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WO2008140302A1 - Polymorphic forms of tenofovir disoproxil fumarate - Google Patents

Polymorphic forms of tenofovir disoproxil fumarate Download PDF

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Publication number
WO2008140302A1
WO2008140302A1 PCT/NL2008/000129 NL2008000129W WO2008140302A1 WO 2008140302 A1 WO2008140302 A1 WO 2008140302A1 NL 2008000129 W NL2008000129 W NL 2008000129W WO 2008140302 A1 WO2008140302 A1 WO 2008140302A1
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Prior art keywords
ult
tenofovir
theta
degrees
crystallising
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French (fr)
Inventor
Evanthia Dova
Jaroslaw Marek Mazurek
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ULTIMORPHIX TECHNOLOGIES BV
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ULTIMORPHIX TECHNOLOGIES BV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention relates to novel crystalline forms of tenofovir disoproxil fumarate (tenofovir DF) , methods for their preparation and their formulation and application in the field of medicine, in particular antiviral medicines.
  • tenofovir DF tenofovir disoproxil fumarate
  • Tenofovir disoproxil fumarate (also known as Viread(R), Tenofovir DF, Tenofovir disoproxil, TDF, Bis-POC-PMPA (U.S. Pat. Nos . 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249) is a prodrug of tenofovir.
  • the chemical name of tenofovir disoproxil fumarate is 9- [(R) -2- [ [bis [ [ (isopropoxycarbonyl) oxyjmethoxy] phosphinyl]methoxy] propyl] adenine fumarate (1:1).
  • the CAS Registry number is 202138-50-9. It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:
  • Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor approved in the United States for the treatment of HIV-I infection in combination with other antiretroviral agents.
  • Tenofovir disoproxil DF is available as Viread(R) (Gilead Science, Inc. ) .
  • the anti-HIV drugs which have been developed are those which target the HIV reverse transcriptase (RT) enzyme or protease enzyme, both of which enzymes are necessary for the replication of the virus.
  • RT inhibitors include nucleoside/nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) .
  • Tenofovir DF is described inter alia in WO99/05150 and EP998480.
  • This crystalline form is characterised as having XRPD peaks at about 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1 and 30.4.
  • these crystals are described as opaque or off-white and exhibit a DSC absorption peak at about 118 0 C with an onset at about 116 0 C and an IR spectrum showing characteristic bands expressed in reciprocal centimetres at approximately 3224, 3107-3052, 2986-2939, 1759, 1678, 1620, 1269 and 1102.
  • Bulk densities have been described of about 0.15-0.30 g/mL, usually about 0.2-0.25 g/mL.
  • Polymorphs is often characterised as the ability of a solid substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • the arrangement of the molecules in the space can affect the physical properties of the material and can be influenced by controlling the conditions under which the solid form is obtained.
  • the present invention relates to the discovery of various solid forms of tenofovir DF and their solid state physical properties .
  • TGA differential scanning calorimetry
  • DSC differential scanning calorimetry
  • Solid state physical properties affect the ease with which the material is handled during processing into a pharmaceutical product such as a tablet or capsule formulation.
  • the physical properties impact the sort of excipients, for instance, to add to a tenofovir DF formulation.
  • the solid state physical property of a pharmaceutical compound is important to its dissolution in aqueous fluid or even in a patient's stomach fluid, which have therapeutic consequences.
  • the rate of dissolution is also a consideration in liquid forms of medicine as well.
  • the solid state form of a compound may also affect its storage conditions.
  • the present invention relates to novel crystalline forms of tenofovir DF.
  • the present inventors have identified novel crystalline forms, herein depicted as ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT- 19, ULT-20, ULT-21 and ULT-22.
  • Figure IA illustrates the X-Ray Powder Diffraction pattern
  • Figure IB illustrates the DSC thermogram of Tenofovir DF Form ULT-4
  • Figure 1C illustrates the TGA thermogram of Tenofovir DF Form ULT-4.
  • Figure 2A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-5.
  • Figure 3A illustrates the X-Ray Powder Diffraction pattern
  • FIG. 4A illustrates the X-Ray Powder Diffraction pattern of
  • Figure 4B illustrates the DSC thermogram of Tenofovir DF Form ULT-7.
  • Figure 4C illustrates the TGA thermogram of Tenofovir DF Form ULT-7.
  • Figure 5A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-8.
  • Figure 5B illustrates the DSC thermogram of Tenofovir DF Form ULT-8.
  • Figure 5C illustrates the TGA thermogram of Tenofovir DF Form ULT-8.
  • Figure 7A illustrates the X-Ray Powder Diffraction pattern of
  • FIG. 8A illustrates the X-Ray Powder Diffraction pattern of
  • Figure 8B illustrates the DSC thermogram of Tenofovir DF Form ULT-Il.
  • Figure 8C illustrates the TGA thermogram of Tenofovir DF Form ULT-Il.
  • Figure 6D illustrates the molecular structure of base-acid-base entity from the crystals of Tenofovir DF Form ULT-Il.
  • Figure 6E illustrates the Crystal arrangement for Tenofovir DF Form
  • Figure 9A illustrates the X-Ray Powder Diffraction pattern of
  • FIG. 9B illustrates the DSC thermogram of Tenofovir DF Form ULT-12.
  • Figure 9C illustrates the TGA thermogram of Tenofovir DF Form ULT-12.
  • Figure IOA illustrates the X-Ray Powder Diffraction pattern
  • Figure HA illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-14.
  • Figure 12A illustrates the X-Ray Powder Diffraction pattern of
  • Figure 12B illustrates the DSC thermogram of Tenofovir DF Form ULT- 15.
  • Figure 12C illustrates the TGA thermogram of Tenofovir DF Form ULT- 15.
  • Figure 13A illustrates the X-Ray Powder Diffraction pattern of
  • Figure 14A illustrates the X-Ray Powder Diffraction pattern of
  • FIG. 15A illustrates the X-Ray Powder Diffraction pattern of
  • Figure 16C illustrates the TGA thermogram of Tenofovir DF Form ULT-
  • Figure 17A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-20.
  • Figure 17C illustrates the TGA thermogram of Tenofovir DF Form ULT- 20.
  • Figure 18A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-21.
  • Figure 18B illustrates the DSC thermogram of Tenofovir DF Form ULT- 21.
  • Figure 18C illustrates the TGA thermogram of Tenofovir DF Form ULT- 21.
  • Figure 19A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-22.
  • Form ULT-4 can be characterised by an XRPD substantially according to Fig IA.
  • Form ULT-4 can be characterised by an
  • Form ULT-4 can be characterised by an
  • Form ULT-4 of the present invention can be characterised by DSC with an onset at 96.2°C and a characterising peak at 108.9 0 C.
  • Form ULT-4 of the present invention can be further characterised by DSC with an onset at
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-4 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-4 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-4 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-5, characterised by an XRPD substantially according to Fig 2A.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-5 by evaporation of the solvent.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-5 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-5 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-5 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-6, characterised by an XRPD substantially according to Fig 3A.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-6 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-6 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-6 by anti-solvent addition as in Table III.
  • the present invention m another aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-6 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline " tenofovir DF herein defined as Form ULT-7, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 6.9, 8.9, 9.6, 10.2, 11.3, 13.2, 14.1, 17.8, 18.7, 20.0, 21.8, 23.8, 25.3, 27.8, 30.5, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen and most preferred sixteen X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-7 can be characterised by the following set of XRPD peaks (Table 4) and, optionally, by the associated intensities:
  • Form ULT-7 can be characterised by an XRPD substantially according to Fig 4A.
  • Form ULT-7 can be characterised by an DSC substantially according to Fig 4B. In another embodiment, Form ULT-7 can be characterised by an TGA substantially according to Fig 4C.
  • Form ULT-7 of the present invention can be characterised by DSC with an onset at 98.4°C and a characterising peak at 108.4 0 C. From the thermal analysis, it is concluded that solid form ULT-7 is anhydrous.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-7 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-7 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-7 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-7 by slurry crystallisation and/or seed crystallisation.
  • Crystalline tenofovir DF form ULT-8 (C)
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-8, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 10.3, 13.4, 14.7, 15.7, 17.3, 18.4, 19.1, 20.7, 21.2, 25.2 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • Form ULT-8 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-8 can be characterised by an XRPD substantially according to Fig 5A . In another embodiment, Form ULT-8 can be characterised by an
  • Form ULT-8 can be characterised by an
  • Form ULT-8 of the present invention can be characterised by DSC with an onset at 104.8 0 C and a characterising peak at 113.0 0 C. From the thermal analysis, it is concluded that solid form ULT-8 is anhydrous.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-8 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-8 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-10, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 1,.O 1 10.6, 11.8, 12.7, 13.5, 15.2, 16.3, 17.3, 18.8, 20.7, 21.3, 22.2, 25.3, 27.3, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-10 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-10 can be characterised by an XRPD substantially according to Fig 7A.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-10 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-10 by evaporation of the solvent.
  • the present invention m another aspect relates to a method for the preparation of the crystalline form ULT-10of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as m Table II and crystallising tenofovir DF Form ULT-10 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-10 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-10 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-10 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-10 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-Il, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 7.0, 9.5, 10.6, 11.7, 13.5, 16.0, 17.4, 18.8, 20.4, 21.2, 22.0, 25.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • at least twelve, more preferably at least thirteen X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-Il can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-Il can be characterised by an XRPD substantially according to Fig 8A.
  • Form ULT-Il can be characterised by an DSC substantially according to Fig 8B. In another embodiment, Form ULT-Il can be characterised by an TGA substantially according to Fig 8C.
  • Form ULT-Il of the present invention can be characterised by DSC with an onset at 104.5 0 C and a characterising peak at 112.8°C. From the thermal analysis, it is concluded that solid form ULT-Il is anhydrous.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-Il by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the_ preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-Il by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-Il by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-Il by slurry crystallisation and/or seed crystallisation.
  • the present invention in one aspect relates to the crystal structure of tenofovir DF Form ULT-Il as depicted in figure 8D and/or 8E and/or in the table Xl, Yl and Zl below:
  • Wavelength 0 . 71073 Crystal system Monoclinic Space group P 2 Unit cell dimensions 9.7440(3) [9.963(2)]* 18.0330(5) [18.410(5)] 17.4080(6) [18.160(2)] 102.759(2) [104.66(2)]
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-12, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.2, 5.2, 9.5, 14.5, 16.7, 18.6, 19.2, 20.2, 11.1, 13.4, 17.3, 21.2, 25.4 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-12 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-12 can be characterised by an XRPD substantially according to Fig 9A.
  • Form ULT-12 can be characterised by an DSC substantially according to Fig 9B.
  • Form ULT-12 can be characterised by an TGA substantially according to Fig 9C.
  • Form ULT-12 of the present invention can be characterised by DSC with an onset at 90.0 0 C and a characterising peak at 100.4 0 C.
  • Form ULT- 12 of the present invention can be further characterised by DSC with an onset at 107.9 0 C and a characterising peak at 113.7°C. From the thermal analysis, it is concluded that solid form ULT-12 is a solvate with an alcohol, preferably cyclopentanol, cyclohexanol or isobutanol .
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-12 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-12 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-12 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-12 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-13, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 5.6, 9.1, 10.4, 13.3, 14.8, 16.0, 16.0, 19.4, 21.4, 23.7, 28.6 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • twelve X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-13 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-13 can be characterised by an
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-13 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-13 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-13 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-13 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-14, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five X-ray powder diffraction peaks selected from the group consisting of 4.7, 10.3, 18.4, 20.6, 21.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • Form ULT-14 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
  • Form ULT-14 can be characterised by an XRPD substantially according to Fig HA.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-14 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-14 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-14 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-14 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-15, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 5.2, 9.4, 10.5, 13.2, 17.1, 18.3, 21.3, 24.4 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • Form ULT-15 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
  • Form ULT-15 can be characterised by an XRPD substantially according to Fig 12A. In another embodiment, Form ULT-15 can be characterised by an DSC substantially according to Fig 12B.
  • Form ULT-15 can be characterised by an TGA substantially according to Fig 12C.
  • Form ULT-15 of the present invention can be characterised by DSC with an onset at 61.3°C and a characterising peak at 69.8 0 C.
  • Form ULT-15 can be further characterised by DSC with an onset at 92.8 0 C and a characterising peak at 97.8 0 C.
  • Form ULT-15 can be characterised by DSC with an onset at 104.8 0 C and a characterising peak at 111.8 0 C.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-15 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-15 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-16, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 10.3, 13.4, 15.4, 18.5, 20.6, 21.5, 23.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • Form ULT-16 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-16 can be characterised by an XRPD substantially according to Fig 13A.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-16 by evaporation of the solvent.
  • the present invention m another aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-16 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-16 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-16 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-17, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.8, 10.2, 10.8, 11.8, 13.3, 15.6, 17.0, 18.0, 18.8, 20.5, 21.5, 23.2, 24.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • at least twelve, more preferably thirteen X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-17 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-17 can be characterised by an XRPD substantially according to Fig 14A.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-17 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-17 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-17 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-17 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-18, characterised by the selection of at least one, preferably two X-ray powder diffraction peaks selected from the group consisting of 4.3 and 10.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • Form ULT-18 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
  • Form ULT-18 can be characterised by an XRPD substantially according to Fig 15A.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-18 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-18 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-18 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-19, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.3, 9.7, 10.5, 13.3, 17.1, 21.4, 30.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • seven X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-19 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
  • Form ULT-19 can be characterised by an XRPD substantially according to Fig 16A.
  • Form ULT-19 can be characterised by an TGA substantially according to Fig 16C.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-19 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-19 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-19 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-19 by slurry crystallisation and/or seed crystallisation.
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-20, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.1, 9.0, 10.4, 11.3, 13.3, 17.6, 18.7, 19.6, 20.3, 21.3, 23.7, 24.4, 25.6, 26.5, 27.6, 29.4, 30.8 degrees two-theta +/- 0.3 degrees two- theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen and most preferred sixteen X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-20 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-20 can be characterised by an XRPD substantially according to Fig 17A.
  • Form ULT-20 can be characterised by an TGA substantially according to Fig 17C. From the thermal analysis, it is concluded that solid form ULT-20 is anhydrous.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-20 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-20 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-20 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-20 by slurry crystallisation and/or seed crystallisation.
  • Crystalline tenofovir DF form ULT-21 (V)
  • the present invention provides crystalline tenofovir DF herein defined as Form ULT-21, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.1, 9.0, 10.4, 11.3, 13.3, 17.6, 18.7, 19.6, 20.3, 21.3, 23.7, 24.4, 25.6, 26.5, 27.6, 29.4, 30.8 degrees two-theta +/- 0.3 degrees two- theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen and most preferred sixteen X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-21 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-21 can be characterised by an XRPD substantially according to Fig 18A.
  • Form ULT-21 can be characterised by an DSC substantially according to Fig 18B. In another embodiment, Form ULT-21 can be characterised by an TGA substantially according to Fig 18C.
  • Form ULT-21 of the present invention can be characterised by DSC with an onset at 100.8 0 C and a characterising peak at 105.6 0 C.
  • Form ULT-21 can be further characterised by DSC with an onset at 107.6 0 C and a characterising peak at 114.7°C. From the thermal analysis, it is concluded that solid form ULT-21 is anhydrous.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-21 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-21 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-21 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-21 by slurry crystallisation and/or seed crystallisation.
  • Crystalline tenofovir DF form ULT-22 (X) provides crystalline tenofovir DF herein defined as Form ULT-22, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.4, 8.9, 9.3, 9.9, 10.4, 13.3, 17.6, 19.2, 21.2, 21.8, 23.0, 23.5, 25.7, 26.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
  • At least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group.
  • at least twelve, more preferably at least thirteen, even more preferably fourteen X-ray powder diffraction peaks are selected from the above group.
  • Form ULT-22 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
  • Form ULT-22 can be characterised by an
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-22 by evaporation of the solvent.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-22 by cooling and/or evaporation crystallization of a saturated solution.
  • the present invention in one aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-22 by anti-solvent addition as in Table III.
  • the present invention in another aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-22 by slurry crystallisation and/or seed crystallisation.
  • Form ULT-22 was obtained by slow evaporation of saturated solution of tenofovir DF in methanol/water (50/50) at room temperature. During cooling of the saturated solution, solid material crystallized out. The solution was heated anew until dissolution of the solid material and as diluted to half the concentration. The solution was slowly cooled to room temperature and aged for several days. Purity
  • the forms ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, , ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT- 16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22 of the present invention are, independently, in a substantially pure form, preferably substantially free from other amorphous, and/or crystalline solid forms such as ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT- 18, ULT-19, ULT-20, ULT-21 and ULT-22 or the solid forms as described in the prior art as referred herein before or of ULT-I, ULT-2 or ULT-3 as described in applicant's copending US60/872999 and US60/873267 respectively, respectively.
  • substantially pure form preferably substantially free from other amorphous
  • substantially free from other amorphous, and/or crystalline solid forms means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, and/or crystalline solid forms are present in the form according to the invention.
  • the solvents for evaporation crystallisation, hot filtration anti-solvent addition , seed crystallisation and/or slurry crystallisation are preferably selected from the group consisting of: (R) - (-) -2-Octanol , 1 , 2-Diethoxyethane, 1 , 2-Dimethoxyethane, 1,4-Dioxane, 1-Butanol, 1-Heptanol, 1-Hexanol, l-Methoxy-2-propanol , 1-Nitropropane, 1-Octanol, 2,2,2-
  • Trifluoroethanol 2-Butanone, 2-Ethoxyethanol , 2-Ethoxyethyl acetate, 2-Hexanol, 2-Methoxyethanol, 2-Nitropropane, 2-Pentanol, 2- Propanol, 4-Hydroxy-4-methyl-2-pentanon, Acetone, Acetonitrile, Butyromtrile, Cyclohexanol , Cyclopentanol , Cyclopentanone, Diethylene glycol dimethylether , Dimethylcarbonate,
  • the solvents for hot filtration crystallisation are preferably selected from the group consisting of: (R) - (-) -2-Octanol, 1 , 2-Diethoxyethane, 1 , 2-Dimethoxyethane, 1,4- Dioxane , 1-Butanol, 1-Nitropropane, 1-Propanol, 2-Butanone, 2-
  • the solvents for solvent/anti- solvent crystallisation are preferably selected from the group consisting of: 1 , 2-Dichloroethane, 1 , 2-Dimethoxyethane, 1,4-Dioxane , 2, 6-Dimethyl-4-heptanone, 2-Butanone, Acetone, Acetonitrile, Amyl ether, Butyl benzene, Chloroform, Cyclohexane, Cyclohexane, Cyclohexane, Cyclohexane, Cyclohexane, Cyclohexane, Dichloromethane, Hexafluorobenzene, Methanol, n-Heptane, Nitromethane, N-Methyl Pyrrolidone, tert-Butyl methyl ether, Tetrahydrofuran, Toluene, Water and mixtures thereof.
  • the anti-solvents for anti-solvent crystallisation are preferably selected from the group consisting of: 1 , 2-Dichloroethane, 2, 6-Dimethyl-4-heptanone, Acetone, Amyl ether, Butyl benzene, Chloroform, Cyclohexane, Dichloromethane, Hexafluorobenzene, n-Heptane, Nitromethane, tert-Butyl methyl ether, Toluene and mixtures thereof.
  • the solvents for seeding crystallisation are preferably selected from the group consisting of: methanol, water, 1,4-dioxane, acetonitrile, 2- ethoxyethylacetate, 2- methyl-4-pentanol, tetrahydrofuran, butyl benzene, amylether, tert- butyl methyl ether, cyclopentanone and mixtures thereof.
  • the solvents for slurrying crystallisation are preferably selected from the group consisting of: water, methanol, acetonitrile, 1,4-dioxane and mixtures thereof.
  • the present invention further relates to pharmaceutical formulations comprising the novel crystalline forms of tenofovir DF.
  • compositions of the present invention contain one or more of the crystalline forms according to the present invention, such as ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT- 20, ULT-21 and ULT-22 as disclosed herein.
  • the invention also provides pharmaceutical compositions comprising one or more of the crystal forms according to the present invention.
  • Pharmaceutical formulations of the present invention contains one or more of the crystal form according to the present invention as active ingredient, optionally in a mixture with other crystal form(s).
  • the pharmaceutical formulations according to the invention may further comprise, in addition to the forms ULT-I, ULT-2, ULT-3, ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22 additional pharmaceutical active ingredients, preferably Anti- HIV agents and more preferably Efavirenz and/or Emtricitabine .
  • the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes .
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
  • Diluents for solid compositions include, for example, microcrystallme cellulose (e.g. Avicel(R)), micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, manmtol, polymethacrylates (e.g.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol] carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose,
  • FTydroxypropyl cellulose e.g. Klucel (R)
  • hydroxypropyl methyl cellulose e.g. Methocel (R)
  • liquid glucose magnesium aluminum silicate
  • maltodextrin methylcellulose
  • polymethacrylates povidone (e.g. Kollidon(R), Plasdone (R) )
  • pregelatinized starch sodium alginate and starch.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Pnmellose (R) ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone (R) ) , guar gum, magnesium aluminum silicate, methyl cellulose, microcrystallme cellulose, polacrilm potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Pnmellose (R) ) , colloidal silicon dioxide, croscar
  • Glidants can be added to improve the flowability of a non- compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium t ⁇ silicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid. Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention the crystalline forms according to the present invention and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth- feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient (s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to
  • the active ingredients When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include Tween ⁇ 60, Spans 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers .
  • Straight or branched chain, mono- or dibasic alkyl esters such as dnsoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and m others about 1.0% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal or mhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc).
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active inqredient such carriers as are known in the art to be appropriate.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (Including subcutaneous, intramuscularV and intravenous) , inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
  • the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.
  • a tabletting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include macocrystallme cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tarrretl ⁇ g " :
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • the crystalline forms according to the present invention can be formulated for administration to a mammal, preferably a human, via injection.
  • the crystalline forms according to the present invention may be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection.
  • the formulation may contain solvents. Among considerations for such solvent include the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability) , fluidity, boiling point, miscibility and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and Castor oil USP. Additional substances may be added to the formulation such as buffers, solubilizers, antioxidants, among others. Ansel et al. , Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed.
  • the present invention also provides pharmaceutical formulations comprising the crystalline form according to the present invention, optionally in combination with other polymorphic forms or co-crystals, to be used in a method of treatment of a mammal, preferably a human, in need thereof.
  • a pharmaceutical composition of the present invention comprises the crystalline form ULT-I.
  • the crystalline form according to the present invention may be used in a method of treatment of a mammal comprising administering to a mammal suffering from the ailments described herein before a therapeutically effective amount of such pharmaceutical composition.
  • the invention further relates to the use of the crystalline form of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV.
  • XRPD patterns were obtained using a T2 high-throughput XRPD set-up by Avantium technologies, The Netherlands. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings. Data collection was carried out at room temperature using monochromatic CuK (alpha) radiation in the two-theta region between 1.5 ° and 41.5 °.
  • the diffraction pattern of each well is collected in two two-theta ranges (1.5 ° ⁇ 2 ⁇ ⁇ 21.5 ° for the first frame, and 19.5 ° ⁇ 2 ⁇ ⁇ 41.5 ° for the second) with an exposure time of 120 s for each frame.
  • XRPD data are collected with a variance of about 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees. This has consequences for when X-ray peaks are considered overlapping.
  • Suitable single crystals were selected and glued to a glass fibre, which was then mounted on an X-ray diffraction goniometer. X-ray diffraction data were collected for these crystals at a temperature of 120K and at room temperature, using a KappaCCD system and MoKa radiation, generated by a FR590 X-ray generator (Bruker Nonius, Delft, The Netherlands) .
  • Unit-cell parameters and crystal structures were determined and refined using the software package MaXus .
  • Mass loss due to solvent or water loss from the crystals was de ⁇ termi ⁇ ned ⁇ by TGA/SDTA ⁇ MonTfoFing bf ⁇ th ⁇ e ⁇ samp ⁇ e ⁇ weight , duFing heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve.
  • the TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed into 100 microliter aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25°C to 300 0 C at a heating rate of 20°C/mm. Dry N 2 gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.
  • Raman spectroscopy The Raman spectra were collected with a Raman microscope mW (Kaiser Opticals Inc) at 0.96 cm ⁇ resolution using a laser of 780 nm and a power output of 100.
  • a small quantity, about 2-3 mg of the starting material was placed in a plate well.
  • the starting material was stock-dosed in tetrahydrofuran/water (80/20 v/v) mixture.
  • the solvent was removed by evaporation under 2OkPa for about 45-75 h and the starting material was dry.
  • the crystallisation solvent or mixture of crystallisation solvents (50/50 v/v) was added in small amounts to the well containing the dry starting material at room temperature to a total volume of 40 microliter and a stock concentration of 50 or 80 mg/ml.
  • the solution was heated and maintained at 60 0 C for 30 minutes.
  • Crystallisation of Tenofovir DF on millilitre scale using hot filtration A small quantity, about 70-75 mg of the starting material was placed in a HPLC vial.
  • the crystallisation solvent (or 50/50 v/v mixture of solvents) was added in small amounts to the vial containing the dry sZaFE ⁇ n ⁇ pff ⁇ ateTTa1 ⁇ aZ ⁇ roo ⁇ TTemperatureTto a ⁇ tota]T ⁇ volume of ⁇ 20CPTO00 microliter.
  • the solvents and conditions employed are m Table II. Subsequently, the solutions were heated with a rate of 20 degrees Celsius to 60 0 C for 60 mm and they were filtered at this temperature.
  • the anti-solvent addition experiments were carried out following two different protocols.
  • a slurry was prepared at ambient temperature, which was equilibrated for about 17-19 hours before filtering into a vial.
  • the anti-solvent was added, using a solvent : anti-solvent ratio of 1:1. This ratio was increased to 1:4 in those cases where no precipitation occurred, by subsequent anti- solvent additions.
  • the time interval between the additions was Ih.
  • the total volume of the anti-solvent was equal to that of the saturated solution.
  • a slurry was prepared at ambient temperature, which was equilibrated for about 17- 19 hours before filtering into a set of four vials. The content of each of these vials was added to a vial containing anti-solvent. The total volume of the four vials of saturated solutions was equal to that of the anti-solvent. The time interval between the additions was
  • Precipitates were recovered by centrifugation, and the solid products were dried and analyzed by XRPD. In the cases that no precipitation occurred the solutions were evaporated for 96-314 hrs at room temperature and the residues were analysed by XRPD. See Table III for experimental details Crystallisation of Tenofovir DF on millilitre scale using slurry crystallisation.
  • An XRPD measurement of the materials in slurries after 10 days showed that the solid form was still form ULT-9.
  • Slurry experiments of the starting material in 1,4-dioxane and acetonitrile at RT did not lead to any solid form conversion after 2 and 10 days, while the same type of experiments performed at 35°C led to the conversion of the starting material to form ULT-8.
  • Slurry experiments of the starting material in methanol at room temperature led to form ULT-20 after 2 days while in the same experiment at 35°C ULT-3 was obtained.
  • Type 1 A 5Lur.r-y—was—made -at—RT-using- about—LOOmg—o-f—t-h-e—s-fca-Et-i-ng—ma4e-r-i-a-l-.-
  • the slurry was filtered at RT and a small quantity of about 2mg of the corresponding seed was added.
  • the solution remained at RT or 5°C overnight. Subsequently the solution was evaporated and the solid material was checked by XRPD.
  • Type 3 A slurry was made at RT using about lOOmg of the starting material. A small quantity of about 5 mg of the corresponding seed was added. The slurry was stirred for about Ih and there after it remained at RT for 2 days. Subsequently the solution was evaporated and the solid material was checked by XRPD. The specific conditions and seeds used in each experiment are listed in Table B
  • Table B Seeding experiments performed using tenofovir form A. In all solvent mixtures the ration was 50/50. The anti-solvent addition was reverse as described in the corresponding paragraph.
  • Form ULT 22 Form ULT-22 was obtained by slow evaporation of saturated solution of tenofovir DF in methanol/water (50/50) at room temperature. During cooling of the saturated solution, solid material crystallized out. The solution was heated anew until dissolution of the solid material and as diluted to half the concentration. The solution was slowly cooled to room temperature and aged for several days.

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Abstract

The present invention provides novel crystalline forms of Tenofovir disoproxil fumarate (Tenofovir DF), designated form ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-IO, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22, methods for the preparation thereof and its use in pharmaceutical applications, in particular in anti-HIV medicaments. The crystalline form of Tenofovir DF can be used in combination with other anti-HIV medicaments such as Efavirenz and Emtricitabine.

Description

P28724PC00/RLA
Title: Polymorphic forms of tenofovir disoproxil fumarate
The present invention relates to novel crystalline forms of tenofovir disoproxil fumarate (tenofovir DF) , methods for their preparation and their formulation and application in the field of medicine, in particular antiviral medicines.
Tenofovir disoproxil fumarate (also known as Viread(R), Tenofovir DF, Tenofovir disoproxil, TDF, Bis-POC-PMPA (U.S. Pat. Nos . 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249) is a prodrug of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9- [(R) -2- [ [bis [ [ (isopropoxycarbonyl) oxyjmethoxy] phosphinyl]methoxy] propyl] adenine fumarate (1:1). The CAS Registry number is 202138-50-9. It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:
Figure imgf000002_0001
Tenofovir disoproxil fumarate (DF) is a nucleotide reverse transcriptase inhibitor approved in the United States for the treatment of HIV-I infection in combination with other antiretroviral agents. Tenofovir disoproxil DF is available as Viread(R) (Gilead Science, Inc. ) . Among the anti-HIV drugs which have been developed are those which target the HIV reverse transcriptase (RT) enzyme or protease enzyme, both of which enzymes are necessary for the replication of the virus. Examples of RT inhibitors include nucleoside/nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) . Currently, HIV-infected patients are routinely being treated with three-drug combinations. Regimens containing (at least) three NRTIs; two NRTIs in combination with one or two protease inhibitors (PI) (s); or two NRTIs in combination with a NNRTI, are widely used. When two or more PIs are used in these combinations, one of the PIs is often ritonavir, given at a low sub-therapeutic dose, which acts as an effective inhibitor of the elimination of the other PI (s) in the regimen, resulting in maximal suppression of the virus and thereby reducing the emergence of resistance.
Clinical studies have shown that three-drug combinations of these anti-HIV drugs are much more effective than one drug used alone or two-drug combinations in preventing disease progression and death. Numerous studies of drug combinations with various combinations of such drugs have established that such combinations greatly reduce disease progression and deaths in people with HIV infections. The name now commonly given to combinations of anti-HIV drugs is HAART (Highly Active Anti-Retroviral Therapy) .
Tenofovir DF is described inter alia in WO99/05150 and EP998480. This crystalline form is characterised as having XRPD peaks at about 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24.0, 25.0, 25.5, 27.8, 30.1 and 30.4. Furthermore these crystals are described as opaque or off-white and exhibit a DSC absorption peak at about 118 0C with an onset at about 116 0C and an IR spectrum showing characteristic bands expressed in reciprocal centimetres at approximately 3224, 3107-3052, 2986-2939, 1759, 1678, 1620, 1269 and 1102. Bulk densities have been described of about 0.15-0.30 g/mL, usually about 0.2-0.25 g/mL.
Polymorphs : Polymorphism is often characterised as the ability of a solid substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. The arrangement of the molecules in the space (crystal packing) can affect the physical properties of the material and can be influenced by controlling the conditions under which the solid form is obtained.
Many pharmaceutical solids exhibit polymorphism and can exist in different solid forms. The present invention relates to the discovery of various solid forms of tenofovir DF and their solid state physical properties .
These physical characteristics are influenced by the particular solid form of a substance. One solid form may give rise to thermal behaviour different from that of the amorphous material or other solid forms. Thermal behaviour is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis
(TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular solid ~Υorm"~may"alscπgive ~rise"~tό~ dYstϊnct spectroscopic "pTfbperti"e~s~Εhat may" be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared and Raman ' spectrometry .
Solid state physical properties affect the ease with which the material is handled during processing into a pharmaceutical product such as a tablet or capsule formulation. The physical properties impact the sort of excipients, for instance, to add to a tenofovir DF formulation. Furthermore, the solid state physical property of a pharmaceutical compound is important to its dissolution in aqueous fluid or even in a patient's stomach fluid, which have therapeutic consequences. The rate of dissolution is also a consideration in liquid forms of medicine as well. The solid state form of a compound may also affect its storage conditions.
Indications have been found by the present inventors that the solid form of Tenofovir DF in commercially available products experiences a conversion of its crystalline form when put under stress, indicating that the solid form currently used is not stable or at least has a reduced stability.
The present invention relates to novel crystalline forms of tenofovir DF. The present inventors have identified novel crystalline forms, herein depicted as ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT- 19, ULT-20, ULT-21 and ULT-22.
Description of the Drawings:
Figure IA illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-4.
Figure IB illustrates the DSC thermogram of Tenofovir DF Form ULT-4
Figure 1C illustrates the TGA thermogram of Tenofovir DF Form ULT-4.
Figure 2A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-5.
Figure 3A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-6. Figure 4A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-7.
Figure 4B illustrates the DSC thermogram of Tenofovir DF Form ULT-7.
Figure 4C illustrates the TGA thermogram of Tenofovir DF Form ULT-7.
Figure 5A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-8.
Figure 5B illustrates the DSC thermogram of Tenofovir DF Form ULT-8.
Figure 5C illustrates the TGA thermogram of Tenofovir DF Form ULT-8.
Figure 7A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-10. Figure 8A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-Il.
Figure 8B illustrates the DSC thermogram of Tenofovir DF Form ULT-Il.
Figure 8C illustrates the TGA thermogram of Tenofovir DF Form ULT-Il.
Figure 6D illustrates the molecular structure of base-acid-base entity from the crystals of Tenofovir DF Form ULT-Il.
Figure 6E illustrates the Crystal arrangement for Tenofovir DF Form
ULT-Il.
Figure 9A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-12. Figure 9B illustrates the DSC thermogram of Tenofovir DF Form ULT-12.
Figure 9C illustrates the TGA thermogram of Tenofovir DF Form ULT-12.
Figure IOA illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-13.
Figure HA illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-14.
Figure 12A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-15.
Figure 12B illustrates the DSC thermogram of Tenofovir DF Form ULT- 15. Figure 12C illustrates the TGA thermogram of Tenofovir DF Form ULT- 15. Figure 13A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-16.
Figure 14A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-17. Figure 15A illustrates the X-Ray Powder Diffraction pattern of
Teπofovir DF Form ULT-18. Figure 16A illustrates the X-Ray Powder Diffraction pattern of
Tenofovir DF Form ULT-19.
Figure 16C illustrates the TGA thermogram of Tenofovir DF Form ULT-
19. Figure 17A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-20. Figure 17C illustrates the TGA thermogram of Tenofovir DF Form ULT- 20.
Figure 18A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-21. Figure 18B illustrates the DSC thermogram of Tenofovir DF Form ULT- 21.
Figure 18C illustrates the TGA thermogram of Tenofovir DF Form ULT- 21.
Figure 19A illustrates the X-Ray Powder Diffraction pattern of Tenofovir DF Form ULT-22.
Crystalline tenofovir DF form ULT-4 (Al) :
Thus, in one embodiment, Form ULT-4 can be characterised by an XRPD substantially according to Fig IA.
In another embodiment, Form ULT-4 can be characterised by an
DSC substantially according to Fig IB. In another embodiment, Form ULT-4 can be characterised by an
TGA substantially according to Fig 1C.
In another embodiment, Form ULT-4 of the present invention can be characterised by DSC with an onset at 96.2°C and a characterising peak at 108.90C. In a further embodiment, Form ULT-4 of the present invention can be further characterised by DSC with an onset at
111.2°C and a characterising peak at 114.3°C.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-4 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-4 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-4 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
(paragraph on solvents) crystallising tenofovir DF Form ULT-4 by slurry crystallisation and/or seed crystallisation. Crystalline tenofovir DF form ULT-5 (A3) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-5, characterised by an XRPD substantially according to Fig 2A.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-5 by evaporation of the solvent.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-5 by cooling and/or evaporation crystallization of a saturated solution. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-5 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-5 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovxr DF form ULT-6 (A4) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-6, characterised by an XRPD substantially according to Fig 3A.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-6 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-6 by cooling and/or evaporation crystallization of a saturated solution. The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-6 by anti-solvent addition as in Table III. The present invention m another aspect relates to a method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-6 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-7 (Bl) :
Thus, in one aspect, the present invention provides crystalline" tenofovir DF herein defined as Form ULT-7, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 6.9, 8.9, 9.6, 10.2, 11.3, 13.2, 14.1, 17.8, 18.7, 20.0, 21.8, 23.8, 25.3, 27.8, 30.5, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen and most preferred sixteen X-ray powder diffraction peaks are selected from the above group. In another embodiment Form ULT-7 can be characterised by the following set of XRPD peaks (Table 4) and, optionally, by the associated intensities:
Figure imgf000010_0001
14 25 . 3 H 25 . 34 H
15 27 . 8 L 27 . 84 L
16 30 . 5 L 30 . 49 L normalised intensity values : L 0 4 5
M 45 70
H 70 100
In another embodiment, Form ULT-7 can be characterised by an XRPD substantially according to Fig 4A.
In another embodiment, Form ULT-7 can be characterised by an DSC substantially according to Fig 4B. In another embodiment, Form ULT-7 can be characterised by an TGA substantially according to Fig 4C.
In another embodiment, Form ULT-7 of the present invention can be characterised by DSC with an onset at 98.4°C and a characterising peak at 108.40C. From the thermal analysis, it is concluded that solid form ULT-7 is anhydrous.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-7 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-7 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-7 by anti-solvent addition as in Table III.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-7 by slurry crystallisation and/or seed crystallisation. Crystalline tenofovir DF form ULT-8 (C) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-8, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 10.3, 13.4, 14.7, 15.7, 17.3, 18.4, 19.1, 20.7, 21.2, 25.2 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In another embodiment Form ULT-8 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000012_0001
In another embodiment, Form ULT-8 can be characterised by an XRPD substantially according to Fig 5A . In another embodiment, Form ULT-8 can be characterised by an
DSC substantially according to Fig 5B.
In another embodiment, Form ULT-8 can be characterised by an
TGA substantially according to Fig 5C.
In another embodiment, Form ULT-8 of the present invention can be characterised by DSC with an onset at 104.80C and a characterising peak at 113.00C. From the thermal analysis, it is concluded that solid form ULT-8 is anhydrous.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form
ULT-8 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-8 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-8 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
(paragraph on solvents) crystallising tenofovir DF Form ULT-8 by slurry crystallisation and/or seed crystallisation. Crystalline tenofσvir DF form ULT-10 (F) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-10, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 1,.O1 10.6, 11.8, 12.7, 13.5, 15.2, 16.3, 17.3, 18.8, 20.7, 21.3, 22.2, 25.3, 27.3, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen X-ray powder diffraction peaks are selected from the above group.
In another embodiment Form ULT-10 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000014_0001
Figure imgf000015_0001
In another embodiment, Form ULT-10 can be characterised by an XRPD substantially according to Fig 7A.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-10 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-10 by evaporation of the solvent.
The present invention m another aspect relates to a method for the preparation of the crystalline form ULT-10of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as m Table II and crystallising tenofovir DF Form ULT-10 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-10 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-10 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-10 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-10 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-Il (Fl) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-Il, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 7.0, 9.5, 10.6, 11.7, 13.5, 16.0, 17.4, 18.8, 20.4, 21.2, 22.0, 25.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen X-ray powder diffraction peaks are selected from the above group.
In another embodiment Form ULT-Il can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000016_0001
In another embodiment, Form ULT-Il can be characterised by an XRPD substantially according to Fig 8A.
In another embodiment, Form ULT-Il can be characterised by an DSC substantially according to Fig 8B. In another embodiment, Form ULT-Il can be characterised by an TGA substantially according to Fig 8C.
In another embodiment, Form ULT-Il of the present invention can be characterised by DSC with an onset at 104.50C and a characterising peak at 112.8°C. From the thermal analysis, it is concluded that solid form ULT-Il is anhydrous.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-Il by evaporation of the solvent.
The present invention in another aspect relates to a method for the_ preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-Il by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-Il by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-Il by slurry crystallisation and/or seed crystallisation.
The present invention in one aspect relates to the crystal structure of tenofovir DF Form ULT-Il as depicted in figure 8D and/or 8E and/or in the table Xl, Yl and Zl below:
Table Xl Crystal data and structure refinement for tenofovir form ULT-Il . Empirical formula C19H31N5O10P+ • C4H3CV
Formula weight 635 . 52 Temperature 120 ( 2 )
Wavelength 0 . 71073 Crystal system Monoclinic Space group P 2, Unit cell dimensions 9.7440(3) [9.963(2)]* 18.0330(5) [18.410(5)] 17.4080(6) [18.160(2)] 102.759(2) [104.66(2)]
Volume 2983.3(2) [3222.4(1I)]
Z 4
Density (calculated) 1.415 [1.310]
F(OOO) 1336
Crystal size 0.25 x 0.25 x 0.05
Theta range for data 2.5 → 27.5 collection
Reflections collected 20281
Independent reflections 11699 [R(int) = 0.0812]
Data / restraints / parameters 1 1 699 / 1 / 783
Goodness-of-fit on F^ 1 . 106
Final R indices [ I>2sigma ( I ) ] Rl = 0.0774, wR2 = 0.1194
R indices (all data) Rl = 0.1239, wR2 = 0.1340
Absolute structure parameter 0.07 (13)
* Values in square brackets were taken at 293(2) K
Crystalline tenofovir DF form ULT-12 (H) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-12, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.2, 5.2, 9.5, 14.5, 16.7, 18.6, 19.2, 20.2, 11.1, 13.4, 17.3, 21.2, 25.4 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more ~pr~e~ferab~ly a1f~llfas~tf~ehXr~te~errx-ray powder~di"ffr^c"tTon~^p"ealcs^~arre selected from the above group.
In another embodiment Form ULT-12 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000019_0001
In another embodiment, Form ULT-12 can be characterised by an XRPD substantially according to Fig 9A.
In another embodiment, Form ULT-12 can be characterised by an DSC substantially according to Fig 9B.
In another embodiment, Form ULT-12 can be characterised by an TGA substantially according to Fig 9C.
In another embodiment, Form ULT-12 of the present invention can be characterised by DSC with an onset at 90.00C and a characterising peak at 100.40C. In a preferred embodiment, Form ULT- 12 of the present invention can be further characterised by DSC with an onset at 107.90C and a characterising peak at 113.7°C. From the thermal analysis, it is concluded that solid form ULT-12 is a solvate with an alcohol, preferably cyclopentanol, cyclohexanol or isobutanol .
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-12 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-12 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-12 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-12 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-13 (K) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-13, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 5.6, 9.1, 10.4, 13.3, 14.8, 16.0, 16.0, 19.4, 21.4, 23.7, 28.6 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment twelve X-ray powder diffraction peaks are selected from the above group.
In another embodiment Form ULT-13 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000021_0001
In another embodiment, Form ULT-13 can be characterised by an
XRPD substantially according to Fig 1OA.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-13 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-13 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-13 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-13 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-14 (Kl) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-14, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five X-ray powder diffraction peaks selected from the group consisting of 4.7, 10.3, 18.4, 20.6, 21.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In another embodiment Form ULT-14 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
Figure imgf000023_0001
In another embodiment, Form ULT-14 can be characterised by an XRPD substantially according to Fig HA.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-14 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-14 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-14 by anti-solvent addition as in Table III.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-14 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-15 (L) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-15, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 5.2, 9.4, 10.5, 13.2, 17.1, 18.3, 21.3, 24.4 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably nine X-ray powder diffraction peaks are selected from the above group. In another embodiment Form ULT-15 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
Figure imgf000025_0001
In another embodiment, Form ULT-15 can be characterised by an XRPD substantially according to Fig 12A. In another embodiment, Form ULT-15 can be characterised by an DSC substantially according to Fig 12B.
In another embodiment, Form ULT-15 can be characterised by an TGA substantially according to Fig 12C. In another embodiment, Form ULT-15 of the present invention can be characterised by DSC with an onset at 61.3°C and a characterising peak at 69.80C. In a further embodiment, Form ULT-15 can be further characterised by DSC with an onset at 92.80C and a characterising peak at 97.80C. In another embodiment, Form ULT-15 can be characterised by DSC with an onset at 104.80C and a characterising peak at 111.80C.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form
ULT-15 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-15 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-15 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
(paragraph on solvents) crystallising tenofovir DF Form ULT-15 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-I6 (Q) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-16, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 10.3, 13.4, 15.4, 18.5, 20.6, 21.5, 23.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably eight X-ray powder diffraction peaks are selected from the above group. In another embodiment Form ULT-16 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000027_0001
In another embodiment, Form ULT-16 can be characterised by an XRPD substantially according to Fig 13A.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-16 by evaporation of the solvent.
The present invention m another aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-16 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-16 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-16 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-17 (R) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-17, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.8, 10.2, 10.8, 11.8, 13.3, 15.6, 17.0, 18.0, 18.8, 20.5, 21.5, 23.2, 24.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably thirteen X-ray powder diffraction peaks are selected from the above group.
In another embodiment Form ULT-17 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000029_0001
In another embodiment, Form ULT-17 can be characterised by an XRPD substantially according to Fig 14A.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-17 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-17 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-17 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-17 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-18 (S) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-18, characterised by the selection of at least one, preferably two X-ray powder diffraction peaks selected from the group consisting of 4.3 and 10.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In another embodiment Form ULT-18 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
Figure imgf000031_0001
In another embodiment, Form ULT-18 can be characterised by an XRPD substantially according to Fig 15A.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-18 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-18 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-18 by anti-solvent addition as in Table III.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere
(paragraph on solvents) crystallising tenofovir DF Form ULT-18 by slurry crystallisation and/or sped crvstallisatinn.
Crystalline tenofovir DF form ULT-I9 (T) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-19, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.3, 9.7, 10.5, 13.3, 17.1, 21.4, 30.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment seven X-ray powder diffraction peaks are selected from the above group. In another embodiment Form ULT-19 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities:
Figure imgf000033_0001
In another embodiment, Form ULT-19 can be characterised by an XRPD substantially according to Fig 16A.
In another embodiment, Form ULT-19 can be characterised by an TGA substantially according to Fig 16C.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-19 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-19 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-19 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-19 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-20 (U) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-20, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.1, 9.0, 10.4, 11.3, 13.3, 17.6, 18.7, 19.6, 20.3, 21.3, 23.7, 24.4, 25.6, 26.5, 27.6, 29.4, 30.8 degrees two-theta +/- 0.3 degrees two- theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen and most preferred sixteen X-ray powder diffraction peaks are selected from the above group.
In another embodiment Form ULT-20 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000035_0001
Figure imgf000036_0001
In another embodiment, Form ULT-20 can be characterised by an XRPD substantially according to Fig 17A.
In another embodiment, Form ULT-20 can be characterised by an TGA substantially according to Fig 17C. From the thermal analysis, it is concluded that solid form ULT-20 is anhydrous.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-20 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-20 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-20 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-20 by slurry crystallisation and/or seed crystallisation. Crystalline tenofovir DF form ULT-21 (V) :
Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-21, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.1, 9.0, 10.4, 11.3, 13.3, 17.6, 18.7, 19.6, 20.3, 21.3, 23.7, 24.4, 25.6, 26.5, 27.6, 29.4, 30.8 degrees two-theta +/- 0.3 degrees two- theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably at least fourteen, particularly preferred at least fifteen and most preferred sixteen X-ray powder diffraction peaks are selected from the above group.
In another embodiment Form ULT-21 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000037_0001
Figure imgf000038_0001
In another embodiment, Form ULT-21 can be characterised by an XRPD substantially according to Fig 18A.
In another embodiment, Form ULT-21 can be characterised by an DSC substantially according to Fig 18B. In another embodiment, Form ULT-21 can be characterised by an TGA substantially according to Fig 18C.
In another embodiment, Form ULT-21 of the present invention can be characterised by DSC with an onset at 100.80C and a characterising peak at 105.60C. In a further embodiment, Form ULT-21 can be further characterised by DSC with an onset at 107.60C and a characterising peak at 114.7°C. From the thermal analysis, it is concluded that solid form ULT-21 is anhydrous.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-21 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-21 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-21 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-21 by slurry crystallisation and/or seed crystallisation.
Crystalline tenofovir DF form ULT-22 (X) : Thus, in one aspect, the present invention provides crystalline tenofovir DF herein defined as Form ULT-22, characterised by the selection of at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.4, 8.9, 9.3, 9.9, 10.4, 13.3, 17.6, 19.2, 21.2, 21.8, 23.0, 23.5, 25.7, 26.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta. In a preferred embodiment, at least seven, more preferably at least eight, even more preferably at least nine, particularly preferred at least ten and most preferred eleven X-ray powder diffraction peaks are selected from the above group. In a more preferred embodiment, at least twelve, more preferably at least thirteen, even more preferably fourteen X-ray powder diffraction peaks are selected from the above group.
In another embodiment Form ULT-22 can be characterised by the following set of XRPD peaks and, optionally, by the associated intensities :
Figure imgf000039_0001
Figure imgf000040_0001
In another embodiment, Form ULT-22 can be characterised by an
XRPD substantially according to Fig 19A.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-22 by evaporation of the solvent.
The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-22 by cooling and/or evaporation crystallization of a saturated solution.
The present invention in one aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-22 by anti-solvent addition as in Table III. The present invention in another aspect relates to a method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as outlined herein elsewhere (paragraph on solvents) crystallising tenofovir DF Form ULT-22 by slurry crystallisation and/or seed crystallisation. In particular, Form ULT-22 was obtained by slow evaporation of saturated solution of tenofovir DF in methanol/water (50/50) at room temperature. During cooling of the saturated solution, solid material crystallized out. The solution was heated anew until dissolution of the solid material and as diluted to half the concentration. The solution was slowly cooled to room temperature and aged for several days. Purity
In one aspect of the invention, the forms ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, , ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT- 16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22 of the present invention are, independently, in a substantially pure form, preferably substantially free from other amorphous, and/or crystalline solid forms such as ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT- 18, ULT-19, ULT-20, ULT-21 and ULT-22 or the solid forms as described in the prior art as referred herein before or of ULT-I, ULT-2 or ULT-3 as described in applicant's copending US60/872999 and US60/873267 respectively, respectively. In this respect, "substantially pure" relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the pure compound. In this respect,
"substantially free from other amorphous, and/or crystalline solid forms" means that no more than about 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% of these other amorphous, and/or crystalline solid forms are present in the form according to the invention.
Solvents
In certain embodiments of the method for the preparation of ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22 of the present invention, the solvents for evaporation crystallisation, hot filtration anti-solvent addition , seed crystallisation and/or slurry crystallisation are preferably selected from the group consisting of: (R) - (-) -2-Octanol , 1 , 2-Diethoxyethane, 1 , 2-Dimethoxyethane, 1,4-Dioxane, 1-Butanol, 1-Heptanol, 1-Hexanol, l-Methoxy-2-propanol , 1-Nitropropane, 1-Octanol, 2,2,2-
Trifluoroethanol , 2-Butanone, 2-Ethoxyethanol , 2-Ethoxyethyl acetate, 2-Hexanol, 2-Methoxyethanol, 2-Nitropropane, 2-Pentanol, 2- Propanol, 4-Hydroxy-4-methyl-2-pentanon, Acetone, Acetonitrile, Butyromtrile, Cyclohexanol , Cyclopentanol , Cyclopentanone, Diethylene glycol dimethylether , Dimethylcarbonate,
Dimethylcarbonate, Ethanol, Ethyl formate, Ethylacetate, Ethylene glycol monobutyl ether, Furfuryl alcohol, Isobutanol, Isopropyl acetate, Methanol, Methoxyethyl acetate, Methyl acetate, Methyl butyrate, Methyl propionate, Methyl-4-2-Pentanol, N, N-
Dimethylacetamide, N, N-Dimethylformamide, Nitrobenzene, Nitroethane, Nitromethane, N-Methyl Pyrrolidone, Propionitrile, Propyl acetate,
Propylene glycol methyl ether acetate, tert-Butanol, Tetrahydrofuran, Tetrahydrofurfurylalcohol, Tetrahydropyran, Water and mixtures therof.
In certain embodiments of the method for the preparation of ULT-4-21 of the present invention, the solvents for hot filtration crystallisation are preferably selected from the group consisting of: (R) - (-) -2-Octanol, 1 , 2-Diethoxyethane, 1 , 2-Dimethoxyethane, 1,4- Dioxane , 1-Butanol, 1-Nitropropane, 1-Propanol, 2-Butanone, 2-
Ethoxyethyl acetate, 2-Methyl-4-pentanol , 2-Nitropropane, 2-Propanol, Acetone, Acetonitrile, Cyclopentanol , Ethanol, Isobutanol, Isopropyl acetate, Methanol, Methoxy-2-l-Propanol, Methyl propionate, N, N- Dimethylacetamide, N, N-Dimethylformamide, Nitromethane, tert-Butanol, Tetrahydrofuran, Water and mixtures thereof.
In certain embodiments of the method for the preparation of ULT-4-21 of the present invention, the solvents for solvent/anti- solvent crystallisation are preferably selected from the group consisting of: 1 , 2-Dichloroethane, 1 , 2-Dimethoxyethane, 1,4-Dioxane , 2, 6-Dimethyl-4-heptanone, 2-Butanone, Acetone, Acetonitrile, Amyl ether, Butyl benzene, Chloroform, Cyclohexane, Cyclohexane, Cyclohexane, Cyclohexane, Cyclohexane, Dichloromethane, Hexafluorobenzene, Methanol, n-Heptane, Nitromethane, N-Methyl Pyrrolidone, tert-Butyl methyl ether, Tetrahydrofuran, Toluene, Water and mixtures thereof.
In certain embodiments of the method for the preparation of ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20 , ULT-21 and ULT-22 of the present invention, the anti-solvents for anti-solvent crystallisation are preferably selected from the group consisting of: 1 , 2-Dichloroethane, 2, 6-Dimethyl-4-heptanone, Acetone, Amyl ether, Butyl benzene, Chloroform, Cyclohexane, Dichloromethane, Hexafluorobenzene, n-Heptane, Nitromethane, tert-Butyl methyl ether, Toluene and mixtures thereof. In certain embodiments of the method for the preparation of
ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22 of the present invention, the solvents for seeding crystallisation are preferably selected from the group consisting of: methanol, water, 1,4-dioxane, acetonitrile, 2- ethoxyethylacetate, 2- methyl-4-pentanol, tetrahydrofuran, butyl benzene, amylether, tert- butyl methyl ether, cyclopentanone and mixtures thereof.
Ih" certain embodiments of the method for the preparation of ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22 of the present invention, the solvents for slurrying crystallisation are preferably selected from the group consisting of: water, methanol, acetonitrile, 1,4-dioxane and mixtures thereof.
Pharmaceutical formulations .
The present invention further relates to pharmaceutical formulations comprising the novel crystalline forms of tenofovir DF.
Pharmaceutical formulations of the present invention contain one or more of the crystalline forms according to the present invention, such as ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT- 20, ULT-21 and ULT-22 as disclosed herein. The invention also provides pharmaceutical compositions comprising one or more of the crystal forms according to the present invention. Pharmaceutical formulations of the present invention contains one or more of the crystal form according to the present invention as active ingredient, optionally in a mixture with other crystal form(s).
The pharmaceutical formulations according to the invention, may further comprise, in addition to the forms ULT-I, ULT-2, ULT-3, ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22 additional pharmaceutical active ingredients, preferably Anti- HIV agents and more preferably Efavirenz and/or Emtricitabine .
In addition to the active ingredient (s ), the pharmaceutical formulations of the present invention may contain one or more excipients. Excipients are added to the formulation for a variety of purposes .
Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystallme cellulose (e.g. Avicel(R)), micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, manmtol, polymethacrylates (e.g. Eudragit (R) ) , potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc. Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol] carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose,
FTydroxypropyl cellulose (e.g. Klucel (R) ) , hydroxypropyl methyl cellulose (e.g. Methocel (R) ) , liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone (R) ) , pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Pnmellose (R) ) , colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone (R) ) , guar gum, magnesium aluminum silicate, methyl cellulose, microcrystallme cellulose, polacrilm potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.
Glidants can be added to improve the flowability of a non- compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium tπsilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid. Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, the crystalline forms according to the present invention and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth- feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste. Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability. According to the present invention, a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field. For infections of the eye or other external tissues, e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient (s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient (s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to
2% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabiliser (s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include Tweenδ 60, Spans 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers . Straight or branched chain, mono- or dibasic alkyl esters such as dnsoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and m others about 1.0% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for nasal or mhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc). Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active inqredient such carriers as are known in the art to be appropriate. The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (Including subcutaneous, intramuscularV and intravenous) , inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts. Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art. A composition for tablettmg or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.
A tabletting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include miciocrystallme cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tarrretlπg":
A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
Moreover, the crystalline forms according to the present invention can be formulated for administration to a mammal, preferably a human, via injection. The crystalline forms according to the present invention may be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection. The formulation may contain solvents. Among considerations for such solvent include the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability) , fluidity, boiling point, miscibility and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP and Castor oil USP. Additional substances may be added to the formulation such as buffers, solubilizers, antioxidants, among others. Ansel et al. , Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed.
The present invention also provides pharmaceutical formulations comprising the crystalline form according to the present invention, optionally in combination with other polymorphic forms or co-crystals, to be used in a method of treatment of a mammal, preferably a human, in need thereof. A pharmaceutical composition of the present invention comprises the crystalline form ULT-I. The crystalline form according to the present invention may be used in a method of treatment of a mammal comprising administering to a mammal suffering from the ailments described herein before a therapeutically effective amount of such pharmaceutical composition. The invention further relates to the use of the crystalline form of the invention for the preparation of a medicament for the treatment of the ailments described herein before, in particular HIV. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the compounds of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Examples
Experimental conditions
X-ray Powder Diffraction:
XRPD patterns were obtained using a T2 high-throughput XRPD set-up by Avantium technologies, The Netherlands. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings. Data collection was carried out at room temperature using monochromatic CuK (alpha) radiation in the two-theta region between 1.5 ° and 41.5 °. The diffraction pattern of each well is collected in two two-theta ranges (1.5 ° < 2θ < 21.5 ° for the first frame, and 19.5 ° < 2Θ < 41.5 ° for the second) with an exposure time of 120 s for each frame. One of ordinary skill in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation, or other factors. Typically XRPD data are collected with a variance of about 0.3 degrees two-theta, preferable about 0.2 degrees, more preferably 0.1 degrees, even more preferable 0.05 degrees. This has consequences for when X-ray peaks are considered overlapping.
Single-crystal X-ray diffraction
Suitable single crystals were selected and glued to a glass fibre, which was then mounted on an X-ray diffraction goniometer. X-ray diffraction data were collected for these crystals at a temperature of 120K and at room temperature, using a KappaCCD system and MoKa radiation, generated by a FR590 X-ray generator (Bruker Nonius, Delft, The Netherlands) .
Unit-cell parameters and crystal structures were determined and refined using the software package MaXus .
Thermal analysis:
Melting properties were obtained from DSC thermograms, recorded with a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland) . The DSC822e was calibrated for temperature and enthalpy with a small piece of indium (m.p. = 156.6°C; delta-H(f) = 28.45 J/g). Samples were sealed in standard 40 microliter aluminum pans and heated in the DSC from 25°C to 3000C, at a heating rate of 20°C/mm. Dry N2 gas, at a flow rate of 50 ml/min, was used to purge the DSC equipment during measurement .
Mass loss due to solvent or water loss from the crystals was de~termi~ned~by TGA/SDTA~ MonTfoFing bf~th~e~ sampϊe~~weight , duFing heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve. The TGA/SDTA851e was calibrated for temperature with indium and aluminium. Samples were weighed into 100 microliter aluminium crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25°C to 3000C at a heating rate of 20°C/mm. Dry N2 gas is used for purging. Melting point determinations based on DSC have a variability of +/- 2.0 degrees Celsius, preferably 1.0 degrees Celsius.
Raman spectroscopy: The Raman spectra were collected with a Raman microscope mW (Kaiser Opticals Inc) at 0.96 cm λ resolution using a laser of 780 nm and a power output of 100.
Examples
Crystallisation of Tenofovir DF on microliter scale.
A small quantity, about 2-3 mg of the starting material was placed in a plate well. The starting material was stock-dosed in tetrahydrofuran/water (80/20 v/v) mixture. The solvent was removed by evaporation under 2OkPa for about 45-75 h and the starting material was dry. The crystallisation solvent or mixture of crystallisation solvents (50/50 v/v) was added in small amounts to the well containing the dry starting material at room temperature to a total volume of 40 microliter and a stock concentration of 50 or 80 mg/ml. The solution was heated and maintained at 600C for 30 minutes.
Following, controlled cooling was applied with a cooling rate of about l°C/h or 50°C/h to a final temperature of 5°C or 200C and remained at this temperature for 1, 48, 75, 117 or 139h. Subsequently, the solvent was evaporated under pressure of 20 kPa at RT for 48-120 h. The resulting residue was analysed by X-ray powder diffraction, DSC and TG-MS. The solvents employed are in Table I.
Crystallisation of Tenofovir DF on millilitre scale using hot filtration . A small quantity, about 70-75 mg of the starting material was placed in a HPLC vial. The crystallisation solvent (or 50/50 v/v mixture of solvents) was added in small amounts to the vial containing the dry sZaFEϊnςpffϊateTTa1~aZ~~rooπTTemperatureTto a~tota]T~volume of~20CPTO00 microliter. The solvents and conditions employed are m Table II. Subsequently, the solutions were heated with a rate of 20 degrees Celsius to 600C for 60 mm and they were filtered at this temperature. The filtrated solutions were cooled with 1.1 or 50°C/h to a temperature of 3 or 200C where they remained for 24h. Subsequently, the solvents were evaporated from the vial under 20 kPa pressure at 20-250C for 15-20Oh (see table II, in the case of (R) -(- )-2-Octanol at 0,2 kPa for 500 h) . The resulting residue was analysed by X-ray powder diffraction, DSC and TGA.
Crystallisation of Tenofovir DF on millilitre scale using anti- solvent addition.
The anti-solvent addition experiments were carried out following two different protocols. According to the first protocol (forward anti- solvent addition) for each solvent, a slurry was prepared at ambient temperature, which was equilibrated for about 17-19 hours before filtering into a vial. The anti-solvent was added, using a solvent : anti-solvent ratio of 1:1. This ratio was increased to 1:4 in those cases where no precipitation occurred, by subsequent anti- solvent additions. The time interval between the additions was Ih. The total volume of the anti-solvent was equal to that of the saturated solution.
For the second protocol (reverse anti-solvent addition) , a slurry was prepared at ambient temperature, which was equilibrated for about 17- 19 hours before filtering into a set of four vials. The content of each of these vials was added to a vial containing anti-solvent. The total volume of the four vials of saturated solutions was equal to that of the anti-solvent. The time interval between the additions was
Ih.
Precipitates were recovered by centrifugation, and the solid products were dried and analyzed by XRPD. In the cases that no precipitation occurred the solutions were evaporated for 96-314 hrs at room temperature and the residues were analysed by XRPD. See Table III for experimental details Crystallisation of Tenofovir DF on millilitre scale using slurry crystallisation.
ArToTTt 5~0mg of"the starting material was used to make a slurry with a solvent (see Table A) . The slurries were stirred for the time interval of 2 and 10 days at RT or 35°C as shown in Table A. The materials were checked by XRPD in order to check for solid form changes . Table A: Slurry experiments of Tenofovir DF
Figure imgf000055_0001
SM = Starting Material, am = amorphous Slurry experiments in water both at room temperature and at 35°C led to the conversion of the starting material to form ULT-9 after 2 days. An XRPD measurement of the materials in slurries after 10 days showed that the solid form was still form ULT-9. Slurry experiments of the starting material in 1,4-dioxane and acetonitrile at RT did not lead to any solid form conversion after 2 and 10 days, while the same type of experiments performed at 35°C led to the conversion of the starting material to form ULT-8. Slurry experiments of the starting material in methanol at room temperature led to form ULT-20 after 2 days while in the same experiment at 35°C ULT-3 was obtained. An XRPD measurement after 10 days of the materials in slurries showed that the solid form was still form ULT-20 in the case of the RT experiment while the material of the slurry at 35°C had been converted to form ULT-13 containing a large part of amorphous component.
Crystallisation of Tenofovir DF on milliliter scale using seeding crystallisation. Three types of seeding experiments were performed as described below:
Type 1 A—5Lur.r-y—was—made -at—RT-using- about—LOOmg—o-f—t-h-e—s-fca-Et-i-ng—ma4e-r-i-a-l-.-
The slurry was filtered at RT and a small quantity of about 2mg of the corresponding seed was added. The solution remained at RT or 5°C overnight. Subsequently the solution was evaporated and the solid material was checked by XRPD.
Type 2
The experiments were performed as described in the anti-solvent addition example with the following modification: immediately after precipitation, a small quantity of about 2mg of the corresponding seed was added to the solution. The solution remained at RT or 5°C overnight. Subsequently the solution was evaporated and the solid material was checked by XRPD.
Type 3 A slurry was made at RT using about lOOmg of the starting material. A small quantity of about 5 mg of the corresponding seed was added. The slurry was stirred for about Ih and there after it remained at RT for 2 days. Subsequently the solution was evaporated and the solid material was checked by XRPD. The specific conditions and seeds used in each experiment are listed in Table B
Table B. Seeding experiments performed using tenofovir form A. In all solvent mixtures the ration was 50/50. The anti-solvent addition was reverse as described in the corresponding paragraph.
Figure imgf000056_0001
Figure imgf000057_0001
From type 3 of seeding experiments it was shown that independently of the seed used in the water slurry, the outcome was form ULT-9.
Form ULT 22 Form ULT-22 was obtained by slow evaporation of saturated solution of tenofovir DF in methanol/water (50/50) at room temperature. During cooling of the saturated solution, solid material crystallized out. The solution was heated anew until dissolution of the solid material and as diluted to half the concentration. The solution was slowly cooled to room temperature and aged for several days.

Claims

c± aims
1. Crystalline tenofovir DF Form ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22.
2. Crystalline tenofovir DF Form ULT-4, characterised by one or more of:
- DSC with an onset at 96.2°C and a characterising peak at 108.90C. - DSC with an onset at 111.2°C and a characterising peak at 114.3°C.
3. Crystalline tenofovir DF Form ULT-4 according to claim 1, characterised by one or more of: - a XRPD pattern substantially as set out in Fig IA; a DSC substantially as set out in Fig IB;
- a TGA substantially as set out in Fig 1C.
4. Method for the preparation of the crystalline form ULT-4 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-4 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir
DF Form ULT-4 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-4 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-4 by slurry crystallisation and/or seed crystallisation.
5. Crystalline tenofovir DF Form ULT-5, characterised by an XRPD pattern substantially as set out in Fig 2A.
6. Method for the preparation of the crystalline form ULT-5 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-5 by evaporation of the solvent; and/or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-5 by cooling and/or evaporation crystallization of a saturated solution; and /or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-5 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-5 by slurry crystallisation and/or seed crystallisation.
7. Crystalline tenofovir DF Form ULT-6 characterised by an XRPD pattern substantially as set out in Fig 3A;
8. Method for the preparation of the crystalline form ULT-6 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-6 by evaporation of the solvent; and/or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-6 by cooling and/or evaporation crystallization of a saturated solution; and /or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-6 by anti-solvent addition as in Table III
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-6 by slurry crystallisation and/or seed crystallisation.
9. Crystalline tenofovir Dr Form ULT-7, characterised by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 6.9, 8.9, 9.6, 10.2, 11.3, 13.2, 14.1, 17.8, 18.7, 20.0, 21.8, 23.8, 25.3, 27.8, 30.5, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two- theta, most preferably +/- 0.05 degrees two-theta;
- DSC with an onset at 98.4°C and a characterising peak at 108.40C.
10. Crystalline tenofovir DF Form ULT-7 according to claim 1, characterised by one or more of: a XRPD pattern substantially as set out in Table 4 and/or Fig 4A; a DSC substantially as set out in Fig 4B; a TGA substantially as set out in Fig 4C.
11. Method for the preparation of the crystalline form ULT-7 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-7 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-7 by cooling and/or evaporation crystallization of a saturated solution; and /or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-7 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-7 by slurry crystallisation and/or seed crystallisation.
12. Crystalline tenofovir L6L0 Form ULT-8, characterised by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 10.3, 13.4, 14.7, 15.7, 17.3, 18.4, 19.1, 20.7, 21.2, 25.2 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta;
DSC with an onset at 104.80C and a characterising peak at 113.O0C.
13. Crystalline tenofovir DF Form ULT-8 according to claim 1, characterised by one or more of: a XRPD pattern substantially as set out in Table 5 and/or
Fig 5A; a DSC substantially as set out in Fig 5B;
- a TGA substantially as set out in Fig 5C.
14. Method for the preparation of the crystalline form ULT-8 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-8 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-8 by cooling and/or evaporation crystallization of a saturated solution; and /or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-8 by anti-solvent addition as in Table III dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-8 by slurry crystallisation and/or seed crystallisation.
15. Crystalline tenofovir be Form ULT-10, characterised by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 1,.O1 10.6, 11.8, 12.7, 13.5, 15.2, 16.3, 17.3, 18.8, 20.7, 21.3, 22.2, 25.3, 27.3, degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two- theta, most preferably +/- 0.05 degrees two-theta.
16. Crystalline tenofovir DF Form ULT-10 according to claim 1, characterised by an XRPD pattern substantially as set out in Table 7 and/or Fig 7A.
17. Method for the preparation of the crystalline form ULT-10 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-10 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-10 by cooling and/or evaporation crystallization of a saturated solution; and /or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-10 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-10 by slurry crystallisation and/or seed crystallisation.
18. Crystalline tenofovir DF Form ULT-Il, characterised by one or more of: - at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.0, 7.0,629.5, 10.6, 11.7, 13.5, 16.0, 17.4,
18.8, 20.4, 21.2, 22.0, 25.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta; - DSC with an onset at 104.50C and a characterising peak at 112.80C.
19. Crystalline tenofovir DF Form ULT-Il according to claim 1, characterised by one or more of: a XRPD pattern substantially as set out in Table 8 and/or
Fig 8A; a DSC substantially as set out in Fig 8B;
- a TGA substantially as set out in Fig 8C.
20. Method for the preparation of the crystalline form ULT-Il of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-Il by evaporation of the solvent; and/or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-Il by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir
DF Form ULT-Il by anti-solvent addition as in Table III; and/or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-Il by slurry crystallisation and/or seed crystallisation.
21. Crystalline tenofovir DF Form ULT-12, characterised by one or more of:
- at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.2, 5.2^39.5, 14.5, 16.7, 18.6, 19.2, 20.2,
11.1, 13.4, 17.3, 21.2, 25.4 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta; - DSC with an onset at 90.00C and a characterising peak at 100.40C.
22. Crystalline tenofovir DF Form ULT-12 according to claim 1, characterised by one or more of: - a XRPD pattern substantially as set out in Table 9 and/or Fig 9A;
- a DSC substantially as set out in Fig 9B; a TGA substantially as set out in Fig 9C.
23. Method for the preparation of the crystalline form ULT-12 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-12 by evaporation of the solvent; and/or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-12 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir
DF Form ULT-12 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-12 by slurry crystallisation and/or seed crystallisation.
24. Crystalline tenofovir DF Form ULT-13, characterised by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 5.6,649.1 , ' lϋ.'4,' T373" "13.8 , ' 16.0,TB .0,
19.4, 21.4, 23.7, 28.6 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta.
25. Crystalline tenofovir DF Form ULT-13 according to claim 1, characterised by an XRPD pattern substantially as set out in Table 10 and/or Fig 1OA;
26. Method for the preparation of the crystalline form ULT-13 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-13 by evaporation of the solvent; and/or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-13 by cooling and/or evaporation crystallization of a saturated solution; and /or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir
DF Form ULT-13 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-13 by slurry crystallisation and/or seed crystallisation.
27. Crystalline tenofovir DF Form ULT-14, characterised by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 10.3, 18.4, 20.6, 21.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two- theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta;
28. Crystalline tenofovir $r Form ULT-14 according to claim 1, characterised by an XRPD pattern substantially as set out in Table 11 and/or Fig HA.
29. Method for the preparation of the crystalline form ULT-14 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-14 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir
DF Form ULT-14 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-14 by anti-solvent addition as in Table III; and/or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-14 by slurry crystallisation and/or seed crystallisation.
30. Crystalline tenofovir DF Form ULT-15, characterised by one or more of:
- at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six
X-ray powder diffraction peaks selected from the group consisting of 4.7, 5.2, 9.4, 10.5, 13.2, 17.1, 18.3, 21.3, 24.4 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta;
DSC with an onset at 104.80C and a characterising peak at 111.8°C.
31. Crystalline tenofovir DF Form ULT-15 according to claim 1, characterised by one or more of: a XRPD pattern substantially as set out in Table 12 and/or Fig 12A; - a DSC substantially as set out in Fig 12B; a TGA substantially as set out in Fig 12C.
32. Method for the preparation of the crystalline form ULT-15 of tenofovir DF comprising the steps of - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-15 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-15 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-15 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-15 by slurry crystallisation and/or seed crystallisation.
33. Crystalline tenofovir DF Form ULT-16, characterised by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.7, 10.3, 13.4, 15.4, 18.5, 20.6, 21.5, 23.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two- theta, most preferably +/- 0.05 degrees two-theta;
34. Crystalline tenofovir DF Form ULT-16 according to claim 1, characterised by an XRPD pattern substantially as set out in Table 13 and/or Fig 13A;
35. Method for the preparation of the crystalline form ULT-16 of tenofovir DF comprising the steps of - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-16 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-16 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-16 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-16 by slurry crystallisation and/or seed crystallisation.
36. Crystalline tenofovir DF Form ULT-17, characterised by one or more of:
- at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 4.8, 10.2, 10.8, 11.8, 13.3, 15.6, 17.0, 18.0, 18.8, 20.5, 21.5, 23.2, 24.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two- theta, more preferably +/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta;
Crystalline tenofovir DF Form ULT-17 according to claim 1, characterised by an XRPD pattern substantially as set out in Table 14 and/or Fig 14A.
37. Method for the preparation of the crystalline form ULT-17 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-17 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-17 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-17 by anti-solvent addition as in Table III; and/or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-17 by slurry crystallisation and/or seed crystallisation.
38. Crystalline tenofovir DF Form ULT-18, characterised by one or more of: at least one, preferably two X-ray powder diffraction peaks selected from the group consisting of 4.3 and 10.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two- theta, most preferably +/- 0.05 degrees two-theta;
39. Crystalline tenofovir DF Form ULT-18 according to claim 1, characterised by one or more of: - a XRPD pattern substantially as set out in Table 15 and/or Fig 15A.
40. Method for the preparation of the crystalline form ULT-18 of tenofovir DF comprising the steps of - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-18 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-18 by cooling and/or evaporation crystallization of a saturated solution; and /or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-18 by anti-solvent addition as in Table III; and/or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-18 by slurry crystallisation and/or seed crystallisation.
41. Crystalline tenofovir DF Form ULT-19, characterised by one or more of:
- at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.3, 9.7, 10.5, 13.3, 17.1, 21.4, 30.5 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two- theta, most preferably +/- 0.05 degrees two-theta;
42. Crystalline tenofovir DF Form ULT-19 according to claim 1, characterised by one or more of:
- a XRPD pattern substantially as set out in Table 16 and/or Fig 16A; a TGA substantially as set out in Fig 16C.
43. Method for the preparation of the crystalline form ULT-19 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-19 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-19 by cooling and/or evaporation crystallization of a saturated solution; and /or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-19 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-19 by slurry crystallisation and/or seed crystallisation.
44. Crystalline tenofovir Dr Form ULT-20, characterised by one or more of: at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of 5.1, 9.0, 10.4, 11.3, 13.3, 17.6, 18.7, 19.6, 20.3, 21.3, 23.7, 24.4, 25.6, 26.5, 27.6, 29.4, 30.8 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two- theta, most preferably +/- 0.05 degrees two-theta;
45. Crystalline tenofovir DF Form ULT-20 according to claim 1, characterised by one or more of: a XRPD pattern substantially as set out in Table 17 and/or Fig 17A; a TGA substantially as set out in Fig 17C.
46. Method for the preparation of the crystalline form ULT-20 of tenofovir DF comprising the steps of - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir DF Form ULT-20 by evaporation of the solvent; and/or dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-20 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-20 by anti-solvent addition as in Table III; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-20 by slurry crystallisation and/or seed crystallisation.
47. Crystalline tenofovir DF Form ULT-21, characterised by one or more of:
- at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred 7it least five and most preferred six
X-ray powder diffraction peaks selected from the group consisting of 5.1, 9.0, 10.4, 11.3, 13.3, 17.6, 18.7, 19.6, 20.3, 21.3, 23.7, 24.4, 25.6, 26.5, 27.6, 29.4, 30.8 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two-theta, more preferably +/- 0.1 degrees two- theta, most preferably +/- 0.05 degrees two-theta;
48. Crystalline tenofovir DF Form ULT-21 according to claim 1, characterised by a XRPD pattern substantially as set out in Table 18 and/or Fig 18A.
49. Method for the preparation of the crystalline form ULT-21 of tenofovir DF comprising the steps of
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir
DF Form ULT-21 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-21 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-21 by anti-solvent addition as in Table III; and/or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-21 by slurry crystallisation and/or seed crystallisation.
50. Crystalline tenofovir DF Form ULT-22, characterised by one or more of:
- at least one, preferably at least two, more preferably at least three, even more preferably at least four, particularly preferred at least five and most preferred six X-ray powder diffraction peaks selected from the group consisting of of 5.4, 8.9, 9.3, 9.9, 10.4, 13.3, 17.6,
19.2, 21.2, 21.8, 23.0, 23.5, 25.7, 26.3 degrees two-theta +/- 0.3 degrees two-theta, preferably +/- 0.2 degrees two- theta, more preferably x/- 0.1 degrees two-theta, most preferably +/- 0.05 degrees two-theta;
51. Crystalline tenofovir DF Form ULT-21 according to claim 1, characterised by a XRPD pattern substantially as set out in Table 19 and/or Fig 19A.
52. Method for the preparation of the crystalline form ULT-22 of tenofovir DF comprising the steps of dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table I and crystallising tenofovir
DF Form ULT-22 by evaporation of the solvent; and/or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table II and crystallising tenofovir DF Form ULT-22 by cooling and/or evaporation crystallization of a saturated solution; and /or
- dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof as in Table III and crystallising tenofovir DF Form ULT-22 by anti-solvent addition as in Table III; and/or - dissolving or mixing tenofovir DF in a suitable solvent or mixture thereof and crystallising tenofovir DF Form ULT-22 by slurry crystallisation and/or seed crystallisation.
53. Pharmaceutical formulation comprising one or more crystalline forms of tenofovir FD selected from the group consisting of ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT-13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-21 and ULT-22.
54. Use of one or more selected from the group consisting of
ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT- 13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT- 21 and ULT-22 as a medicament.
55. Use of one or more selected from the group consisting of
ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT- 13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT- 21 and ULT-22 in the preparation of a medicament for the treatment of HIV.
56. Use of one or more selected from the group consisting of ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT- 13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT- 21 and ULT-22 in the treatment of HIV.
57. Use of one or more selected from the group consisting of ULT-4, ULT-5, ULT-6, ULT-7, ULT-8, ULT-10, ULT-Il, ULT-12, ULT- 13, ULT-14, ULT-15, ULT-16, ULT-17, ULT-18, ULT-19, ULT-20, ULT-
21 and ULT-22 in combination with another pharmaceutical ingredient, preferably an anti HIV agent, preferably Efavirenz and/or Emtricitabine
PCT/NL2008/000129 2007-05-14 2008-05-15 Polymorphic forms of tenofovir disoproxil fumarate Ceased WO2008140302A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009064174A1 (en) * 2007-11-14 2009-05-22 Ultimorphix Technologies B.V. Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use
EP2389929A1 (en) * 2010-05-30 2011-11-30 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Pharmaceutical formulations of tenofovir
WO2015051875A1 (en) 2013-10-09 2015-04-16 Zentiva, K.S. Dihydrogenphosphate salt of tenofovir disoproxil
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5935946A (en) * 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method
WO2007013086A1 (en) * 2005-07-26 2007-02-01 Hetero Drugs Limited Novel polymorphs of tenofovir disoproxil fumarate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5935946A (en) * 1997-07-25 1999-08-10 Gilead Sciences, Inc. Nucleotide analog composition and synthesis method
WO2007013086A1 (en) * 2005-07-26 2007-02-01 Hetero Drugs Limited Novel polymorphs of tenofovir disoproxil fumarate

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009064174A1 (en) * 2007-11-14 2009-05-22 Ultimorphix Technologies B.V. Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use
EP2389929A1 (en) * 2010-05-30 2011-11-30 Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi Pharmaceutical formulations of tenofovir
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
WO2015051875A1 (en) 2013-10-09 2015-04-16 Zentiva, K.S. Dihydrogenphosphate salt of tenofovir disoproxil

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