalline form II and form I.
  • crystal transition occurrs in the amorphism disclosed herein under high temperature (140 °C to 215 °C) that is, amorphism transfers to crystalline form I, the endothermic peak at 203.30 °C and the exothermic peaks at temperatures from about 140 °C to about 180 °C are present in the DSC thermogram.
  • the error margin of each melting peak is ⁇ 3°.
  • Thermogravimetric analysis is a technology used for measuring the quality change of a substance which varies with temperature under program control, which can apply to detecting the process of the solvent loss in the crystal, sublimation and dissociation of the sample, and the crystal water and the crystal solvent contained in crystal may be speculated through analysis of the detection results.
  • the measurement of quality change described in TGA curve depends on many factors related to sample preparation and instrument, which could be different because of different instruments and different samples.
  • the crystalline form V disclosed herein loses 16.59%of weight by heating at temperatures from 50 °C to 150 °C.
  • the amorphism disclosed herein is characterized by the weight loss percentage ranged from 1.75%to 4.10%detected through TGA under high temperature (50 °C to 150 °C) . According to the state of the instrument for the experiment disclosed herein, the error margin of the quality change is ⁇ 0.1%.
  • Raman spectroscopy is a spectrophotometry used for studying vibration mode and rotation mode of molecule and other low frequency mode in one system. Different spatial structures of the same molecule have different Raman actives. Therefore, Raman spectroscopy could be used for measuring and identifying crystalline form or amorphism.
  • the peak position of Raman spectroscopy mainly depends on the substance structure, which is relatively insensitive to experimental details, and the peak intensity depends on factors such as sample preparation and instrument.
  • the crystalline form or amorphism disclosed herein is characterized by a Raman spectrogram in which the peak positions are substantially in accordance with those shown in Raman spectrograms provided in appended figures of the present invention.
  • the Raman spectrogram could have some experimental error, for example the peak position and the peak value in Raman spectrogram could be different because of different instruments and different samples. Therefore, the peak position and the peak value in Raman spectrogram are not absolute. According to the state of the instrument for the experiment disclosed herein, the error margin in the absorption peaks is ⁇ 2 cm -1 .
  • the crystalline form or amorphism disclosed herein is characterized by a Fourier infrared spectrogram in which the peak positions are substantially in accordance with those shown in a Fourier infrared spectrogram provided in appended figures of the present invention.
  • the Fourier infrared spectrogram could have some experimental error, for example the peak position and the peak value in Fourier infrared spectrogram could be different because of different instruments and different samples. Therefore, the peak position and the peak value in Fourier infrared spectrogram are not absolute. According to the state of the instrument for the experiment disclosed herein, the error margin in the absorption peaks is ⁇ 2 cm -1 .
  • term “substantially the same as shown in a figure” refers to an X-ray powder diffraction (XRPD) pattern, or a differential scanning calorimetry (DSC) thermogram, or a Raman spectrogram, or a Fourier transform infrared spectrogram having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%of the peaks shown in the figure.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • peak refers to a feature that one skilled in the art would recognize as not attributable to background noise.
  • the compound represented by Formula (I) or “The compound of Formula (I) ” disclosed herein is a solid compound 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino-4-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamideprepared by the method described in WO 2014110971.
  • a crystalline form that is “substantially pure” refers to a crystalline form that is substantially free of one or more other crystalline forms, i.e., the crystalline form has a purity of at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%; or the crystalline form has less than 20%, less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01%of the one or more other crystalline forms, based on the total volume or weight of the crystalline form and the one or more other crystalline forms.
  • a crystalline form that is “substantially free” of one or more other crystalline forms refers to a crystalline form containing less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01%of the one or more other crystalline forms, based on the total volume or weight of the crystalline form and the one or more other crystalline forms.
  • relative intensity refers to the intensity of a peak with respect to the intensity of the strongest peak in the X-ray powder diffraction (XRPD) pattern which is regarded as 100%.
  • thromboembolism diseases are diseases caused by thrombosis and thromboembolism, which also are called thrombotic diseases.
  • thrombosis is a pathological process that the visible components form emboluses in blood vessels or local endocardium, and then causes a part or complete blockage in a blood vessel and a disturbance of the corresponding circulation.
  • Thromboembolism is a pathological process that thrombus falls off from the region of thrombosis which blocks partly or completely blood vessel along with the flow of blood, and then causes blood vessel or system ischemia, anoxia, necrosis, extravasated blood and edema.
  • Some non-limiting examples of the thromboembolism diseases include arterial thromboembolic disease, intravenous thromboembolic disease and thromboembolic disease in cardiac chambers.
  • Some non-limiting examples of the specific diseases include myocardial infarction, angina pectoris (including unstable angina) , acute coronary syndrome, reocclusion and restenosis after angioplasty or aortocoronary artery bypass surgery, stroke, transient ischemic attack, peripheral arterial occlusive disease, arterial thrombosis, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal artery embolism, pulmonary embolism, thrombophlebitis, venous thrombosis and deep venous thrombosis, etc.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) ) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the present compounds are within the scope disclosed herein.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • compositions disclosed herein additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants etc, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants etc, as suited to the particular dosage form desired.
  • Some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients
  • the crystalline forms or amorphism of the compound of Formula (I) disclosed herein may be administered orally, such as tablets, capsules (each one all comprises formula released continuously or regularly) , pills, powders, granules, elixirs, tinctures, suspending agents, syrups and emulsifiers. They also may be administered intravenously (bolus or infusion) , intraperitoneally, subcutaneously or intramuscularly, all dosage forms used are well known to ordinary technical personnel in pharmaceutical field. They could be administered alone, but usually combined with a pharmaceutical carrier selected base on the selected method of administration and standard pharmacy practice.
  • the dosing schedule of crystalline form or amorphism of the compounds of Formula (I) disclosed herein may changes with the known various factors, such as pharmacokinetic characteristics of a specific reagent, and pattern and administrative way thereof; the race, age, sex, health conditions, medical conditions and weight of the receiver; the symptom property and degree; the types of treatment in parallel; the frequency of administration; the way of administration; kidney and liver function of the patient; and the desired effect.
  • a physician or veterinarian can make a decision and prescribe effective amount of drugs to prevent, offset or stop the development of a thromboembolic disease.
  • the oral daily dosage of each one active ingredient can range from about 0.001 to 1000 mg/kg of body weight according to the common guidelines to achieve the specified effects.
  • the dosage is about from 0.01 to 100 mg/kg of body weight.
  • the most preferably, the dosage is about from 1.0 to 20 mg/kg of body weight per day.
  • the most optimal dose range is from about 1 to about 10 mg/kg of body weight per minute in the transfusion process at a conventional rate for intravenous administration.
  • the crystalline forms or amorphism of the compounds of Formula (I) disclosed herein can be administered in a single dose a day, or in two, three or four divided doses a day.
  • the crystalline forms or amorphism of the compound of Formula (I) disclosed herein could be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches.
  • the dosage administration will be continuous rather than intermittent throughout the dosage regimen.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • suitable pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups etc, and consistent with conventional pharmaceutical practices.
  • the active pharmaceutical ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol etc; for oral administration in liquid form, the active pharmaceutical ingredient can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water etc.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes etc.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
  • the crystalline forms or amorphism of the compound of Formula (I) disclosed herein can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the crystalline forms or amorphism of the compound of Formula (I) disclosed herein may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue.
  • the crystalline forms or amorphism of the compounds of Formula (I) disclosed herein may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymer of polylactic acid with polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug
  • a drug for example, polylactic acid, polyglycolic acid, copolymer of polylactic acid with polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Each of these dosage units suited for administering dosage form could be contain from about 1 mg to about 100 mg active ingredient.
  • the activity ingredient accounts for about from 0.5 to 95%of the total weight.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene gycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propylparaben, and chlorobutanol.
  • a daily dosage may be about 0.1 to 100 milligrams of the crystalline forms or amorphism of the compounds of Formula (I) disclosed herein and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight.
  • the crystalline forms or amorphism of the compounds of Formula (I) disclosed herein generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.
  • the other anticoagulants include, without limitation, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran etexilate, bemiparin sodium, enoxaparin sodium, tinzaparin sodium, danaparoid sodium, fondaparinux sodium, nadroparin calcium, ardeparin sodium and parnaparin sodium, etc.
  • a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
  • a daily dosage may be about 0.1 to 1 milligrams of the crystalline forms or amorphism of the compound of Formula (I) disclosed herein, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80%when administered with the crystalline forms or amorphism of the compounds of Formula (I) disclosed herein.
  • the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination
  • the crystalline forms or amorphism of the compound of Formula (I) disclosed herein and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced) , although active ingredients are combined in one single dose unit.
  • one active ingredient may be enteric coated.
  • enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
  • One of the active ingredients may also be coated with a material which affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low-viscosity grade of hydroxypropyl methylcelluiose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
  • HPMC hydroxypropyl methylcelluiose
  • the polymer coating serves to form an additional barrier to interaction with the other component.
  • Figure 1 provides an X-ray powder diffraction (XRPD) pattern of Form I of the compound of Formula (I) .
  • Figure 2 provides a differential scanning calorimetry (DSC) curve of Form I of the compound of Formula (I) .
  • Figure 3 provides a Raman spectrogram of Form I of the compound of Formula (I) .
  • Figure 4 provides a Fourier transform infrared spectrogram of Form I of the compound of Formula (I) .
  • Figure 5 provides an X-ray powder diffraction (XRPD) pattern of Form II of the compound of Formula (I) .
  • Figure 6 provides a differential scanning calorimetry (DSC) curve of Form II of the compound of Formula (I) .
  • Figure 7 provides a Raman spectrogram of Form II of the compound of Formula (I) .
  • Figure 8 provides a Fourier transform infrared spectrogram of Form II of the compound of Formula (I) .
  • Figure 9 provides an X-ray powder diffraction (XRPD) pattern of Form III of the compound of Formula (I) .
  • Figure 10 provides a differential scanning calorimetry (DSC) curve of Form III of the compound of Formula (I) .
  • Figure 11 provides a Raman spectrogram of Form III of the compound of Formula (I) .
  • Figure 12 provides a Fourier transform infrared spectrogram of Form III of the compound of Formula (I) .
  • Figure 13 provides an X-ray powder diffraction (XRPD) pattern of Form IV of the compound of Formula (I) .
  • Figure 14 provides a differential scanning calorimetry (DSC) curve of Form IV of the compound of Formula (I) .
  • Figure 15 provides a Raman spectrogram of Form IV of the compound of Formula (I) .
  • Figure 16 provides a Fourier transform infrared spectrogram of Form IV of the compound of Formula (I) .
  • Figure 17 provides an X-ray powder diffraction (XRPD) pattern of amorphism of the compound of Formula (I) .
  • Figure 18 provides a differential scanning calorimetry (DSC) curve of amorphism of the compound of Formula (I) .
  • Figure 19 provides a Raman spectrogram of amorphism of the compound of Formula (I).
  • Figure 20 provides a Fourier transform infrared spectrogram of amorphism of the compound of Formula (I) .
  • Figure 21 provides a single-crystal structure of Form V of the compound of Formula (I) .
  • Figure 22 provides an X-ray powder diffraction (XRPD) pattern of Form V of the compound of Formula (I) .
  • Figure 23 provides a differential scanning calorimetry (DSC) curve of Form V of the compound of Formula (I) .
  • Figure 24 provides a thermogravimetric analysis diagram of Form V of the compound of Formula (I) .
  • Figure 25 provides a dynamic vapor sorption (DVS) profile of Form I of the compound of Formula (I) .
  • Figure 26 provides a dynamic vapor sorption (DVS) profile of Form II of the compound of Formula (I) .
  • Figure 27 provides a dynamic vapor sorption (DVS) profile of amorphism of the compound of Formula (I) .
  • the X-Ray powder Diffraction (XRPD) analysis method of the present invention comprises recording an X-ray powder diffraction diagram on a PANalytical Empyrean X-ray diffractometer using Cu-K ⁇ radiation (45 KV, 40 mA) .
  • a thin layer is prepared from powder sample on the single-crystal silicon wafer, and a sample spinner is used.
  • the angular range extends from 3 ° to 40 ° in 2 ⁇ with a 0.0168 ° step size in 2 ⁇ .
  • Data are collected by Data Collector software, and processed by HighScore Plus software, read by Data Viewer software.
  • X-Ray Single-crystal diffractometer of the present invention X-ray powder diffraction diagram is recorded on an Agilent Technologies Gemini A Ultra X-ray diffractometer using Cu-K ⁇ radiation (40 KV, 40 mA) and ⁇ -scan, the total number of diffraction counts is 29017, the number of observable counts (> 2 sigma (I) ) is 7286, analyzing the single-crystal structure by SHELXS-97 software.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric Analysis (TGA) : Thermogravimetric curve is recorded on a TA Q500 instrument with a thermoanalysis controller. The data are collected and analyzed by TA Instruments Thermal Solutions software. About 10 mg sample is weighed accurately in platinum sample pans, and heated under dry nitrogen purge. The scan rate is 10 °C /minute and the sample is heated from ambient temperature to 300 °C.
  • Raman spectrum Raman spectrogram is recorded on a Thermo DXR confocal laser Raman spectrometer. The data are collected and analyzed by MONIC software.
  • the laser wavelength is 780 nm
  • the laser energy is 24 Mw
  • the detection range is from 3500 cm -1 to 50 cm -1
  • the scan times is 20 times
  • the resolution ratio is from 4.7 cm -1 to 8.7 cm -1 .
  • Fourier transform infrared spectrum Fourier transform infrared spectrogram is recorded on TENSOR27 Germanic Bruker infrared spectrometer. The data are collected and analyzed by OPUS software. Using KBr disc method, the scan times is 16 times, the wave number range is from 4000 cm -1 to 400 cm -1 , the resolution ratio is 2 cm -1 .
  • the spay-drying instrument used herein is SHANGHAI OHKAWARA SCL-12 spay dryer and Swiss BUCHI B-290 spay dryer.
  • the solubility of the compound disclosed herein is measured by Aglient 1200 high performance liquid chromatography with VWD detector.
  • the hygroscopicity disclosed herein is detected on a DVS INT-Std dynamic vapor and gas absorption analyzer (England Surface Measurement Systems Company) under the humidity ranged from 0%to 95%, the airflow rate is 200 mL/min, the temperature is 25 °C, and one test point is provided per rising 5%humidity.
  • the invention discloses crystalline forms and amorphism of oxazolidinone compound named 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino-4-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide (represented by Formula (I) ) and methods of preparation thereof.
  • the person skilled in the art can learn from this article to properly improve the process parameters to implement the preparation method. It particularly needs to note that all the similar replacements and changes are obvious for the skilled persons and are deemed to be within the scope of the present invention.
  • the methods disclosed herein are described in the preferred examples. Related person can clearly realize and apply the techniques disclosed herein by making some changes, appropriate alterations or combinations to the methods without departing from spirit, principles and scope of the present disclosure.
  • the DSC thermogram of amorphism was analyzed and identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, glass transition temperature is 107.44 °C; the DSC thermogram comprises an endothermic peak at 203.43 °C, and the error margin is ⁇ 3 °C.
  • DSC differential scanning calorimetry
  • the Raman spectrogram of amorphism was analyzed and identified by using Thermo DXR confocal laser Raman spectrometer, having the following absorption peaks at 181, 276, 392, 425, 512, 672, 694, 739, 795, 1080, 1120, 1298, 1328, 1427, 1549, 1612, 2981 and 3088 cm -1 , the error margin is ⁇ 2 cm -1 .
  • the TGA curve of amorphism was analyzed and identified by using TA Q500 thermal gracity analysis (TGA) with a scan rate of 10 °C/minute, the weight loss ratio is from 1.75%to 4.10%. The error margin in the weight loss ratio is ⁇ 0.1%.
  • the XRPD pattern of crystalline form II was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) with Cu-K ⁇ radiation, having the following characteristic peaks expressed in degrees 2 ⁇ at 9.39°, 12.70°, 14.65°, 15.41°, 15.85°, 16.90°, 19.00°, 19.96°, 20.99°, 21.98°, 22.45°, 23.07°, 23.32°, 24.73°, 25.42°, 27.23°, 27.56°, 28.18°, 29.94°, 30.36°, 30.86°, 31.36°, 33.43°, 34.14°, 34.37°, 34.68°, 35.22°, 36.24°, 36.85°, 37.07°, 37.84°, 38.31° and 39.10°.
  • the error margin in 2 ⁇ of the characteristic peaks is ⁇ 0.2°.
  • the DSC thermogram of crystalline form II was analyzed and identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, comprising an endothermic peak at 194.90 °C.
  • the error margin in the melting peaks is ⁇ 3 °C.
  • the Raman spectrogram of crystalline form III was analyzed and identified by using Thermo DXR confocal laser Raman spectrometer, having the following absorption peaks at 201, 245, 283, 367, 407, 450, 510, 525, 571, 639, 665, 693, 714, 742, 769, 802, 864, 903, 949, 974, 1005, 1034, 1080, 1099, 1231, 1272, 1291, 1309, 1328, 1388, 1426, 1507, 1554, 1608, 1640, 1662, 1762, 2834, 2874, 2939, 2981 and 3089 cm -1 , the error margin is ⁇ 2 cm -1 .
  • the XRPD pattern of crystalline form IV was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) with Cu-K ⁇ radiation, having the following characteristic peaks expressed in degrees 2 ⁇ at 8.84°, 9.48°, 14.26°, 14.98°, 16.12°, 16.63°, 17.76°, 18.26°, 18.97°, 19.93°, 20.41°, 20.76°, 22.07°, 22.64°, 23.13°, 24.28°, 24.56°, 25.08°, 25.43°, 26.56°, 28.68°, 29.39°, 29.67°, 30.35°, 31.21°, 32.39°, 32.72°, 33.64°, 34.30°, 34.59°, 36.07°, 37.00°, 37.92° and 39.44°.
  • the error margin in 2 ⁇ of the characteristic peaks is ⁇ 0.2°.
  • the DSC thermogram of crystalline form IV was analyzed and identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, comprising endothermic peaks at 116.97 °C and 203.20 °C.
  • the error margin in the melting peaks is ⁇ 3 °C.
  • the Raman spectrogram of crystalline form IV was analyzed and identified by using Thermo DXR confocal laser Raman spectrometer, having the following absorption peaks at 202, 241, 283, 381, 510, 668, 692, 714, 742, 800, 1035, 1081, 1228, 1273, 1305, 1327, 1428, 1554, 1608, 1643, 1703, 1765, 2924, 2987 and 3085 cm -1 , the error margin is ⁇ 2 cm -1 .
  • the crystalline form V is a chloroform solvate of 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino-4-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide
  • each unit cell of the single crystal structure contains two molecules of 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino-4-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide
  • the characteristics parameters of the single crystalline are as shown in table 1, the single
  • the DSC thermogram of crystalline form V was analyzed and identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, comprising endothermic peaks at 106.98 °C, 193.82 °C and 203.62 °C.
  • the error margin in the melting peaks is ⁇ 3 °C.
  • the TGA curve of amorphism was analyzed and identified by using TA Q500 thermal gracity analysis (TGA) with a scan rate of 10 °C/minute, the weight loss ratio is 16.59%.
  • the error margin in the weight loss ratio is ⁇ 0.1%.
  • test solution 40 ⁇ L was detected by HPLC and the concentration was calculated by the external standard one point method.
  • concentration was calculated by the external standard one point method.
  • the control group is the compound named 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino-4-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thi ophene-2-carboxamide (Formula (I) ) synthesized according to patent WO2014110971.
  • Test samples Male Beagle dogs weighting 8-12 kg were divided into three groups, 3 in each group, and administered orally capsules filled with the test samples, the dose was 2.5 mg/kg. Blood collection was carried out at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 h after administration. The test sample concentration was measured in MRM mode by using AB SCIEX API4000 LC-MS/MS, and the quantitative analysis was carried out to establish the standard curve. The pharmacokinetic parameters were calculated according to non-compartment model based on drug concentration-time curve using WinNonLin 6.3 software. For detailed data, see the table 2 below.
  • Table 7 The high temperature tests of the crystalline form I, form II or amorphism disclosed herein
  • Table 8 The high humidity test of the crystalline form I, form II or amorphism disclosed herein
  • form I has 0.22%of weigh increase under relative humidity (RH) 80%, which belongs to Slight hygroscopicity according to the definition standard of hygroscopic weight gain; form II has 0.15%of weigh increase under relative humidity (RH) 80%, which belongs to No or almost no hygroscopicity; amorphism has 2.24%of weigh increase under relative humidity (RH) 80%, which belongs to Hygroscopicity but there is no obvious in the weight increase of the hygroscopicity; i.e. the crystalline form I, form II or amorphism is not easy to deliquesce under high humidity conditions.
  • RH relative humidity
  • form II has 0.15%of weigh increase under relative humidity (RH) 80%, which belongs to No or almost no hygroscopicity
  • amorphism has 2.24%of weigh increase under relative humidity (RH) 80%, which belongs to Hygroscopicity but there is no obvious in the weight increase of the hygroscopicity;

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Abstract

La présente invention concerne des formes cristallines et l'amorphisme de composés d'oxazolidinone et une composition pharmaceutique contenant la forme cristalline ou l'amorphisme ou une combinaison correspondante. La forme cristalline ou l'amorphisme, ou la composition pharmaceutique de l'invention, peuvent être utilisées dans la fabrication d'un inhibiteur de facteur Xa de coagulation sanguine et/ou dans le traitement de maladies thromboemboliques chez un patient. L'invention concerne également un procédé de préparation de la forme cristalline I.
PCT/CN2015/079522 2014-05-22 2015-05-21 Formes cristallines et amorphisme de composé d'oxazolidinone Ceased WO2015176677A1 (fr)

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