WO2016012470A1 - New amorphous and crystalline forms of (3s)-4-[[(4r)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid - Google Patents

New amorphous and crystalline forms of (3s)-4-[[(4r)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid Download PDF

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WO2016012470A1
WO2016012470A1 PCT/EP2015/066695 EP2015066695W WO2016012470A1 WO 2016012470 A1 WO2016012470 A1 WO 2016012470A1 EP 2015066695 W EP2015066695 W EP 2015066695W WO 2016012470 A1 WO2016012470 A1 WO 2016012470A1
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crystalline form
xrpd
ray powder
powder diffraction
exhibits
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PCT/EP2015/066695
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French (fr)
Inventor
Xinhui HU
Wei Zhang
Wei Li
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Publication of WO2016012470A1 publication Critical patent/WO2016012470A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to novel amorphous and crystalline forms of compound (I),
  • Hepatitis B is recognized as a chronic viral disease of the liver which is characterized by liver disease.
  • Inhibitors of hepatitis B virus (HBV) are useful to limit the establishment and progression of infection by HBV as well as in diagnostic assays for HBV.
  • WO2014/037480 Al disclosed HBV inhibitor compound 00, (3S)-4-[[(4R)-4-(2-chloro-4- fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- 1 , 4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid.
  • Compound (I) simultaneously has tautomer as compound (la), (3S)-4-[[(6R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- l,6-dihydropyrimidin-4-yl]methyl]moipholine-3-carboxylic acid.
  • the compound (I) and its tautomer, compound (la), have rapid transforming speed at ambient temperature, which exist as the structure of (3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-l, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid at ambient temperature.
  • Solid form is a term to describe how one compound exists as solid state which includes amorphous, polymorph, salt, co-crystal, etc. It has fundamental influences on the
  • physicochemical properties such as solubility, chemical stability, physical stability, powder properties, etc.
  • MSA Methyl sulfonic acid
  • the present disclosure relates generally to novel solid forms of compound (I), and processes to make the forms.
  • the present invention relates to polymorphs, amorphous, salts, co-crystals and methods for the synthesis of selective production of amorphous and crystalline forms of (3S)-4-[[(4R)-4-(2- chloro-4-fiuoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- 1 , 4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid.
  • an amorphous or crystalline form of compound (I) or salts, solvates or combination thereof is provided herein.
  • the XRPD pattern of amorphous form is shown in FIG. 1.
  • the amorphous or crystalline form of compound (I) is Form A, Form B,
  • Form C Form C, Form D, Form E, Form F, Form G, Form H, Form L, Form M, Form N, Form P, Form Q or a combination thereof.
  • the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77° ⁇ 0.1°, 8.22° ⁇ 0.1°, 19.71° ⁇ 0.1°, 19.99° ⁇ 0.1°, 24.77° ⁇ 0.1° and 25.68° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77° ⁇ 0.1°, 8.22° ⁇ 0.1°, 9.10° ⁇ 0.1°, 9.81° ⁇ 0.1°, 11.33° ⁇ 0.1°, 12.60° ⁇ 0.1°, 14.31° ⁇ 0.1°, 19.71° ⁇ 0.1°,
  • XRPD X-ray powder diffraction
  • the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 2.
  • the crystalline form is Form A which is a hydrate of compound (I).
  • Form A is a monohydrate, bihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate of compound (I).
  • the water content of Form A is from 0.5% to 10%, particularly from 2.5% to 4.5%.
  • the crystalline form is Form A with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42° ⁇ 0.1°, 19.62° ⁇ 0.1°, 20.42° ⁇ 0.1°, 23.03° ⁇ 0.1°, 25.51° ⁇ 0.1° and 26.65° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42° ⁇ 0.1°, 9.34° ⁇ 0.1°, 11.72° ⁇ 0.1°, 12.63° ⁇ 0.1°, 18.67° ⁇ 0.1°, 19.62° ⁇ 0.1°, 20.42° ⁇ 0.1°, 23.03° ⁇ 0.1°, 24.04° ⁇ 0.1°, 25.51° ⁇ 0.1°, 25.99° ⁇ 0.1°, 26.65° ⁇ 0.1°, 27.74° ⁇ 0.1° and 28.36° ⁇ 0.1°.
  • the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 5.
  • the crystalline form is Form B which is an anhydrous form of compound (I).
  • the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 17.04° ⁇ 0.1 °, 20.93° ⁇ 0.1°, 21.28° ⁇ 0.1°, 22.56° ⁇ 0.1°, 24.17° ⁇ 0.1° and 24.38° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.65° ⁇ 0.1°, 12.58° ⁇ 0.1°, 14.89° ⁇ 0.1°, 17.04° ⁇ 0.1°, 19.40° ⁇ 0.1°, 20.93° ⁇ 0.1°, 21.28° ⁇ 0.1°, 22.56° ⁇ 0.1°, 23.67° ⁇ 0.1°, 24.17° ⁇ 0.1°, 24.38° ⁇ 0.1° and 24.81° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 6.
  • the crystalline form is Form C which is a co-crystal of monohydrate of compound (I) and tetrafluoroborate of compound (I).
  • the crystalline form is Form C with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 171°C ⁇ 3°C.
  • DSC differential scanning calorimetry
  • the crystalline form is Form C with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.7.
  • DSC differential scanning calorimetry
  • the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74° ⁇ 0.1°, 17.20° ⁇ 0.1°, 20.46° ⁇ 0.1°, 23.43° ⁇ 0.1°, 28.38° ⁇ 0.1° and 30.88° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74° ⁇ 0.1°, 17.20° ⁇ 0.1°, 20.46° ⁇ 0.1°, 21.96° ⁇ 0.1°, 23.43° ⁇ 0.1°, 24.76° ⁇ 0.1°, 28.38° ⁇ 0.1°, 30.88° ⁇ 0.1°, 31.72° ⁇ 0.1°, 32.80° ⁇ 0.1°, 33.55° ⁇ 0.1° and 37.17° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form D with the X-ray crystal structure showed in FIG. 9.
  • the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 10.
  • the crystalline form is Form D with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 216°C ⁇ 3°C.
  • the crystalline form is Form D with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.l l.
  • the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39° ⁇ 0.1°, 7.96° ⁇ 0.1°, 9.82° ⁇ 0.1°, 20.74° ⁇ 0.1°, 22.50° ⁇ 0.1°, 23.82° ⁇ 0.1°, 24.69° ⁇ 0.1° and 26.20° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39° ⁇ 0.1°, 7.96° ⁇ 0.1°, 9.82° ⁇ 0.1°, 12.22° ⁇ 0.1°, 16.92° ⁇ 0.1°, 20.02° ⁇ 0.1°, 20.74° ⁇ 0.1°, 21.65° ⁇ 0.1°, 22.50° ⁇ 0.1°, 23.82° ⁇ 0.1°, 24.69° ⁇ 0.1°, 26.20° ⁇ 0.1°, 27.76° ⁇ 0.1° and 28.92° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 13.
  • the crystalline form is Form E with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form E with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.14.
  • DSC differential scanning calorimetry
  • the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.73° ⁇ 0.1°, 20.87° ⁇ 0.1°, 21.80° ⁇ 0.1°, 23.15° ⁇ 0.1°, 27.03° ⁇ 0.1° and 28.58° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.02° ⁇ 0.1 °, 11.73° ⁇ 0.1°, 14.89° ⁇ 0.1°, 18.36° ⁇ 0.1°, 20.87° ⁇ 0.1°, 21.80° ⁇ 0.1°, 23.15° ⁇ 0.1°, 24.44° ⁇ 0.1°, 25.35° ⁇ 0.1°, 27.03° ⁇ 0.1°, 28.58° ⁇ 0.1°, 32.21° ⁇ 0.1°, 33.52° ⁇ 0.1° and 39.03° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 16.
  • the crystalline form is Form F with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 141°C ⁇ 3°C.
  • the crystalline form is Form F with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.17.
  • the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.85° ⁇ 0.1°, 12.32° ⁇ 0.1°, 17.37° ⁇ 0.1°, 23.07° ⁇ 0.1°, 24.86° ⁇ 0.1°, 25.31° ⁇ 0.1° and 28.48° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.81° ⁇ 0.1°, 8.20° ⁇ 0.1°, 9.85° ⁇ 0.1°, 12.32° ⁇ 0.1°, 15.01° ⁇ 0.1°, 17.37° ⁇ 0.1°, 19.35° ⁇ 0.1°, 21.19° ⁇ 0.1°, 22.42° ⁇ 0.1°, 23.07° ⁇ 0.1°, 24.86° ⁇ 0.1°, 25.31° ⁇ 0.1°, 26.57° ⁇ 0.1°, 28.48° ⁇ 0.1° and 35.38° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 19.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form G with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 152°C ⁇ 3°C.
  • DSC differential scanning calorimetry
  • the crystalline form is Form G with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.20.
  • DSC differential scanning calorimetry
  • the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88° ⁇ 0.1°, 18.31° ⁇ 0.1°, 19.94° ⁇ 0.1°, 21.49° ⁇ 0.1°, 23.12° ⁇ 0.1°, 23.91° ⁇ 0.1°, 25.69° ⁇ 0.1° and 26.83° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88° ⁇ 0.1°, 13.23° ⁇ 0.1°, 14.42° ⁇ 0.1°, 17.69° ⁇ 0.1°, 18.31° ⁇ 0.1°, 19.94° ⁇ 0.1°, 21.49° ⁇ 0.1°, 23.12° ⁇ 0.1°, 23.91° ⁇ 0.1°, 25.69° ⁇ 0.1° and 26.83° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 22.
  • the crystalline form is Form H with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form H with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.23.
  • DSC differential scanning calorimetry
  • the crystalline form is Form D, Form E, Form F, Form G or Form H, which is a hydrochloride salt of compound (I).
  • the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29° ⁇ 0.1°, 15.86° ⁇ 0.1°, 18.99° ⁇ 0.1°, 20.88° ⁇ 0.1°, 22.96° ⁇ 0.1° and 23.30° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29° ⁇ 0.1°, 10.56° ⁇ 0.1°, 10.95° ⁇ 0.1°, 15.86° ⁇ 0.1°, 18.99° ⁇ 0.1°, 20.88° ⁇ 0.1°, 21.19° ⁇ 0.1°, 21.71° ⁇ 0.1°, 22.96° ⁇ 0.1°, 23.30° ⁇ 0.1°, 25.02° ⁇ 0.1°, 26.84° ⁇ 0.1°, 28.29° ⁇ 0.1° and 32.36° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 30.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form L with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
  • the crystalline form is Form L with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.31.
  • DSC differential scanning calorimetry
  • the crystalline form is Form L is an ethylsulfate of compound (I).
  • the crystalline form is Form L with the X-ray crystal structure showed in FIG. 33.
  • the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24° ⁇ 0.1°, 8.57° ⁇ 0.1°, 13.64° ⁇ 0.1°, 14.53° ⁇ 0.1°, 16.50° ⁇ 0.1°, 17.18° ⁇ 0.1°, 19.47° ⁇ 0.1° and 22.11 ° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24° ⁇ 0.1°, 8.57° ⁇ 0.1°, 9.80° ⁇ 0.1°, 13.64° ⁇ 0.1°, 14.53° ⁇ 0.1°, 16.50° ⁇ 0.1°, 17.18° ⁇ 0.1°, 19.47° ⁇ 0.1°, 22.11° ⁇ 0.1°, 25.23° ⁇ 0.1°, 28.11° ⁇ 0.1° and 29.39° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 34.
  • the crystalline form is Form M with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 59°C ⁇ 3°C.
  • the crystalline form is Form M with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG. 35.
  • DSC differential scanning calorimetry
  • the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62° ⁇ 0.1°, 9.22° ⁇ 0.1°, 18.50° ⁇ 0.1°, 19.05° ⁇ 0.1°, 23.14o ⁇ 0.1o and 23.88° ⁇ 0.1o.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62° ⁇ 0.1°, 9.22° ⁇ 0.1°, 11.81° ⁇ 0.1°, 13.10° ⁇ 0.1°, 13.83° ⁇ 0.1°, 17.44° ⁇ 0.1°, 18.50° ⁇ 0.1°, 19.05° ⁇ 0.1°, 20.63° ⁇ 0.1°, 21.98° ⁇ 0.1°, 23.14° ⁇ 0.1°, 23.88° ⁇ 0.1°, 25.61° ⁇ 0.1°, 27.85° ⁇ 0.1°, 29.31° ⁇ 0.1° and 39.07° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 37.
  • the crystalline form is Form N with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 63°C ⁇ 3°C.
  • the crystalline form is Form N with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.38.
  • DSC differential scanning calorimetry
  • the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.27° ⁇ 0.1°, 12.18° ⁇ 0.1°, 17.57° ⁇ 0.1°, 18.01° ⁇ 0.1°, 22.38° ⁇ 0.1° and 23.16° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.23° ⁇ 0.1°, 11.27° ⁇ 0.1°, 12.18° ⁇ 0.1°, 15.51° ⁇ 0.1°, 16.46° ⁇ 0.1°, 17.57° ⁇ 0.1°, 18.01° ⁇ 0.1°, 21.18° ⁇ 0.1°, 22.38° ⁇ 0.1°, 23.16° ⁇ 0.1°, 24.44° ⁇ 0.1°, 29.59° ⁇ 0.1° and 31.83° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 40.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form P with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 230°C ⁇ 3°C.
  • DSC differential scanning calorimetry
  • the crystalline form is Form P with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG. 41.
  • DSC differential scanning calorimetry
  • the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.04° ⁇ 0.1°, 12.77° ⁇ 0.1°, 16.33° ⁇ 0.1°, 16.71° ⁇ 0.1°, 18.06° ⁇ 0.1° and 20.65° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.35° ⁇ 0.1°, 9.96° ⁇ 0.1°, 11.04° ⁇ 0.1°, 12.77° ⁇ 0.1°, 15.04° ⁇ 0.1°, 16.33° ⁇ 0.1°, 16.71° ⁇ 0.1°, 18.06° ⁇ 0.1°, 20.65° ⁇ 0.1°, 22.19° ⁇ 0.1°, 23.76° ⁇ 0.1°, 25.36° ⁇ 0.1°, 26.64° ⁇ 0.1°, 29.34° ⁇ 0.1° and 30.26° ⁇ 0.1°.
  • XRPD X-ray powder diffraction
  • the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 43.
  • the crystalline form is Form Q with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 191°C ⁇ 3°C.
  • the crystalline form is Form Q with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.44.
  • DSC differential scanning calorimetry
  • the crystalline form is Form M, Form N, Form P or Form Q, which is a calcium salt of compound (I).
  • composition comprising the amorphous or crystalline form disclosed herein; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • amorphous or crystalline form disclosed herein or the pharmaceutical composition for the manufacture of a medicament for the treatment or prophylaxis of a viral disease in a patient.
  • the viral disease disclosed herein is hepatitis B infection or a disease caused by hepatitis B infection.
  • a method for the treatment or prophylaxis of hepatitis B infection or a disease caused by hepatitis B infection comprises administering an therapeutically effective amount of the amorphous or crystalline form or the pharmaceutical composition disclosed herein.
  • XRPD X-ray powder diffraction
  • the relative peak height of X-ray powder diffraction (XRPD) pattern depends on many factors related to sample preparation and geometric shapes of the instrument, however peak position is insensitive to experimental details.
  • the crystalline form disclosed herein characterized by XRPD pattern with some listed peak positions essentially can also be characterized by XRPD pattern provided in the appended drawings of the present invention. According to the state of the instrument for the experiment, the error margin in 2-theta of the characteristic peaks is ⁇ 0.1 °.
  • the relative peak height of differential scanning calorimetry depends on many factors related to sample preparation and geometric shapes of the instrument, however peak position is insensitive to experimental details.
  • the crystalline form disclosed herein characterized by DSC thermogram with some listed peak positions essentially can also be characterized by DSC thermogram provided in the appended drawings of the present invention. According to the state of the instrument for the experiment, the error margin in the melting peaks is ⁇ 3°C.
  • TGA thermal gravimetric analysis
  • relative intensity refers to the intensity of a peak with respect to the intensity of the strongest peak in the XRPD pattern which is regarded as 100%.
  • the term “combination” refers to a crystalline form containing a tautomer thereof, or a crystalline form containing one or more other crystalline forms or amorphous form
  • the term “peak” refers to a feature, in a spectrum and/or data presented in a graph, that one skilled in the art would recognize as not attributable to background noise.
  • pharmaceutical composition is used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.
  • therapeutically effective amount denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease or condition or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • composition or medicament contain the amorphous or crystalline forms of the compound (I) of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the amorphous or crystalline forms of compound (I) of the invention to prepare such compositions and medicaments.
  • amorphous or crystalline forms of compound (I) of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • amorphous or crystalline forms of compound (I) of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • An embodiment therefore, includes a pharmaceutical composition comprising an amorphous or crystalline form of compound (I).
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • the amorphous or crystalline form of compound (I) of the invention can be used together with interferon, pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxis of HBV.
  • FIG. 1 X-ray powder diffraction pattern for Amorphous Form
  • FIG. 2 X-ray powder diffraction pattern for Form A
  • FIG. 3 DSC thermogram of Form A
  • FIG. 4 TGA diagram of Form A
  • FIG. 5 X-ray powder diffraction pattern for Form B
  • FIG. 6 X-ray powder diffraction pattern for Form C
  • FIG. 7 DSC thermogram of Form C
  • FIG. 8 TGA diagram of Form C
  • FIG. 9 X-ray crystal structure of Form C
  • FIG. 10 X-ray powder diffraction pattern for Hydrochloride Salt Form D
  • FIG. 11 DSC thermogram of Hydrochloride Salt Form D
  • FIG. 12 TGA diagram of Hydrochloride Salt Form D
  • FIG. 13 X-ray powder diffraction pattern for Hydrochloride Salt Form E
  • FIG. 14 DSC thermogram of Hydrochloride Salt Form E
  • FIG. 15 TGA diagram of Hydrochloride Salt Form E
  • FIG. 16 X-ray powder diffraction pattern for Hydrochloride Salt Form F F1G. 17 DSC thermogram of Hydrochloride Salt Form F
  • FIG. 18 TGA diagram of Hydrochloride Salt Form F
  • FIG. 19 X-ray powder diffraction pattern for Hydrochloride Salt Form G
  • FIG. 20 DSC thermogram of Hydrochloride Salt Form G
  • FIG. 21 TGA diagram of Hydrochloride Salt Form G
  • FIG. 22 X-ray powder diffraction pattern for Hydrochloride Salt Form H
  • FIG. 23 DSC thermogram of Hydrochloride Salt Form H
  • FIG. 24 TGA diagram of Hydrochloride Salt Form H
  • FIG. 25 Omitted
  • FIG. 26 Omitted
  • FIG. 27 Omitted
  • FIG. 30 X-ray powder diffraction pattern for Ethylsulfate Form L
  • FIG.31 DSC thermogram of Ethylsulfate Form L
  • FIG.32 TGA diagram of Ethylsulfate Form L
  • FIG. 33 X-ray crystal structure of Ethylsulfate Form L
  • FIG. 34 X-ray powder diffraction pattern for Calcium Salt Form M
  • FIG. 35 DSC thermogram of Calcium Salt Form M
  • FIG. 36 TGA thermogram of Calcium Salt Form M F1G. 37 X-ray powder diffraction pattern for Calcium Salt Form N
  • FIG. 38 DSC thermogram of Calcium Salt Form N
  • FIG. 39 TGA thermogram of Calcium Salt FormN
  • FIG. 40 X-ray powder diffraction pattern for Calcium Salt Form P
  • FIG. 41 DSC thermogram of Calcium Salt Form P
  • FIG. 42 TGA diagram of Calcium Salt Form P
  • FIG. 43 X-ray powder diffraction pattern for Calcium Salt Form Q
  • FIG. 44 DSC thermogram of Calcium Salt Form Q
  • FIG. 45 TGA diagram of Calcium Salt Form Q
  • FIG. 46 X-ray powder diffraction pattern for Mesylate Form J
  • FIG. 47 DSC thermogram of Mesylate Form J
  • FIG. 48 TGA diagram of Mesylate Form J
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation using 40KV tube voltage and 40mA tube currentScan range was from 4 to 40 degree 2- theta.
  • the step size was 0.0525° at a scanning speed of 6.66°/min.
  • the XRPD pattern is shown in FIG. 2. Major peaks and their related intensities in the XRPD pattern are shown in Table 1.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation using 40KV tube voltage and 40mA tube current. Scan range was from 4 to 40 degree 2 -theta. The step size was 0.0525° at a scanning speed of 6.66°/min.
  • TGA analysis TA Q5000, 25-350°C, heating rate 10°C/min.
  • Form B of compound (I).
  • Form B was formed by using Form A as prepared in Example 2 either after dehydration at high temperature (>70°C) or low humidity (0% RH), and characterized by XRPD pattern shown in FIG. 5. Major peaks and their related intensities in the XRPD pattern are shown in Table 2.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • the solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of Form C of compound (I) is shown in FIG. 6. Major peaks and their related intensities in the XRPD pattern are shown in Table 3 below.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • FIG. 9 shows the X-ray structure of Form C of compound (I), indicating that Form C is a monohydrate of co-crystal formed by compound (I) and its tetrafluoroborate with a molar ratio 1:2.
  • the crystal data and structure refinement is shown in Table 4.
  • the solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of hydrochloride salt Form D of compound (I) is shown in FIG. 10. Major peaks and their related intensities in the XRPD pattern are shown in Table 5.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • hydrochloride salt Form D of compound (I) has an onset melting temperature at 216°C.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • DSC analysis TA Q2000, 25-250°C, heating rate 10°C/min.
  • TGA analysis TA Q5000, 25-250°C, heating rate 10°C/min.
  • the XRPD pattern of hydrochloride salt Form F of compound (I) is shown in FIG. 16. Major peaks and their related intensities in the XRPD pattern are shown in Table 7.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-200°C, heating rate 10°C/min.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • amorphous form of compound (I) as prepared in Example 1 40 mg was weighed and transferred to a 2-mL vial. 1 mL 0.1 N HC1 was added to form slurry. The vial was mounted to a shaker and kept shaking for 1 day at room temperature. After 1 day, the slurry was removed from the vial, transferred to a 1.5mL centrifuge tube and centrifuge at 12000rpm for 5 minutes. The supernatant was removed and the residual solid was analysed using XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of hydrochloride salt Form H of compound (I) is shown in FIG. 22. Major peaks and their related intensities in the XRPD pattern are shown in Table 9.
  • XRPD Bruker D8 Advance X-ray diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 40KV and tube current was 40mA.
  • Scan range was from 4 to 40 degree 2-theta.
  • the step size was 0.05° at a scanning speed of 3°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the XRPD pattern of ethylsulfate Form L of compound (I) is shown in FIG. 30. Major peaks and their related intensities in the XRPD pattern are shown in Table 12.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-250°C, heating rate 10°C/min.
  • FIG. 33 shows the X-ray structure of ethylsulfate Form L.
  • the crystal data and structure refinement is shown in Table 13.
  • the solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of calcium salt Form M of compound (I) is shown in FIG. 34. Major peaks and their related intensities in the XRPD pattern are shown in Table 14.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the XRPD pattern of calcium salt Form N of compound (I) is shown in FIG. 37. Major peaks and their related intensities in the XRPD pattern are shown in Table 15.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of calcium salt Form P of compound (I) is shown in FIG. 40. Major peaks and their related intensities in the XRPD pattern are shown in Table 16.
  • XRPD PANalytical EMPYREAN X-ray powder diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-325°C, heating rate 10°C/min.
  • Tube voltage was 45KV and tube current was 40mA.
  • Scan range was from 3 to 40 degree 2-theta.
  • the step size was 0.013° at a scanning speed of 10°/min.
  • TGA analysis TA Q5000, 25-300°C, heating rate 10°C/min.
  • the result of water content was 2.5%.
  • the water content of final product was determined using Karl Fischer Coulometric titration.
  • the result of water content was 3.9%.
  • the result of water content was 4.5%.
  • the solid was collected by filtration, washed with MIBK and analysed using XRPD analysis, DSC analysis and TGA analysis.
  • the XRPD pattern of mesylate Form J of compound (I) is shown in FIG. 46. Major peaks and their related intensities in the XRPD pattern are shown in Table 10 below.
  • XRPD Bruker D8 Advance X-ray diffractometer with Cu- ⁇ radiation.
  • Tube voltage was 40KV and tube current was 40mA.
  • Scan range was from 4 to 40 degree 2-theta.
  • the step size was 0.05° at a scanning speed of 3°/min.
  • TGA analysis TA Q5000, 25-400°C, heating rate 10°C/min.
  • Aqueous solubility was determined by suspending lOmg compound in different bio- relevant media including SGF, FaSSIF and FeSSIF. The suspension was equilibrated at 25 °C for 24 hours then the final pH was measured. The suspension was then filtered through a 0.22um PVDF filter into a 2-mL HPLC vial. The quantitation was conducted by HPLC (described in Example AD) with reference to a standard solution. The solubility results of selected novel solid forms in this invention are shown in Table 12 which showed good aqueous solubility higher than 0.5mg/mL.
  • HPLC condition is disclosed here in Table 13.

Abstract

The present invention relates to a novel amorphous and crystalline form of compound (I) (3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid and pharmaceutical compositions comprising the amorphous or crystalline forms or tautomers thereof disclosed herein, which may be used for the treatment or prophylaxis of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.

Description

New amorphous and crystalline forms of (3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5- methoxycarbonyl-2-thiazol-2-yl-l, 4-dihydxopyrirnidin-6-yl] methyl] morpholine-3-carboxylic acid
The present invention relates to novel amorphous and crystalline forms of compound (I),
Figure imgf000003_0001
(3S)-4-[[(4R)-4-(2-chtoro-4-fluoro-phenyl)-5-memoxycarbonyl-2-thiazol-2-yl-1, 4- dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid and pharmaceutical compositions comprising the amorphous or crystalline forms or tautomers thereof disclosed herein, which may be used for the treatment or prophylaxis of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.
BACKGROUAND OF THE INVENTION
Hepatitis B is recognized as a chronic viral disease of the liver which is characterized by liver disease. Inhibitors of hepatitis B virus (HBV) are useful to limit the establishment and progression of infection by HBV as well as in diagnostic assays for HBV. WO2014/037480 Al disclosed HBV inhibitor compound 00, (3S)-4-[[(4R)-4-(2-chloro-4- fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- 1 , 4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid. Compound (I) simultaneously has tautomer as compound (la), (3S)-4-[[(6R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- l,6-dihydropyrimidin-4-yl]methyl]moipholine-3-carboxylic acid. The compound (I) and its tautomer, compound (la), have rapid transforming speed at ambient temperature, which exist as the structure of (3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-l, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid at ambient temperature.
Compound (I) and compound (la) are shown below:
Figure imgf000004_0001
Solid form is a term to describe how one compound exists as solid state which includes amorphous, polymorph, salt, co-crystal, etc. It has fundamental influences on the
physicochemical properties such as solubility, chemical stability, physical stability, powder properties, etc.
Methyl sulfonic acid (MSA) is a commonly used counterion for salt formation in pharmaceutical industry (Salt and Cocrystal Form Selection in Preclinical Development Handbook. Wiley-Interscience, Hoboken. 2008, 455-481). The MSA salt of compound (I) was identified and used at the early research stage. However, serious chemical stability issue of this MSA salt was observed, limiting the developability of compound (I) dramatically. As an action of risk mitigation, comprehensive studies were conducted. Several novel crystalline solid forms were synthesized and characterized, showing significantly improved stability compared with MSA salt. These novel crystalline forms enhanced the developability of compound (I)
fundamentally. At the same time, amorphous form of compound (I) was also synthesized and showed amazing stability although amorphous is generally considered as metastable solid form.
The present disclosure relates generally to novel solid forms of compound (I), and processes to make the forms.
SUMMARY OF THE INVENTION
The present invention relates to polymorphs, amorphous, salts, co-crystals and methods for the synthesis of selective production of amorphous and crystalline forms of (3S)-4-[[(4R)-4-(2- chloro-4-fiuoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl- 1 , 4-dihydropyrimidin-6- yl]methyl]morpholine-3-carboxylic acid.
In one aspect, provided herein is an amorphous or crystalline form of compound (I) or salts, solvates or combination thereof. The XRPD pattern of amorphous form is shown in FIG. 1. In another aspect, the amorphous or crystalline form of compound (I) is Form A, Form B,
Form C, Form D, Form E, Form F, Form G, Form H, Form L, Form M, Form N, Form P, Form Q or a combination thereof.
In another embodiment, the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77°±0.1°, 8.22°±0.1°, 19.71°±0.1°, 19.99°±0.1°, 24.77°±0.1° and 25.68°±0.1°.
In a further embodiment, the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77°±0.1°, 8.22°±0.1°, 9.10°±0.1°, 9.81°±0.1°, 11.33°±0.1°, 12.60°±0.1°, 14.31°±0.1°, 19.71°±0.1°,
19.99°±0.1°, 21.56°±0.1°, 21.97°±0.1°, 22.46°±0.1°, 23.22°±0.1°, 24.77°±0.1°, 25.68°±0.1°, 26.10°±0.1°, 27.47°±0.1° and 28.22°±0.1°.
In a further embodiment, the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 2. In a further embodiment, the crystalline form is Form A which is a hydrate of compound (I). In a further embodiment, Form A is a monohydrate, bihydrate, trihydrate, tetrahydrate, pentahydrate or hexahydrate of compound (I). In a further embodiment, the water content of Form A is from 0.5% to 10%, particularly from 2.5% to 4.5%. In a further embodiment, the crystalline form is Form A with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
39°C±3°C.
In another embodiment, the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42°±0.1°, 19.62°±0.1°, 20.42°±0.1°, 23.03°±0.1°, 25.51°±0.1° and 26.65°±0.1°.
In a further embodiment, the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42°±0.1°, 9.34°±0.1°, 11.72°±0.1°, 12.63°±0.1°, 18.67°±0.1°, 19.62°±0.1°, 20.42°±0.1°, 23.03°±0.1°, 24.04°±0.1°, 25.51°±0.1°, 25.99°±0.1°, 26.65°±0.1°, 27.74°±0.1° and 28.36°±0.1°. In a further embodiment, the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 5.
In a further embodiment, the crystalline form is Form B which is an anhydrous form of compound (I).
In another embodiment, the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 17.04°±0.1 °, 20.93°±0.1°, 21.28°±0.1°, 22.56°±0.1°, 24.17°±0.1° and 24.38°±0.1°.
In a further embodiment, the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.65°±0.1°, 12.58°±0.1°, 14.89°±0.1°, 17.04°±0.1°, 19.40°±0.1°, 20.93°±0.1°, 21.28°±0.1°, 22.56°±0.1°, 23.67°±0.1°, 24.17°±0.1°, 24.38°±0.1° and 24.81°±0.1°.
In a further embodiment, the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 6. In a further embodiment, the crystalline form is Form C which is a co-crystal of monohydrate of compound (I) and tetrafluoroborate of compound (I).
In a further embodiment, the crystalline form is Form C with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 171°C±3°C.
In a further embodiment, the crystalline form is Form C with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.7.
In another embodiment, the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74°±0.1°, 17.20°±0.1°, 20.46°±0.1°, 23.43°±0.1°, 28.38°±0.1° and 30.88°±0.1°.
In a further embodiment, the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74°±0.1°, 17.20°±0.1°, 20.46°±0.1°, 21.96°±0.1°, 23.43°±0.1°, 24.76°±0.1°, 28.38°±0.1°, 30.88°±0.1°, 31.72°±0.1°, 32.80°±0.1°, 33.55°±0.1° and 37.17°±0.1°.
In a further embodiment, the crystalline form is Form D with the X-ray crystal structure showed in FIG. 9.
In a further embodiment, the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 10. In a further embodiment, the crystalline form is Form D with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 216°C±3°C.
In a further embodiment, the crystalline form is Form D with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.l l. In another embodiment, the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39°±0.1°, 7.96°±0.1°, 9.82°±0.1°, 20.74°±0.1°, 22.50°±0.1°, 23.82°±0.1°, 24.69°±0.1° and 26.20°±0.1°.
In a further embodiment, the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39°±0.1°, 7.96°±0.1°, 9.82°±0.1°, 12.22°±0.1°, 16.92°±0.1°, 20.02°±0.1°, 20.74°±0.1°, 21.65°±0.1°, 22.50°±0.1°, 23.82°±0.1°, 24.69°±0.1°, 26.20°±0.1°, 27.76°±0.1° and 28.92°±0.1°.
In a further embodiment, the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 13. In a further embodiment, the crystalline form is Form E with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
136°C±3°C.
In a further embodiment, the crystalline form is Form E with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.14.
In another embodiment, the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.73°±0.1°, 20.87°±0.1°, 21.80°±0.1°, 23.15°±0.1°, 27.03°±0.1° and 28.58°±0.1°.
In a further embodiment, the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.02°±0.1 °, 11.73°±0.1°, 14.89°±0.1°, 18.36°±0.1°, 20.87°±0.1°, 21.80°±0.1°, 23.15°±0.1°, 24.44°±0.1°, 25.35°±0.1°, 27.03°±0.1°, 28.58°±0.1°, 32.21°±0.1°, 33.52°±0.1° and 39.03°±0.1°.
In a further embodiment, the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 16. In a further embodiment, the crystalline form is Form F with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 141°C±3°C. In a further embodiment, the crystalline form is Form F with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.17.
In another embodiment, the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.85°±0.1°, 12.32°±0.1°, 17.37°±0.1°, 23.07°±0.1°, 24.86°±0.1°, 25.31°±0.1° and 28.48°±0.1°.
In a further embodiment, the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.81°±0.1°, 8.20°±0.1°, 9.85°±0.1°, 12.32°±0.1°, 15.01°±0.1°, 17.37°±0.1°, 19.35°±0.1°, 21.19°±0.1°, 22.42°±0.1°, 23.07°±0.1°, 24.86°±0.1°, 25.31°±0.1°, 26.57°±0.1°, 28.48°±0.1° and 35.38°±0.1°.
In a further embodiment, the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 19.
In a further embodiment, the crystalline form is Form G with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 152°C±3°C.
In a further embodiment, the crystalline form is Form G with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.20.
In another embodiment, the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88°±0.1°, 18.31°±0.1°, 19.94°±0.1°, 21.49°±0.1°, 23.12°±0.1°, 23.91°±0.1°, 25.69°±0.1° and 26.83°±0.1°.
In a further embodiment, the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88°±0.1°, 13.23°±0.1°, 14.42°±0.1°, 17.69°±0.1°, 18.31°±0.1°, 19.94°±0.1°, 21.49°±0.1°, 23.12°±0.1°, 23.91°±0.1°, 25.69°±0.1° and 26.83°±0.1°.
In a further embodiment, the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 22. In a further embodiment, the crystalline form is Form H with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
136°C±3°C.
In a further embodiment, the crystalline form is Form H with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.23.
In a further embodiment, the crystalline form is Form D, Form E, Form F, Form G or Form H, which is a hydrochloride salt of compound (I).
In another embodiment, the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29°±0.1°, 15.86°±0.1°, 18.99°±0.1°, 20.88°±0.1°, 22.96°±0.1° and 23.30°±0.1°.
In a further embodiment, the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29°±0.1°, 10.56°±0.1°, 10.95°±0.1°, 15.86°±0.1°, 18.99°±0.1°, 20.88°±0.1°, 21.19°±0.1°, 21.71°±0.1°, 22.96°±0.1°, 23.30°±0.1°, 25.02°±0.1°, 26.84°±0.1°, 28.29°±0.1° and 32.36°±0.1°.
In another embodiment, the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 30.
In a further embodiment, the crystalline form is Form L with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at
160°C±3°C.
In a further embodiment, the crystalline form is Form L with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.31.
In a further embodiment, the crystalline form is Form L is an ethylsulfate of compound (I). In a further embodiment, the crystalline form is Form L with the X-ray crystal structure showed in FIG. 33. In another embodiment, the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24°±0.1°, 8.57°±0.1°, 13.64°±0.1°, 14.53°±0.1°, 16.50°±0.1°, 17.18°±0.1°, 19.47°±0.1° and 22.11 °±0.1°.
In a further embodiment, the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24°±0.1°, 8.57°±0.1°, 9.80°±0.1°, 13.64°±0.1°, 14.53°±0.1°, 16.50°±0.1°, 17.18°±0.1°, 19.47°±0.1°, 22.11°±0.1°, 25.23°±0.1°, 28.11°±0.1° and 29.39°±0.1°.
In a further embodiment, the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 34. In a further embodiment, the crystalline form is Form M with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 59°C±3°C.
In a further embodiment, the crystalline form is Form M with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG. 35.
In another embodiment, the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62°±0.1°, 9.22°±0.1°, 18.50°±0.1°, 19.05°±0.1°, 23.14º±0.1º and 23.88°±0.1º.
In a further embodiment, the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62°±0.1°, 9.22°±0.1°, 11.81°±0.1°, 13.10°±0.1°, 13.83°±0.1°, 17.44°±0.1°, 18.50°±0.1°, 19.05°±0.1°, 20.63°±0.1°, 21.98°±0.1°, 23.14°±0.1°, 23.88°±0.1°, 25.61°±0.1°, 27.85°±0.1°, 29.31°±0.1° and 39.07°±0.1°.
In a further embodiment, the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 37. In a further embodiment, the crystalline form is Form N with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 63°C±3°C.
In a further embodiment, the crystalline form is Form N with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.38.
In another embodiment, the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.27°±0.1°, 12.18°±0.1°, 17.57°±0.1°, 18.01°±0.1°, 22.38°±0.1° and 23.16°±0.1°. In a further embodiment, the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.23°±0.1°, 11.27°±0.1°, 12.18°±0.1°, 15.51°±0.1°, 16.46°±0.1°, 17.57°±0.1°, 18.01°±0.1°, 21.18°±0.1°, 22.38°±0.1°, 23.16°±0.1°, 24.44°±0.1°, 29.59°±0.1° and 31.83°±0.1°.
In a further embodiment, the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 40.
In a further embodiment, the crystalline form is Form P with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 230°C±3°C.
In a further embodiment, the crystalline form is Form P with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG. 41.
In another embodiment, the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.04°±0.1°, 12.77°±0.1°, 16.33°±0.1°, 16.71°±0.1°, 18.06°±0.1° and 20.65°±0.1°. In a further embodiment, the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.35°±0.1°, 9.96°±0.1°, 11.04°±0.1°, 12.77°±0.1°, 15.04°±0.1°, 16.33°±0.1°, 16.71°±0.1°, 18.06°±0.1°, 20.65°±0.1°, 22.19°±0.1°, 23.76°±0.1°, 25.36°±0.1°, 26.64°±0.1°, 29.34°±0.1° and 30.26°±0.1°.
In a further embodiment, the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 43. In a further embodiment, the crystalline form is Form Q with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak with onset temperature at 191°C±3°C.
In a further embodiment, the crystalline form is Form Q with a differential scanning calorimetry (DSC) thermogram comprising endothermic peak substantially the same as shown in FIG.44.
In a further embodiment, the crystalline form is Form M, Form N, Form P or Form Q, which is a calcium salt of compound (I).
In another aspect, provided herein is a pharmaceutical composition comprising the amorphous or crystalline form disclosed herein; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
In another aspect, provided herein is the use of the amorphous or crystalline form disclosed herein or the pharmaceutical composition for the manufacture of a medicament for the treatment or prophylaxis of a viral disease in a patient.
In another aspect, the viral disease disclosed herein is hepatitis B infection or a disease caused by hepatitis B infection.
In another aspect, provided herein is a method for the treatment or prophylaxis of hepatitis B infection or a disease caused by hepatitis B infection, which method comprises administering an therapeutically effective amount of the amorphous or crystalline form or the pharmaceutical composition disclosed herein. The relative peak height of X-ray powder diffraction (XRPD) pattern depends on many factors related to sample preparation and geometric shapes of the instrument, however peak position is insensitive to experimental details. In some embodiments, the crystalline form disclosed herein characterized by XRPD pattern with some listed peak positions essentially can also be characterized by XRPD pattern provided in the appended drawings of the present invention. According to the state of the instrument for the experiment, the error margin in 2-theta of the characteristic peaks is ±0.1 °.
Similarly, the relative peak height of differential scanning calorimetry (DSC) depends on many factors related to sample preparation and geometric shapes of the instrument, however peak position is insensitive to experimental details. In some embodiments, the crystalline form disclosed herein characterized by DSC thermogram with some listed peak positions essentially can also be characterized by DSC thermogram provided in the appended drawings of the present invention. According to the state of the instrument for the experiment, the error margin in the melting peaks is ±3°C.
Similarly, the weight loss and corresponding temperature of thermal gravimetric analysis (TGA) depends on many factors related to sample preparation and geometric shapes of the instrument. In some embodiments, the crystalline form disclosed herein characterized by TGA thermogram with some listed weight losses essentially can also be characterized by TGA thermogram provided in the appended drawings of the present invention.
Whenever a number disclosed in the invention with "±" stands for a numerical range with a lower limit and an upper limit, any number felling within the rage between lower limit and upper limit is disclosed.
As used herein, the term "relative intensity" refers to the intensity of a peak with respect to the intensity of the strongest peak in the XRPD pattern which is regarded as 100%.
As used herein, the term "combination" refers to a crystalline form containing a tautomer thereof, or a crystalline form containing one or more other crystalline forms or amorphous form As used herein, the term "peak" refers to a feature, in a spectrum and/or data presented in a graph, that one skilled in the art would recognize as not attributable to background noise. The terms "pharmaceutical composition" is used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof. The term "therapeutically effective amount" denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease or condition or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
Pharmaceutical composition or medicament contain the amorphous or crystalline forms of the compound (I) of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the amorphous or crystalline forms of compound (I) of the invention to prepare such compositions and medicaments.
The amorphous or crystalline forms of compound (I) of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
The amorphous or crystalline forms of compound (I) of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. An embodiment, therefore, includes a pharmaceutical composition comprising an amorphous or crystalline form of compound (I). In a further embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
The amorphous or crystalline form of compound (I) of the invention can be used together with interferon, pegylated interferons, Lamivudine, Adefovir dipivoxil, Entecavir, Telbivudine, and Tenofovir disoproxil for the treatment or prophylaxis of HBV.
ABBREVIATIONS [Bmim]BF4 1 -Butyl-3-methylimidazolium tetrafluoroborate
DSC Differential scanning calorimetry
DVS Dynamic vapor sorption
EtOAc Ethyl Acetate
FWHM Full Width at Half Maxima H2SO4 Sulfuric acid
H3PO4 Phosphoric acid
HC1 Hydrochloric acid
MeOH Methanol
MIBK Methyl isobutyl ketone Pos. Position
Rel. Int. Relative Intensity
TGA Thermal gravimetric analysis wt% Weight%
XRPD X-ray powder diffraction
DESCRIPTION OF THE FIGURES
FIG. 1 X-ray powder diffraction pattern for Amorphous Form
FIG. 2 X-ray powder diffraction pattern for Form A
FIG. 3 DSC thermogram of Form A
FIG. 4 TGA diagram of Form A
FIG. 5 X-ray powder diffraction pattern for Form B
FIG. 6 X-ray powder diffraction pattern for Form C
FIG. 7 DSC thermogram of Form C
FIG. 8 TGA diagram of Form C
FIG. 9 X-ray crystal structure of Form C
FIG. 10 X-ray powder diffraction pattern for Hydrochloride Salt Form D
FIG. 11 DSC thermogram of Hydrochloride Salt Form D
FIG. 12 TGA diagram of Hydrochloride Salt Form D
FIG. 13 X-ray powder diffraction pattern for Hydrochloride Salt Form E
FIG. 14 DSC thermogram of Hydrochloride Salt Form E
FIG. 15 TGA diagram of Hydrochloride Salt Form E
FIG. 16 X-ray powder diffraction pattern for Hydrochloride Salt Form F F1G. 17 DSC thermogram of Hydrochloride Salt Form F
FIG. 18 TGA diagram of Hydrochloride Salt Form F
FIG. 19 X-ray powder diffraction pattern for Hydrochloride Salt Form G FIG. 20 DSC thermogram of Hydrochloride Salt Form G
FIG. 21 TGA diagram of Hydrochloride Salt Form G
FIG. 22 X-ray powder diffraction pattern for Hydrochloride Salt Form H FIG. 23 DSC thermogram of Hydrochloride Salt Form H
FIG. 24 TGA diagram of Hydrochloride Salt Form H
FIG. 25 Omitted
FIG. 26 Omitted
FIG. 27 Omitted
FIG. 28 Omitted
FIG. 29 Omitted
FIG. 30 X-ray powder diffraction pattern for Ethylsulfate Form L FIG.31 DSC thermogram of Ethylsulfate Form L
FIG.32 TGA diagram of Ethylsulfate Form L
FIG. 33 X-ray crystal structure of Ethylsulfate Form L
FIG. 34 X-ray powder diffraction pattern for Calcium Salt Form M
FIG. 35 DSC thermogram of Calcium Salt Form M
FIG. 36 TGA thermogram of Calcium Salt Form M F1G. 37 X-ray powder diffraction pattern for Calcium Salt Form N
FIG. 38 DSC thermogram of Calcium Salt Form N
FIG. 39 TGA thermogram of Calcium Salt FormN
FIG. 40 X-ray powder diffraction pattern for Calcium Salt Form P
FIG. 41 DSC thermogram of Calcium Salt Form P
FIG. 42 TGA diagram of Calcium Salt Form P
FIG. 43 X-ray powder diffraction pattern for Calcium Salt Form Q
FIG. 44 DSC thermogram of Calcium Salt Form Q
FIG. 45 TGA diagram of Calcium Salt Form Q
FIG. 46 X-ray powder diffraction pattern for Mesylate Form J
FIG. 47 DSC thermogram of Mesylate Form J
FIG. 48 TGA diagram of Mesylate Form J
EXAMPLES
The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.
Example 1
Preparation of Amorphous Form of compound (I)
The 500mg/mL acetone solution of compound (I) was added into water drop-wise to form solid precipitation. The residual solid was isolated and analysed using XRPD analysis. The result is shown in FIG. 1.
Experimental condition:
XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation using 40KV tube voltage and 40mA tube currentScan range was from 4 to 40 degree 2- theta. The step size was 0.0525° at a scanning speed of 6.66°/min.
Example 2
Preparation of Hydrate Form, Form A of compound (I). 40 mg of amorphous form of compound (I) as prepared in Example 1 was weighed and transferred to a 2-mL vial. 1 mL 0.1M H3PO4 was added to form slurry. The vial was mounted to a shaker and kept shaking for 1 day at room temperature. The slurry was examined periodically by polarized light microscope.
After 1 day, the slurry was removed from the vial and transferred to a 1.5mL centrifuge tube and centrifuged at 12000rpm for 5 minutes. The supernatant was removed and the residual solid was analysed using XRPD. The XRPD pattern is shown in FIG. 2. Major peaks and their related intensities in the XRPD pattern are shown in Table 1.
Experimental conditions:
XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation using 40KV tube voltage and 40mA tube current. Scan range was from 4 to 40 degree 2 -theta. The step size was 0.0525° at a scanning speed of 6.66°/min.
DSC analysis: TA Q2000, 25-250°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-350°C, heating rate 10°C/min.
Table 1. X-Ray Powder Diffraction peaks of Form A of compound (I)
Figure imgf000021_0001
Figure imgf000022_0001
DSC and TGA results shown in FIG. 3 and FIG. 4.
Example 3
Preparation of Anhydrous Form, Form B of compound (I). Form B was formed by using Form A as prepared in Example 2 either after dehydration at high temperature (>70°C) or low humidity (0% RH), and characterized by XRPD pattern shown in FIG. 5. Major peaks and their related intensities in the XRPD pattern are shown in Table 2.
Experimental condition: XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation.
Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
Table 2. X-Ray Powder Diffraction peaks of Form B of compound (I)
Figure imgf000023_0001
Figure imgf000024_0001
Example 4
Preparation of Form C of compound (I).
10 mg of Form A of compound (I) as prepared in Example 2 was weighed and transferred te a 1-mL vial. 300 μL MeOH was added to form a clear solution followed by adding 20 wt% [Bmim]BF4. The clear solution was evaporated slowly to induce precipitation at room temperature.
The solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of Form C of compound (I) is shown in FIG. 6. Major peaks and their related intensities in the XRPD pattern are shown in Table 3 below.
Experimental conditions:
XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation. Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-200°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-300°C, heating rate 10°C/min.
Table 3. X-Ray Powder Diffraction peaks of Form C of compound (I).
Figure imgf000024_0002
Figure imgf000025_0001
DSC and TGA results shown in FIG. 7 and FIG. 8 indicate Form C of compound (I) has an onset melting temperature at 171°C.
FIG. 9 shows the X-ray structure of Form C of compound (I), indicating that Form C is a monohydrate of co-crystal formed by compound (I) and its tetrafluoroborate with a molar ratio 1:2. The single crystal X-ray intensity data were collected at 173K using a Broker APEX-II CCD diffractometer (Cu-Κα radiation, λ= 1.54178 Å). The crystal data and structure refinement is shown in Table 4.
Table 4. Crystal data and structure refinement of Form C of compound (I).
Figure imgf000025_0002
Figure imgf000026_0001
Example 5
Preparation of Hydrochloride Salt Form D of compound (I).
50mg of Form A of compound (I) as prepared in Example 2 was dissolved in lmL EtOAc. 0.1N HC1 solution in EtOAc was added at a molar ratio 2:1 (HC1: compound A) and mixed well. The solution was stirred at room temperature overnight to generate precipitation.
The solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of hydrochloride salt Form D of compound (I) is shown in FIG. 10. Major peaks and their related intensities in the XRPD pattern are shown in Table 5.
Experimental conditions: XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation.
Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-300°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-300°C, heating rate 10°C/min. Table 5. X-Ray Powder Diffraction peaks of hydrochloride salt Form D of compound (I).
Figure imgf000027_0001
Figure imgf000028_0001
DSC and TGA results shown in FIG. 11 and FIG. 12 indicate hydrochloride salt Form D of compound (I) has an onset melting temperature at 216°C.
Example 6 Preparation of Hydrochloride Salt Form E of compound (I).
50mg of Form A of compound (I) as prepared in Example 2 was dissolved in lmL MeOH/H2O (19/1, v/v). Equal molar 0.1N HC1 solution in MeOH/H2O (19/1, v/v) was added and mixed well. The solution was stirred at room temperature overnight to generate precipitation.
The solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis. The XRPD pattern of hydrochloride salt Form E of compound (I) is shown in FIG. 13.
Major peaks and their related intensities in the XRPD pattern are shown in Table 6.
Experimental conditions:
XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation. Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-250°C, heating rate 10°C/min. TGA analysis: TA Q5000, 25-250°C, heating rate 10°C/min.
Table 6. X-Ray Powder Diffraction peaks of hydrochloride salt Form E of compound (I).
Figure imgf000028_0002
Figure imgf000029_0001
DSC and TGA results shown in FIG. 14 and FIG. 15 indicate hydrochloride salt Form E of compound (I) has an onset melting temperature at 136°C.
Example 7 Preparation of Hydrochloride Salt Form F of compound (I).
300 mg of Form A of compound (I) as prepared in Example 2 was suspended in 3.0 mL acetone. 100 uL of 0.1 N HC1 solution was added to form a clear solution. 5 mL heptane was added to the solution over 10 hours. The mixture was stirred for 24 hours to generate precipitation. The solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis
The XRPD pattern of hydrochloride salt Form F of compound (I) is shown in FIG. 16. Major peaks and their related intensities in the XRPD pattern are shown in Table 7.
Experimental conditions: XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation. Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-200°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-200°C, heating rate 10°C/min.
Table 7. X-Ray Powder Diffraction peaks of hydrochloride salt Form F of compound (I).
Figure imgf000030_0001
DSC and TGA results shown in FIG. 17 and FIG. 18 indicate hydrochloride salt Form F of compound (I) has an onset melting temperature at 141°C .
Example 8
Preparation of Hydrochloride Salt Form G of compound (I). 100 mg Form A of compound (I) as prepared in Example 2 was weighed and transferred to a 5-mL viaL 4 mL 0.1 N HC1 solution was added to form slurry and stirred for 4 days before the solid was isolated.
The solid was isolated for XRPD analysis, DSC analysis and TGA analysis. The XRPD pattern of hydrochloride salt Form G of compound (I) is shown in FIG. 19.
Major peaks and their related intensities in the XRPD pattern are shown in Table 8.
Experimental conditions:
XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation. Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-250°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-300°C, heating rate 10°C/min.
Table 8. X-Ray Powder Diffraction peaks of hydrochloride salt Form G of compound (I).
Figure imgf000031_0001
Figure imgf000032_0001
DSC and TGA results shown in FIG. 20 and FIG. 21 indicate hydrochloride salt Form G of compound (I) has an onset melting temperature at 152°C.
Example 9
Preparation of Hydrochloride Salt Form H of compound (I).
40 mg of amorphous form of compound (I) as prepared in Example 1 was weighed and transferred to a 2-mL vial. 1 mL 0.1 N HC1 was added to form slurry. The vial was mounted to a shaker and kept shaking for 1 day at room temperature. After 1 day, the slurry was removed from the vial, transferred to a 1.5mL centrifuge tube and centrifuge at 12000rpm for 5 minutes. The supernatant was removed and the residual solid was analysed using XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of hydrochloride salt Form H of compound (I) is shown in FIG. 22. Major peaks and their related intensities in the XRPD pattern are shown in Table 9.
Experimental conditions:
XRPD: Bruker D8 Advance X-ray diffractometer with Cu-Κα radiation. Tube voltage was 40KV and tube current was 40mA. Scan range was from 4 to 40 degree 2-theta. The step size was 0.05° at a scanning speed of 3°/min.
DSC analysis: TA Q2000, 25-300°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-300°C, heating rate 10°C/min.
Table 9. X-Ray Powder Diffraction peaks of hydrochloride salt Form H of compound (I).
Figure imgf000032_0002
Figure imgf000033_0001
DSC and TGA results shown in FIG. 23 and FIG. 24 indicate hydrochloride salt Form H of compound (I) has an onset melting temperature at 136°C.
Example 10
Omitted
Example 11
Omitted
Example 12
Preparation of Ethylsulfate Form L of compound (I).
100 mg Form A of compound (I) as prepared in Example 2 was dissolved with 3.3 mL EtOAc and then 0.5 mL 0.2 M H2S04 solution in EtOAc was added. The resulting solution was stirred for 24 hours to form solid precipitation. The solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of ethylsulfate Form L of compound (I) is shown in FIG. 30. Major peaks and their related intensities in the XRPD pattern are shown in Table 12.
Experimental conditions: XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation.
Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-200°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-250°C, heating rate 10°C/min.
Table 12. X-Ray Powder Diffraction peaks of ethylsulfate Form L of compound (I)
Figure imgf000034_0001
Figure imgf000035_0001
DSC and TGA results shown in FIG. 31 and FIG. 32 indicate ethylsulfate Form L of compound (I) has an onset melting temperature at 160°C.
FIG. 33 shows the X-ray structure of ethylsulfate Form L. The single crystal X-ray intensity data were collected at 173(2) K using a Broker ΑΡΕΧ-Π CCD diffractometer (Cu-Kα radiation, λ= 1.54178 A). The crystal data and structure refinement is shown in Table 13.
Table 13. Crystal data and structure refinement of ethylsulfate Form L of compound (I).
Figure imgf000035_0002
Figure imgf000036_0001
Example 13
Preparation of Calcium Salt Form M of compound (I).
40mg of Form A of compound (I) as prepared in Example 2 was dissolved in MeOH/H2O (19/1, v/v). Equal molar 0.1M Ca(OH)2 solution in MeOH/H2O (19/1, v/v) was added and mixed well. The solution was stirred at room temperature overnight to generate precipitation.
The solid precipitate was isolated for XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of calcium salt Form M of compound (I) is shown in FIG. 34. Major peaks and their related intensities in the XRPD pattern are shown in Table 14.
Experimental conditions: XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation. Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-200°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-300°C, heating rate 10°C/min.
Table 14. X-Ray Powder Diffraction peaks of calcium salt Form M of compound (I).
Figure imgf000037_0001
DSC and TGA results shown in FIG. 35 and FIG. 36 indicate Calcium Salt Form M of compound (I) has an onset melting temperature at 59°C.
Example 14
Preparation of Calcium Salt Form N of compound (I).
40mg of calcium salt Form M of compound (I) as prepared in Example 13 was heated up to 110°C, held for 5 min and cooled down to room temperature. The solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of calcium salt Form N of compound (I) is shown in FIG. 37. Major peaks and their related intensities in the XRPD pattern are shown in Table 15.
Experimental conditions: XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation.
Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-200°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-300°C, heating rate 10°C/min.
Table IS. X-Ray Powder Diffraction peaks of calcium salt Form N of compound (I).
Figure imgf000038_0001
Figure imgf000039_0001
DSC and TGA results shown in FIG. 38 and FIG. 39 indicate Calcium Salt Form N of compound (I) has a onset melting temperature at 63°C.
Example 15 Preparation of Calcium Salt Form P of compound (I).
40mg calcium salt Form N of compound (I) as prepared in Example 14 was weighed and dispersed in water to form slurry and stirred for 1 hour at room temperature.
The solid was isolated for XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of calcium salt Form P of compound (I) is shown in FIG. 40. Major peaks and their related intensities in the XRPD pattern are shown in Table 16.
Experimental conditions:
XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation. Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-275°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-325°C, heating rate 10°C/min.
Table 16. X-Ray Powder Diffraction peaks of calcium salt Form P of compound (I).
Figure imgf000039_0002
Figure imgf000040_0001
DSC and TGA results shown in FIG. 41 and FIG. 42 indicate Calcium Salt Form P of compound (I) has an onset melting temperature at 230°C.
Example 16
Preparation of Calcium Salt Form Q of compound (I).
20mg calcium salt Form N of compound (I) as prepared in Example 14 was weighed and mounted on the DVS (dynamic vapour sorption) intrinsic from SMS (Surface Measurement Systems Co. Ltd.) and run the method shown in Table 17.
Table 17. The testing parameters of DVS.
Figure imgf000040_0002
Figure imgf000041_0002
After the DVS test, the solid was analysed using XRPD, DSC analysis and TGA analysis. The XRPD pattern of calcium salt Form Q of compound (I) is shown in FIG. 43. Major peaks and their related intensities in the XRPD pattern are shown in Table 18.
Experimental conditions: XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Κα radiation.
Tube voltage was 45KV and tube current was 40mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.013° at a scanning speed of 10°/min.
DSC analysis: TA Q2000, 25-260°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-300°C, heating rate 10°C/min.
Table 18. X-Ray Powder Diffraction peaks of calcium salt Form Q of compound (I).
Figure imgf000041_0001
Figure imgf000042_0001
DSC and TGA results shown in FIG. 44 and FIG. 45 indicating Calcium Salt Form Q of compound (I) has an onset melting temperature at 191°C.
Example 17 Preparation of Hydrate Form, Form A of compound (I).
1 kg of compound (I) crude product was dissolved into 1.875 L actone, the resulting mixture was added dropwise into 15L water at 25°C. Then 90g of seed was added into reaction mixture, the resulting mixture was stirred at 25°C for 3 days. The solid was collected by filtration and washed twice with 5 L water and dried in a vaccum oven at 55°C for 7 days. The water content of final product was determined using Karl Fischer Coulo metric titration.
The result of water content was 2.5%.
Example 18
Preparation of Hydrate Form, Form A of compound (I). 2 kg of compound (I) crude product was dissolved into 3.75 L actone, the resulting mixture was added dropwise into 30L water at 25°C. Then 180g of seed was added into reaction mixture, the resulting mixture was stirred at 25°C for 3 days. The solid was collected by filtration and washed twice with 10 L water and dried in a vaccum oven at 55°C for 7 days.
The water content of final product was determined using Karl Fischer Coulometric titration. The result of water content was 3.9%.
Example 19
Preparation of Hydrate Form, Form A of compound (I). 2 kg of compound (I) crude product was dissolved into 3.75 L actone, the resulting mixture was added dropwise into 30L water at 25°C. Then 18g of seed was added into reaction mixture, the resulting mixture was stirred at 25°C for 3 days. The solid was collected by filtration and washed twice with 10 L water and dried in a vaccum oven at 55°C for 7 days. The water content of final product was determined using Karl Fischer Coulometric titration.
The result of water content was 4.5%.
Example AA
Preparation of Mesylate Form J of compound (I). 40mg of compound (I) was dissolved by MIBK to form a clear solution. Equal molar methylsulfonic acid was added as 0.1 M solution in MIBK. The mixture was heated at 45°C- 50°C for 2h. The resulted suspension was cooled to room temperature over 1 h and maintained at room temperature for 30 min.
The solid was collected by filtration, washed with MIBK and analysed using XRPD analysis, DSC analysis and TGA analysis.
The XRPD pattern of mesylate Form J of compound (I) is shown in FIG. 46. Major peaks and their related intensities in the XRPD pattern are shown in Table 10 below.
Experimental conditions:
XRPD: Bruker D8 Advance X-ray diffractometer with Cu-Κα radiation. Tube voltage was 40KV and tube current was 40mA. Scan range was from 4 to 40 degree 2-theta. The step size was 0.05° at a scanning speed of 3°/min.
DSC analysis: TA Q2000, 25-300°C, heating rate 10°C/min.
TGA analysis: TA Q5000, 25-400°C, heating rate 10°C/min.
Table 10 X-Ray Powder Diffraction peaks of mesylate Form J of compound (I).
Figure imgf000044_0001
DSC and TGA results shown in FIG. 47 and FIG. 48 indicate mesylate Form J of compound (I) has an onset melting temperature at 134°C.
Example AB Chemical stability of solid forms
40mg compound (I) with different solid forms were stored in stability chamber with temperature and humidity controlled as 40°C and 75%RH respectively. After 1 month, the samples were analyzed by HPLC method (described in Example AD) to check their chemical purity and compared with their initial value. According to the results shown in Table 11, the new discovered forms show much better stability than the original Form J as prepared in Example AA. Table 11 Chemical stability data of different solid forms of compound (I)
Figure imgf000045_0001
Example AC
Equilibrium aqueous solubility
Aqueous solubility was determined by suspending lOmg compound in different bio- relevant media including SGF, FaSSIF and FeSSIF. The suspension was equilibrated at 25 °C for 24 hours then the final pH was measured. The suspension was then filtered through a 0.22um PVDF filter into a 2-mL HPLC vial. The quantitation was conducted by HPLC (described in Example AD) with reference to a standard solution. The solubility results of selected novel solid forms in this invention are shown in Table 12 which showed good aqueous solubility higher than 0.5mg/mL.
Table 12 Aqueous solubility of different solid forms
Figure imgf000045_0002
Figure imgf000046_0001
Example AD
HPLC method for chemical purity and assay test
HPLC condition is disclosed here in Table 13.
Table 13 HPLC conditions for chemical purity and assay test
Figure imgf000046_0002
Figure imgf000047_0001

Claims

1. An amorphous or crystalline form of compound (I):
Figure imgf000048_0001
or salts, solvates or combination thereof.
2. An amorphous or crystalline form according to claim 1 , wherein the form is amorphous form, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form L, Form M, Form N, Form P, Form Q or a combination thereof.
3. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77°±0.1°, 8.22°±0.1°, 19.71°±0.1°, 19.99°±0.1°, 24.77°±0.1° and25.68°±0.1°.
4. A crystalline form according to claim 3, wherein the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.77°±0.1°, 8.22°±0.1°, 9.10°±0.1°, 9.81°±0.1°, 11.33°±0.1°, 12.60°±0.1°, 14.31°±0.1°, 19.71°±0.1°, 19.99°±0.1°, 21.56°±0.1°, 21.97°±0.1°, 22.46°±0.1°, 23.22°±0.1°, 24.77°±0.1°, 25.68°±0.1°, 26.10°±0.1°, 27.47°±0.1° and 28.22°±0.1°.
5. A crystalline form according to claim 3 or 4, wherein the crystalline form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 2.
6. A crystalline form according to any one of claims 3 to 5, wherein the crystalline Form A is a hydrate of compound (I) with water content of 0.5% to 10%, particularly 2.5% to 4.5%.
7. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42°±0.1°, 19.62°±0.1°, 20.42°±0.1°, 23.03°±0.1°, 25.51°±0.1° and
26.65°±0.1°.
8. A crystalline form according to claim 7, wherein the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.42°±0.1°, 9.34°±0.1°, 11.72°±0.1°, 12.63°±0.1°, 18.67°±0.1°, 19.62°±0.1°, 20.42°±0.1°, 23.03°±0.1°, 24.04°±0.1°, 25.51°±0.1°, 25.99°±0.1°, 26.65°±0.1°, 27.74°±0.1° and 28.36°±0.1°.
9. A crystalline form according to claim 7 or 8, wherein the crystalline form is Form B that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 5.
10. A crystalline form according to any one of claims 7 to 9, wherein the crystalline Form B is an anhydrous form of compound (I).
11. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 17.04°±0.1°, 20.93°±0.1°, 21.28°±0.1°, 22.56°±0.1°, 24.17°±0.1° and
24.38°±0.1°.
12. A crystalline form according to claim 11, wherein the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.65°±0.1°, 12.58°±0.1°, 14.89°±0.1°, 17.04°±0.1°, 19.40°±0.1°, 20.93°±0.1°, 21.28°±0.1°, 22.56°±0.1°, 23.67°±0.1°, 24.17°±0.1°, 24.38°±0.1° and 24.81°±0.1°.
13. A crystalline form according to claim 11 or 12, wherein the crystalline form is Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 6.
14. A crystalline form according to any one of claims 11 to 13, wherein the crystalline Form C is a co-crystal of monohydrate of compound (I) and tetrafluoroborate of compound (I).
15. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74°±0.1°, 17.20°±0.1°, 20.46°±0.1°, 23.43°±0.1°, 28.38°±0.1° and
30.88°±0.1°.
16. A crystalline form according to claim 15, wherein the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 15.74°±0.1°, 17.20°±0.1°, 20.46°±0.1°, 21.96°±0.1°, 23.43°±0.1°, 24.76°±0.1°, 28.38°±0.1°, 30.88°±0.1°, 31.72°±0.1°, 32.80°±0.1°, 33.55°±0.1° and 37.17°±0.1°.
17. A crystalline form according to claim 15 or 16, wherein the crystalline form is Form D that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 10.
18. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39°±0.1°, 7.96°±0.1°, 9.82°±0.1°, 20.74°±0.1°, 22.50°±0.1°, 23.82°±0.1°, 24.69°±0.1° and 26.20°±0.1°.
19. A crystalline form according to claim 18, wherein the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.39°±0.1°, 7.96°±0.1°, 9.82°±0.1°, 12.22°±0.1°, 16.92°±0.1°, 20.02°±0.1°, 20.74°±0.1°, 21.65°±0.1°, 22.50°±0.1°, 23.82°±0.1°, 24.69°±0.1°, 26.20°±0.1°, 27.76°±0.1° and 28.92°±0.1°.
20. A crystalline form according to claim 18 or 19, wherein the crystalline form is Form E that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 13.
21. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.73°±0.1°, 20.87°±0.1°, 21.80°±0.1°, 23.15°±0.1°, 27.03°±0.1° and
28.58°±0.1°.
22. A crystalline form according to claim 21, wherein the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.02°±0.1°, 11.73°±0.1°, 14.89°±0.1°, 18.36°±0.1°, 20.87°±0.1°, 21.80°±0.1°, 23.15°±0.1°, 24.44°±0.1°, 25.35°±0.1°, 27.03°±0.1°, 28.58°±0.1°, 32.21°±0.1°, 33.52°±0.1° and 39.03°±0.1°.
23. A crystalline form according to claim 21 or 22, wherein the crystalline form is Form F that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 16.
24. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 9.85°±0.1°, 12.32°±0.1°, 17.37°±0.1°, 23.07°±0.1°, 24.86°±0.1°, 25.31°±0.1° and 28.48°±0.1°.
25. A crystalline form according to claim 24, wherein the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.81°±0.1°, 8.20°±0.1°, 9.85°±0.1°, 12.32°±0.1°, 15.01°±0.1°, 17.37°±0.1°, 19.35°±0.1°, 21.19°±0.1°, 22.42°±0.1°, 23.07°±0.1°, 24.86°±0.1°, 25.31°±0.1°, 26.57°±0.1°, 28.48°±0.1° and 35.38°±0.1°.
26. A crystalline form according to claim 24 or 25, wherein the crystalline form is Form G that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 19.
27. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88°±0.1°, 18.31°±0.1°, 19.94°±0.1°, 21.49°±0.1°, 23.12°±0.1°, 23.91°±0.1°, 25.69°±0.1° and 26.83°±0.1°.
28. A crystalline form according to claim 27, wherein the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.88°±0.1°, 13.23°±0.1°, 14.42°±0.1°, 17.69°±0.1°, 18.31°±0.1°, 19.94°±0.1°, 21.49°±0.1°, 23.12°±0.1°, 23.91°±0.1°, 25.69°±0.1° and 26.83°±0.1°.
29. A crystalline form according to claim 27 or 28, wherein the crystalline form is Form H that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 22.
30. A crystalline form according to any one of claims 15 to 29, wherein the crystalline Form D, Form E, Form F, Form G or Form H is a hydrochloride salt of compound (I).
31. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29°±0.1°, 15.86°±0.1°, 18.99°±0.1°, 20.88°±0.1°, 22.96°±0.1° and
23.30°±0.1°.
32. A crystalline form according to claim 31, wherein the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.29°±0.1°, 10.56°±0.1°, 10.95°±0.1°, 15.86°±0.1°, 18.99°±0.1°, 20.88°±0.1°, 21.19°±0.1°, 21.71°±0.1°, 22.96°±0.1°, 23.30°±0.1°, 25.02°±0.1°, 26.84°±0.1°, 28.29°±0.1° and 32.36°±0.1°.
33. A crystalline form according to claim 31 or 32, wherein the crystalline form is Form L that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 30.
34. A crystalline form according to any one of claims 31 to 33, wherein the crystalline Form L is an ethylsulfate of compound (I).
35. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24°±0.1°, 8.57°±0.1°, 13.64°±0.1°, 14.53°±0.1°, 16.50°±0.1°, 17.18°±0.1°, 19.47°±0.1° and 22.11°±0.1°.
36. A crystalline form according to claim 35, wherein the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 6.24°±0.1°, 8.57°±0.1°, 9.80°±0.1°, 13.64°±0.1°, 14.53°±0.1°, 16.50°±0.1°, 17.18°±0.1°, 19.47°±0.1°, 22.11°±0.1°, 25.23°±0.1°, 28.11°±0.1° and 29.39°±0.1°.
37. A crystalline form according to claim 35 or 36, wherein the crystalline form is Form M that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 34.
38. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62°±0.1°, 9.22°±0.1°, 18.50°±0.1°, 19.05°±0.1°, 23.14°±0.1° and23.88°±0.1°.
39. A crystalline form according to claim 38, wherein the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.62°±0.1°, 9.22°±0.1°, 11.81°±0.1°, 13.10°±0.1°, 13.83°±0.1°, 17.44°±0.1°, 18.50°±0.1°, 19.05°±0.1°, 20.63°±0.1°, 21.98°±0.1°, 23.14°±0.1°, 23.88°±0.1°, 25.61°±0.1°, 27.85°±0.1°, 29.31°±0.1° and 39.07°±0.1°.
40. A crystalline form according to claim 38 or 39, wherein the crystalline form is Form N that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 37.
41. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.27°±0.1°, 12.18°±0.1°, 17.57°±0.1°, 18.01°±0.1°, 22.38°±0.1° and
23.16°±0.1°.
42. A crystalline form according to claim 41 , wherein the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.23°±0.1°, 11.27°±0.1°, 12.18°±0.1°, 15.51°±0.1°, 16.46°±0.1°, 17.57°±0.1°, 18.01°±0.1°, 21.18°±0.1°, 22.38°±0.1°, 23.16°±0.1°, 24.44°±0.1°, 29.59°±0.1° and 31.83°±0.1°.
43. A crystalline form according to claim 40 or 41, wherein the crystalline form is Form P that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 40.
44. A crystalline form according to claim 1 or 2, wherein the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 11.04°±0.1°, 12.77°±0.1°, 16.33°±0.1°, 16.71°±0.1°, 18.06°±0.1° and
20.65°±0.1°.
45. A crystalline form according to claim 44, wherein the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.35°±0.1°, 9.96°±0.1°, 11.04°±0.1°, 12.77°±0.1°, 15.04°±0.1°, 16.33°±0.1°,
16.71°±0.1°, 18.06°±0.1°, 20.65°±0.1°, 22.19°±0.1°, 23.76°±0.1°, 25.36°±0.1°, 26.64°±0.1°, 29.34°±0.1° and 30.26°±0.1°.
46. A crystalline form according to claim 44 or 45, wherein the crystalline form is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG. 43.
47. A crystalline form according to any one of claims 35 to 46, wherein the crystalline Form M, Form N, Form P or Form Q is a calcium salt of compound (I).
48. A pharmaceutical composition comprising the amorphous or crystalline form of anyone of the claims 1 to 47 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
49. The use of the amorphous or crystalline form of any one of claims 1 to 47 or the pharmaceutical composition of claim 48 for the manufacture of a medicament for the treatment or prophylaxis of a viral disease in a patient.
50. The use according to claim 49, wherein the viral disease is hepatitis B infection or a disease caused by hepatitis B infection.
51. A method for the treatment or prophylaxis of hepatitis B infection or a disease caused by hepatitis B infection, which method comprises administering an therapeutically effective amount of the amorphous or crystalline form as defined in any one of claims 1 to 47 or the pharmaceutical composition of claim 48.
52. The invention as hereinbefore described.
PCT/EP2015/066695 2014-07-25 2015-07-22 New amorphous and crystalline forms of (3s)-4-[[(4r)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid WO2016012470A1 (en)

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