WO2005100302A1 - Solid state forms of (-)-(1r,2s)-2-amino-4-methylene-cyclopentanecarboxylic acid - Google Patents

Solid state forms of (-)-(1r,2s)-2-amino-4-methylene-cyclopentanecarboxylic acid Download PDF

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Publication number
WO2005100302A1
WO2005100302A1 PCT/IB2005/000971 IB2005000971W WO2005100302A1 WO 2005100302 A1 WO2005100302 A1 WO 2005100302A1 IB 2005000971 W IB2005000971 W IB 2005000971W WO 2005100302 A1 WO2005100302 A1 WO 2005100302A1
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Prior art keywords
solid state
state form
methylene
amino
cyclopentanecarboxylic acid
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PCT/IB2005/000971
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French (fr)
Inventor
Miroslav Zegarac
Ernest Mestrovic
Nada Kosutic Hulita
Darko Filic
Miljenko Dumic
Alfons Grunenberg
Brigit Keil
Helena Ceric
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Glaxosmithkline Istrazivacki Centar Zagreb D.O.O.
Bayer Healthcare Ag
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Publication of WO2005100302A1 publication Critical patent/WO2005100302A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
    • 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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to the solid state forms of (-)-(lR,lS)-2-amino-4-me- thyle ⁇ ecyclopentanecarboxylic acid (in the further text of the application designated by its name "icofungipen”), processes for their preparation, pharmaceutical forms containing the solid state forms as an active ingredient, and methods of using the solid state forms.
  • Icofungipen is an active pharmaceutical ingredient used in the treatment of fungal infections.
  • EP 0571870 Bl is hereby incorporated by reference in its entirety.
  • Suitable organic solvents that may be used in accordance with the present invention include: methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, .seobutyl acetate, tert-butyl acetate, acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, propanol, isopropanol, w-butanol, >yec-butanol, tert-butanol, cyclop entane, cyclohexane, cyclohexanone, cyclohexanol, dibutyl ether and N,N- dimetr ⁇ ylacetamide.
  • An object of this invention is to provide solid state form ⁇ of icofungipen. Another object of this invention is to provide solid state form ⁇ of icofungipen. Another object of this invention is to provide solid state form ⁇ of icofungipen. Another object of this invention is to provide solid state form ⁇ of icofungipen. Another object of this invention is to provide solid state form ⁇ of icofungipen. Another object of this invention is to provide solid state form ⁇ of icofungipen. Another object of this invention is to provide solid state form ⁇ of icofungipen.
  • a further object of this invention is to provide pharmaceutical compositions such as tablets, capsules, suppositories, sachets, injections or spray containing solid state form ⁇ of icofungipen, solid state form ⁇ of icofungipen, or any mixtures of solid state forms ⁇ and ⁇ icofungipen as an active ingredient, without any additives or in corrabination with one or more pharmaceutically acceptable additives such as sugar, starc-h derivatives, cellulose, cellulose derivatives, mold release agents and anti-adhesive agents and optionally agents for flowability regulation.
  • pharmaceutically acceptable additives such as sugar, starc-h derivatives, cellulose, cellulose derivatives, mold release agents and anti-adhesive agents and optionally agents for flowability regulation.
  • a further object of this invention is to provide pharmaceutical compositions such as tablets, capsules, suppositories, sachets, injections or spray containing solid state form ⁇ of icofungipen, solid state form ⁇ of icofungipen, solid state form ⁇ of icofungipen, solid state form ⁇ of icofungipen, solid state form ⁇ of icofungipen or any mixtures of solid state forms ⁇ , ⁇ , ⁇ , ⁇ and ⁇ of icofungipen as the actrve ingredient, without any additives or in combination with one or more pharmaceutically acceptable additives such as sugar, starch derivatives, cellulose, cellulose derivatives, mould release agents and antiadhesive agents and optionally agents for flowability regulation.
  • pharmaceutically acceptable additives such as sugar, starch derivatives, cellulose, cellulose derivatives, mould release agents and antiadhesive agents and optionally agents for flowability regulation.
  • a further object of this invention is to provide compounds or a ⁇ y mixture of said compounds, prepared according to the processes of the present invention, useful for the treatment and prevention of all diseases which are regarded as treatable or avoidable by the use of icofungipen, in particular, the compounds according to the invention ttiat can be employed in the treatment of fungal infections.
  • Solid state form ⁇ of icofungipen, prepared according to Example 1 of the present invention is characterized by a characteristic x-ray powder diffraction pattern comprising 9.2+0.2°, 14.0+0.2°, 15.8+0.2°, 17.5+0.2, 20.4+0.2°, 21.7+0.2°, 28.6+0.2°, and 32.0+0.2° degrees two-theta.
  • Solid state form ⁇ of icofungipen, prepared according to Example 1 of the present invention is characterized by a DSC thermogram comprising one endothermic maximum at about 176 °C (onset at about 174 °C) (heating rate of 10 °C/min).
  • Solid state form ⁇ of icofungipen, prepared according to Example 1 of the present invention is characterized by a Raman spectrum comprising characteristic abso ⁇ tion bands at 3076, 2979, 2921, 2900, 1542, 1427, 826, 545, and 403 cm -1 .
  • Solid state form ⁇ of icofungipen is characterized by solid-solid transformation into high temperature solid state form ⁇ l of icofungipen when heated above about 176 °C.
  • High temperature solid state form ⁇ l of icofungipen, prepared according to Example 3 of the present invention is characterized by a characteristic x-ray powder diffraction pattern comprising 8.2+0.2°, 14.0+0.2°, 14.4+0.2°, 15.3+0.2°, 17.4 ⁇ 0.2°,
  • Example 4 of the present invention is characterized by a DSC thermogram comprising one endothermic maximum at about 237 °C (onset at about 233 °C) (heating rate of 10
  • Solid state form ⁇ of icofungipen is characterized by solid-solid transformation into low temperature solid state form ⁇ 2 of icofungipen when cooled to about -173 °C.
  • low temperature solid state form ⁇ 2 of icofungipen was prepared according to Example 5 of the present invention, and single crystal x-ray diffraction data of low temperature solid state form ⁇ 2 of icofungipen were collected from a Bruker
  • Solid state form ⁇ of icofungipen, prepared according to Example 6, of the present invention is characterized by a characteristic x-ray powder diffraction pattern comprising 9.0+0.2°, 14.4+0.2°, 15.6+0.2°, 17.5 ⁇ 0.2°, 20.3+0.2°, 20.8+0.2°, 22.2+0.2°, 23.6+0.2°, 27.3+0.2°, 28.9+0.2°, and 30.5+0.2° degrees two-theta.
  • Solid state form ⁇ of icofungipen, prepared according to Example 6 of the present invention is characterized by a DSC thermogram comprising one endothermic maximum at about 85 °C (onset at about 83 °C) (heating rate of 10 °C/min).
  • Solid state form ⁇ of icofungipen, prepared according to Example 6 of the present invention is characterized by a Raman spectrum comprising characteristic abso ⁇ tion bands at 3074, 2981, 2950, 2911, 1658, 1431, 1315, 818, 605, 541, and 422 cm “1 .
  • Solid state form ⁇ of icofungipen, prepared according to Example 6 of the present invention is characterized by solid-solid transformation into high temperature solid state form ⁇ l of icofungipen when heated above about 85 °C.
  • Example 8 of the present invention is characterized by a characteristic x-ray powder diffraction pattern comprising 5.9+0.2°, 8.6(2) +0.2°, 14.4+0.2°, 15.6+0.2°, 16.2 ⁇ 0.2°, 17.4+0.2°, 18.9+0.2°, 20.4 ⁇ 0.2°, 20.8+0.2°, 22.2+0.2°, 28.9+0.2°, and 30.6(2)+0.2° degrees two-theta.
  • High temperature solid state form ⁇ l of icofungipen, prepared according to Example 8 of the present invention is characterized by a DSC thermogram comprising one endothermic maximum at about 236 °C (onset at about 232 °C) (heating rate of 10 °C/min).
  • Solid state form ⁇ of icofungipen, prepared according to the Example 10. of the present invention is characterized by an characteristic x-ray powder diffraction pattern comprising 7.6+0.2°, 8.2.0+0.2°, 9.2+0.2°, 18.4+0.2 21.2+0.2° and 29.7+0.2° degrees two- theta.
  • Solid state form ⁇ of icofungipen, prepared according to the Example 10. of the present invention is characterized by an DSC thermogram comprising one endothermic maximum at about 147 °C (onset at about 145 °C) and another endothermic maximum at about 158 °C (onset at about 150 °C) (heating rate of 10 °C/min).
  • High temperature solid state form ⁇ l of icofungipen is characterized by solid-solid transformation into high temperature solid state form ⁇ l of icofungipen when is heated above about 158 °C.
  • High temperature solid state form ⁇ l of icofungipen, prepared according to the Example 11. of the present invention is characterized by an characteristic x-ray powder diffraction pattern comprising 8.5+0.2°, 14.3+0.2°, 18.2+0.2°, 19.7+0.2°, 20.8+0.2°, and 29.3+0.2° degrees two-theta.
  • High temperature solid state form ⁇ l of icofungipen, prepared according to the Example 12 is characterized by solid-solid transformation into high temperature solid state form ⁇ l of icofungipen when is heated above about 158 °C.
  • High temperature solid state form ⁇ l of icofungipen, prepared according to the Example 11. of the present invention is characterized by an characteristic x-ray powder diffraction pattern comprising 8.5+0.2°, 14.3+0.2°, 18.2+
  • Solid state form ⁇ l of icofungipen is characterized by solid-solid transformation into solid state form ⁇ of icofungipen when is cooled below about 78 °C. Solid state form ⁇ of icofungipen, prepared according to the Example 13. and Example 14.
  • Example 14 of the present invention is characterized by solid-solid transformation into high temperature solid state form ⁇ l of icofungipen when is heating above about 81 °C.
  • Solid state form ⁇ of icofungipen, prepared according to the Example 15. of the present invention is characterized by an DSC thermogram comprising one endothermic maximum at about 234 °C (onset at about 229 °C) (heating rate of 10 °C/min).
  • Figure 1 is an x-ray powder diffraction (XRPD) spectrum of solid state form ⁇ of icofungipen.
  • Figure 2 is an XRPD spectrum of solid state form ⁇ 2 of icofungipen.
  • Figure 3 is an XRPD spectrum of solid state form ⁇ l of icofungipen.
  • Figure 4 is an XRPD spectrum of solid state form ⁇ of icofungipen.
  • Figure 5 is an XRPD spectrum of solid state form ⁇ l of icofungipen.
  • Figure 6 is an XRPD spectrum of solid state form ⁇ of icofungipen.
  • Figure 7 is an XRPD spectrum of solid state form ⁇ l of icofungipen.
  • Example 1 (Form ⁇ ) Icofungipen (0.20 g) was dissolved in 96 % ethanol (25 mL). After cooling to room temperature, the solution was left at the same temperature for 24 hours to yield solid state form ⁇ of icofungipen.
  • the x-ray powder diffraction patterns were obtained by x-ray diffraction on a powder sample by methods known in the art.
  • X-ray powder diffraction patterns were collected from a Philips X'PertPRO powder diffractometer using CuK ⁇ radiation.
  • the differential scanning calorimeter thermograms were obtained by methods known in the art using a DSC Mettler Toledo 822 Star 6 . The weight of the samples was about 5 mg.
  • the temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 ⁇ L aluminum crucibles with pierced lids were used.
  • the FT-Raman spectra were obtained by methods known in the art using a spectrophotometer Bruker, model Equinox 55 with a Bruker FT-raman module 106/S. Radiation of 1064 nm from a Nd:YAG laser was used for excitation. Spectra were obtained in the range from 4000 to 0 cm "1 at 4 cm "1 resolution, and 50 mW laser power at the sample.
  • Example 2 (Form ⁇ ) Icofungipen (2.00 g) was sublimated for 2 hours at 140 °C and below 2 mbar to yield solid state form ⁇ of icofungipen.
  • the x-ray powder diffraction patterns of the sample thus obtained corresponded to the x-ray powder diffraction patterns of the solid state form ⁇ of icofungipen obtained according to Example 1.
  • the DSC thermogram of the sample thus obtained corresponded to the DSC thermogram of the solid state form ⁇ of icofungipen obtained according to Example 1.
  • Example 3 (Form ⁇ l) Solid state form ⁇ of icofungipen (0.15 g) was heated above 176 °C by methods known in the art using a Philips X'PertPRO powder diffractometer with an Anton Paar
  • TTK-450 Temperature Camera The temperature of the sample was controlled with an
  • Example 4 (Form ⁇ l) Solid state form ⁇ of icofungipen (0.05 g) was heated above 176 °C by methods known in the art using a DSC Mettler Toledo 822 Star 6 , and yielded high temperature solid state form ctl of icofungipen. The temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 ⁇ h aluminum crucibles with pierced lids were used.
  • Example 5 Solid state form ⁇ of icofungipen in form of single crystal was cooled to about - 173 °C by methods known in the art using a Bruker Nonius FR591/Kappa CCD diffractometer and an Oxford Cryo Unit, and yielded low temperature solid state form ⁇ 2 of icofungipen.
  • Single crystal x-ray diffraction data were collected using CuK ⁇ radiation.
  • Example 6 (Form ⁇ ) Icofungipen (2.00 g) was dissolved in water (50 ml). The solution was filtrated, cooled to about -25 °C, and lyophilized under high vacuum at below 0.37 mbar for 48 hours to yield solid state form ⁇ of icofungipen.
  • the x-ray powder diffraction patterns were obtained by X-ray diffraction on a powder sample by methods known in the art. X-ray powder diffraction patterns were collected from a Philips X'PertPRO powder diffractometer using CuK ⁇ radiation. The differential scanning calorimeter thermograms were obtained by methods known in the art using a DSC Mettler Toledo 822 Star 6 . The weight of the samples was about 5 mg.
  • the temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 ⁇ L aluminum crucibles -with pierced lids were used.
  • the FT-Raman spectra were obtained by methods known in the art using a spectrophotometer Bruker, model Equinox 55 with a Bruker FT-raman module 106/S. Radiation of 1064 nm from a Nd.'YAG laser was used for excitation. Spectra were obtained in the range from 4000 to 0 cm “1 at 4 cm " resolution, and 50 mW laser power at the sample.
  • Example 7 (Form ⁇ ) Icofungipen (2.00 g) was dissolved in water (50 ml). Solution was filtrated, and spray dried for 1 hour to yield solid state form ⁇ of icofungipen.
  • the x-ray powder diffraction patterns of the sample thus obtained corresponded to the x-ray powder diffraction patterns of the solid state form ⁇ of icofungipen obtained according to Example 6.
  • the DSC theimogram of the sample thus obtained corresponded to the DSC thermogram of the solid state form ⁇ of icofungipen obtained according to Example 6.
  • Example 8 (Form ⁇ l) Solid state form ⁇ of icofungipen (0.15 g) was heated above 176 °C by methods known in the art using a Philips X'PertPRO powder diffractometer with an Anton Paar
  • TTK-450 Low-Temperature Camera The temperature of the sample was controlled with an Anton Paar Temperature Control Unit TCU 100. This process resulted in forming high temperature solid state form ⁇ 1 of icofungipen. X-ray powder diffraction patterns were collected using CuK ⁇ radiation.
  • Example 9 (Form ⁇ l) Solid state form ⁇ of icofungipen (0.05 g) was heated above 85 °C by methods known in the art using a DSC Mettler Toledo 822 Star 6 , and yielded high temperature solid state form ⁇ l of icofungipen. The temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 ⁇ L aluminum crucibles with pierced lids were used.
  • Example 10 (Form ⁇ ) Icofungipen (1.00 g) was suspended in chloroform (200 mL). Suspension was stirred for 5 hours at boiling temperature and then stirred at the room temperature for 18 hours to yield solid state form ⁇ of icofungipen.
  • the x-ray powder diffraction patterns were obtained by x-ray diffraction on a powder sample by the methods known in the art. X-ray powder diffraction patterns were collected at Philips X'PertPRO powder diffractometer using CuK ⁇ radiation. The differential scanning calorimeter thermograms were obtained by methods known in the art using DSC Mettler Toledo 822 Star 6 . The weight of the samples was about 5 mg. The temperature range of scans was 25 °C - 250 °C at a rate of 10 °C/min.
  • Example 12 (Form ⁇ l) Solid state form ⁇ of icofungipen (0.005 g) was heated above 158 °C by methods known in the art using DSC Mettler Toledo 822 Star 6 yielded high temperature solid state form ⁇ l. The temperature range of scans was 25 °C - 250 °C at a rate of 10 °C/min.
  • Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 ⁇ L aluminum crucibles with pierced lids were used.
  • Example 13 (Form ⁇ ) Solid state form ⁇ of icofungipen (0.10 g) was heated above about 158 °C by methods known in the art, and then cooled below about 78 °C, yielded solid state form ⁇ .
  • the differential scanning calorimeter thermograms were obtained by methods known in the art using DSC Mettler Toledo 822 Star 6 . The weight of the samples was about 5 mg. The temperature range of scans was 25 °C - 250 °C at a rate of 10 °C/min.
  • Example 15 (Form ⁇ ) Icofungipen (0.125 g) was treated to heating in vacuum sublimation apparatus at oil bath temperature of about 170 °C and pressure of 0.05 mm Hg for 1 hour to yield solid state form ⁇ of icofungipen.
  • the differential scanning calorimeter thermograms were obtained by methods known in the art using DSC Mettler Toledo 822 Star 6 . The weight of the samples was about 5 mg. The temperature range of scans was 25 °C — 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 ⁇ L aluminum crucibles with pierced lids were used.

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Abstract

The present invention relates to the solid state forms α, β, δ, ϵ, and ζ of (-)-(1R,1S)-2-amino-4-methylene-cyclopentanecarboxylic acid, to the processes for their preparation, to pharmaceutical compositions containing the said solid state forms of (-)-(1R,1S)-2-amino-methylene-cyclopentanecarboxylic acid as the active ingredients as well as to a method of treatment using the same.

Description

SOLED STATE FORMS OF (-)-(lR,2S)-2-AMINO-4-METHYLENE- CYCLOPENTANECARBOXYLIC ACID
The present invention relates to the solid state forms of (-)-(lR,lS)-2-amino-4-me- thyleαecyclopentanecarboxylic acid (in the further text of the application designated by its name "icofungipen"), processes for their preparation, pharmaceutical forms containing the solid state forms as an active ingredient, and methods of using the solid state forms. Icofungipen is an active pharmaceutical ingredient used in the treatment of fungal infections. The product as described for the first time in Buropeau patent EP 0571870 Bl. EP 0571870 Bl is hereby incorporated by reference in its entirety. It has now been surprisingly found that by crystallization of icofungipen from organic solvents or their mixtures at a temperature of -20 °C to 80 °C solid state form α has been prepared. Also, it has now been surprisingly found that by crystallization of icofungipen from organic solvents or their mixtures and water at a temperature of -20 °C to 80 °C solid state form α has been prepared. Suitable organic solvents that may be used in accordance with the present invention include: methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, .seobutyl acetate, tert-butyl acetate, acetone, methyl ethyl ketone, diethyl ketone, methanol, ethanol, propanol, isopropanol, w-butanol, >yec-butanol, tert-butanol, cyclop entane, cyclohexane, cyclohexanone, cyclohexanol, dibutyl ether and N,N- dimetrαylacetamide. Also, it has now been surprisingly found that by sublimation of icofungipen, solid state form α has been prepared. Also, it has now been surprisingly found that by heating solid state form α of icofungipen, high temperature solid state form αl of icofungipen has been prepared. Also, it has now been surprisingly found that by cooling solid state form α of icofungipen, low temperature solid state form α2 of icofungipen has been prepared. Also, it has now been surprisingly found that by spray drying a water solution of icofungipen, solid state form β has been prepared. Also, it has now been surprisingly found that by lyophilization of a frozen water solution of icofungipen, solid state form β has been prepared. Also, it has now been surprisingly found that by heating solid state form β of icofungipen solid state form, βl has been prepared. Also, it has now been surprisingly found that by stirring of icofungipen in chloroform at about 61 °C, solid state form δ of icofungipen has been prepared. Also, it has now been surprisingly found that by heating solid state form δ of icofungipen, high temperature solid state form δl of icofungipen has been prepared. Also, it has now been surprisingly found that by cooling solid state form δl of icofungipen, solid state form ε of icofungipen has been prepared. Also, it has now been surprisingly found that by sublimation of icofungipen at high vacuum (0,05 mm Hg) and temperature gradient between about 130 °C to 160 °C solid state form ζ of icofungipen has been prepared. An object of this invention is to provide solid state form α of icofungipen. Another object of this invention is to provide solid state form β of icofungipen. Another object of this invention is to provide solid state form δ of icofungipen. Another object of this invention is to provide solid state form ε of icofungipen. Another object of this invention is to provide solid state form ζ of icofungipen. A further object of this invention is to provide pharmaceutical compositions such as tablets, capsules, suppositories, sachets, injections or spray containing solid state form α of icofungipen, solid state form β of icofungipen, or any mixtures of solid state forms α and β icofungipen as an active ingredient, without any additives or in corrabination with one or more pharmaceutically acceptable additives such as sugar, starc-h derivatives, cellulose, cellulose derivatives, mold release agents and anti-adhesive agents and optionally agents for flowability regulation. Still, a further object of this invention is to provide pharmaceutical compositions such as tablets, capsules, suppositories, sachets, injections or spray containing solid state form α of icofungipen, solid state form β of icofungipen, solid state form δ of icofungipen, solid state form ε of icofungipen, solid state form ζ of icofungipen or any mixtures of solid state forms α, β, δ, ε and ζ of icofungipen as the actrve ingredient, without any additives or in combination with one or more pharmaceutically acceptable additives such as sugar, starch derivatives, cellulose, cellulose derivatives, mould release agents and antiadhesive agents and optionally agents for flowability regulation. Still, a further object of this invention is to provide compounds or a αy mixture of said compounds, prepared according to the processes of the present invention, useful for the treatment and prevention of all diseases which are regarded as treatable or avoidable by the use of icofungipen, in particular, the compounds according to the invention ttiat can be employed in the treatment of fungal infections. Solid state form α of icofungipen, prepared according to Example 1 of the present invention, is characterized by a characteristic x-ray powder diffraction pattern comprising 9.2+0.2°, 14.0+0.2°, 15.8+0.2°, 17.5+0.2, 20.4+0.2°, 21.7+0.2°, 28.6+0.2°, and 32.0+0.2° degrees two-theta. In addition, single crystals of a solid state form α of icofungipen were prepared and accordingly single crystal x-ray diffraction data were collected from a Bruker Nonius FR591/Kappa CCD diffractometer using CuKα radiation. Basic crystallographic data for the solid state form α of icofungipen are represented in Table 1.
TABLE 1. Crystallographic data for the solid state form α of icofungipen
Chemical formula C7H11NO2 Empirical formula weight 141.17 Temperature 293(1) K Crystal size 0.2 x 0.2 x 0.4 mm Crystal system, space group Monoclinic, P 2\ Unit cell dimension a = 6.38(18) A b = 5.98(18) A c = 9.69(19) A β= 96.6(2) ° 367 (1) A3 2 Calculated density 1.28(2)cm"3
Solid state form α of icofungipen, prepared according to Example 1 of the present invention, is characterized by a DSC thermogram comprising one endothermic maximum at about 176 °C (onset at about 174 °C) (heating rate of 10 °C/min). Solid state form α of icofungipen, prepared according to Example 1 of the present invention, is characterized by a Raman spectrum comprising characteristic absoφtion bands at 3076, 2979, 2921, 2900, 1542, 1427, 826, 545, and 403 cm-1. Solid state form α of icofungipen, prepared according to Example 1 of the present invention, is characterized by solid-solid transformation into high temperature solid state form αl of icofungipen when heated above about 176 °C. High temperature solid state form αl of icofungipen, prepared according to Example 3 of the present invention, is characterized by a characteristic x-ray powder diffraction pattern comprising 8.2+0.2°, 14.0+0.2°, 14.4+0.2°, 15.3+0.2°, 17.4±0.2°,
20.4+0.2°, 28.2+0.2°, and 30.9+0.2° degrees two-theta. High temperature solid state form αl of icofungipen, prepared according to
Example 4 of the present invention, is characterized by a DSC thermogram comprising one endothermic maximum at about 237 °C (onset at about 233 °C) (heating rate of 10
°C/min). Solid state form α of icofungipen, prepared according to Example 1 of the present invention, is characterized by solid-solid transformation into low temperature solid state form α2 of icofungipen when cooled to about -173 °C. In addition, low temperature solid state form α2 of icofungipen was prepared according to Example 5 of the present invention, and single crystal x-ray diffraction data of low temperature solid state form α2 of icofungipen were collected from a Bruker
Nonius FR591 Kappa CCD diffractometer using CuKα radiation. Basic crystallographic data for the solid state form α2 of icofungipen are represented in Table 2.
TABLE 2. Crystallographic data for the solid state form α2 of icofungipen
Chemical formula C7HnNO2 Empirical formula weight 141.17 Temperature 100(1) K Crystal size 0.12 x 0.15 x 0.22 mm Crystal system, space group Monoclinic, P 2\ Unit cell dimension a - 6.34(1) A b = 5.95(1) A c = 9.51(1) A β= 96.5(1) ° 356 (1) A3 Z 2 Calculated density 1.32 (l)g cm -3
Solid state form β of icofungipen, prepared according to Example 6, of the present invention, is characterized by a characteristic x-ray powder diffraction pattern comprising 9.0+0.2°, 14.4+0.2°, 15.6+0.2°, 17.5±0.2°, 20.3+0.2°, 20.8+0.2°, 22.2+0.2°, 23.6+0.2°, 27.3+0.2°, 28.9+0.2°, and 30.5+0.2° degrees two-theta.
In addition, single crystals of solid state form β of icofungipen were prepared, and accordingly single crystal X-ray diffraction data were collected from a Bruker Nonius FR591/Kappa CCD diffractometer using CuKα radiation. Basic crystallographic data for the solid state form β of icofungipen, are represented in Table 3. TABLE 3. Crystallographic data for the solid state form β of icofungipen
Chemical formula C7HπNO2 Empirical formula weight 141.17 Temperature 100(1) K Crystal size 0.10 x 0.10 x 0.52 mm Crystal system, space group Orthorhombic, P 2 l\2\ Unit cell dimension a = 6.04(1) A b = 6.42(1) A c = 18.72(1) A 728 (1) A3 Z A Calculated density 1.29 (l)g cm"
Solid state form β of icofungipen, prepared according to Example 6 of the present invention, is characterized by a DSC thermogram comprising one endothermic maximum at about 85 °C (onset at about 83 °C) (heating rate of 10 °C/min). Solid state form β of icofungipen, prepared according to Example 6 of the present invention, is characterized by a Raman spectrum comprising characteristic absoφtion bands at 3074, 2981, 2950, 2911, 1658, 1431, 1315, 818, 605, 541, and 422 cm"1. Solid state form β of icofungipen, prepared according to Example 6 of the present invention, is characterized by solid-solid transformation into high temperature solid state form βl of icofungipen when heated above about 85 °C.
High temperature solid state form βl of icofungipen, prepared according to
Example 8 of the present invention, is characterized by a characteristic x-ray powder diffraction pattern comprising 5.9+0.2°, 8.6(2) +0.2°, 14.4+0.2°, 15.6+0.2°, 16.2±0.2°, 17.4+0.2°, 18.9+0.2°, 20.4±0.2°, 20.8+0.2°, 22.2+0.2°, 28.9+0.2°, and 30.6(2)+0.2° degrees two-theta. High temperature solid state form βl of icofungipen, prepared according to Example 8 of the present invention, is characterized by a DSC thermogram comprising one endothermic maximum at about 236 °C (onset at about 232 °C) (heating rate of 10 °C/min). Solid state form δ of icofungipen, prepared according to the Example 10. of the present invention, is characterized by an characteristic x-ray powder diffraction pattern comprising 7.6+0.2°, 8.2.0+0.2°, 9.2+0.2°, 18.4+0.2 21.2+0.2° and 29.7+0.2° degrees two- theta. Solid state form δ of icofungipen, prepared according to the Example 10. of the present invention, is characterized by an DSC thermogram comprising one endothermic maximum at about 147 °C (onset at about 145 °C) and another endothermic maximum at about 158 °C (onset at about 150 °C) (heating rate of 10 °C/min). Solid state form δ of icofungipen, prepared according to the Example 10. of the present invention, is characterized by solid-solid transformation into high temperature solid state form δl of icofungipen when is heated above about 158 °C. High temperature solid state form δl of icofungipen, prepared according to the Example 11. of the present invention, is characterized by an characteristic x-ray powder diffraction pattern comprising 8.5+0.2°, 14.3+0.2°, 18.2+0.2°, 19.7+0.2°, 20.8+0.2°, and 29.3+0.2° degrees two-theta. High temperature solid state form δl of icofungipen, prepared according to the Example 12 . of the present invention, is characterized by an DSC thermogram comprising one endothermic maximum at about 211 °C (onset at about 202 °C) (heating rate of 10 °C/min) and one exothermic maximum at about 232 °C (onset at about 230 °C). Solid state form δl of icofungipen, prepared according to the Example 11. and Example 12. of the present invention, is characterized by solid-solid transformation into solid state form ε of icofungipen when is cooled below about 78 °C. Solid state form ε of icofungipen, prepared according to the Example 13. and Example 14. of the present invention, is characterized by an DSC thermogram comprising one endothermic maximum at about 81 °C (onset at about 79 °C) (heating rate of 10 °C/min). Solid state form ε of icofungipen, prepared according to the Example 13. and
Example 14. of the present invention, is characterized by solid-solid transformation into high temperature solid state form δl of icofungipen when is heating above about 81 °C. Solid state form ζ of icofungipen, prepared according to the Example 15. of the present invention, is characterized by an DSC thermogram comprising one endothermic maximum at about 234 °C (onset at about 229 °C) (heating rate of 10 °C/min).
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an x-ray powder diffraction (XRPD) spectrum of solid state form α of icofungipen. Figure 2 is an XRPD spectrum of solid state form α2 of icofungipen. Figure 3 is an XRPD spectrum of solid state form αl of icofungipen. Figure 4 is an XRPD spectrum of solid state form β of icofungipen. Figure 5 is an XRPD spectrum of solid state form βl of icofungipen. Figure 6 is an XRPD spectrum of solid state form δ of icofungipen. Figure 7 is an XRPD spectrum of solid state form δl of icofungipen.
EXAMPLES The present invention is next described by means of the following examples. The use of these and other examples anywhere in the specification is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified form. Likewise, the invention is not limited to any particular preferred embodiments described herein. Indeed, modifications and variations of the invention may be apparent to those skilled in the art upon reading this specification, and can be made without departing from its spirit and scope. The invention is therefore to be limited only by the terms of the appended claims, along with the full scope of equivalents to which the claims are entitled.
Example 1 (Form α) Icofungipen (0.20 g) was dissolved in 96 % ethanol (25 mL). After cooling to room temperature, the solution was left at the same temperature for 24 hours to yield solid state form α of icofungipen. The x-ray powder diffraction patterns were obtained by x-ray diffraction on a powder sample by methods known in the art. X-ray powder diffraction patterns were collected from a Philips X'PertPRO powder diffractometer using CuKα radiation. The differential scanning calorimeter thermograms were obtained by methods known in the art using a DSC Mettler Toledo 822 Star6. The weight of the samples was about 5 mg. The temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μL aluminum crucibles with pierced lids were used. The FT-Raman spectra were obtained by methods known in the art using a spectrophotometer Bruker, model Equinox 55 with a Bruker FT-raman module 106/S. Radiation of 1064 nm from a Nd:YAG laser was used for excitation. Spectra were obtained in the range from 4000 to 0 cm"1 at 4 cm"1 resolution, and 50 mW laser power at the sample.
Example 2 (Form α) Icofungipen (2.00 g) was sublimated for 2 hours at 140 °C and below 2 mbar to yield solid state form α of icofungipen. The x-ray powder diffraction patterns of the sample thus obtained corresponded to the x-ray powder diffraction patterns of the solid state form α of icofungipen obtained according to Example 1. The DSC thermogram of the sample thus obtained corresponded to the DSC thermogram of the solid state form α of icofungipen obtained according to Example 1.
Example 3 (Form αl) Solid state form α of icofungipen (0.15 g) was heated above 176 °C by methods known in the art using a Philips X'PertPRO powder diffractometer with an Anton Paar
TTK-450 Temperature Camera. The temperature of the sample was controlled with an
Anton Paar Temperature Control Unit TCU 100. This process resulted in forming high temperature solid state form αl of icofungipen. Example 4 (Form αl) Solid state form α of icofungipen (0.05 g) was heated above 176 °C by methods known in the art using a DSC Mettler Toledo 822 Star6, and yielded high temperature solid state form ctl of icofungipen. The temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μh aluminum crucibles with pierced lids were used.
Example 5 (Form α2) Solid state form α of icofungipen in form of single crystal was cooled to about - 173 °C by methods known in the art using a Bruker Nonius FR591/Kappa CCD diffractometer and an Oxford Cryo Unit, and yielded low temperature solid state form α2 of icofungipen. Single crystal x-ray diffraction data were collected using CuKα radiation.
Example 6 (Form β) Icofungipen (2.00 g) was dissolved in water (50 ml). The solution was filtrated, cooled to about -25 °C, and lyophilized under high vacuum at below 0.37 mbar for 48 hours to yield solid state form β of icofungipen. The x-ray powder diffraction patterns were obtained by X-ray diffraction on a powder sample by methods known in the art. X-ray powder diffraction patterns were collected from a Philips X'PertPRO powder diffractometer using CuKα radiation. The differential scanning calorimeter thermograms were obtained by methods known in the art using a DSC Mettler Toledo 822 Star6. The weight of the samples was about 5 mg. The temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μL aluminum crucibles -with pierced lids were used. The FT-Raman spectra were obtained by methods known in the art using a spectrophotometer Bruker, model Equinox 55 with a Bruker FT-raman module 106/S. Radiation of 1064 nm from a Nd.'YAG laser was used for excitation. Spectra were obtained in the range from 4000 to 0 cm"1 at 4 cm" resolution, and 50 mW laser power at the sample.
Example 7 (Form β) Icofungipen (2.00 g) was dissolved in water (50 ml). Solution was filtrated, and spray dried for 1 hour to yield solid state form β of icofungipen. The x-ray powder diffraction patterns of the sample thus obtained corresponded to the x-ray powder diffraction patterns of the solid state form β of icofungipen obtained according to Example 6. The DSC theimogram of the sample thus obtained corresponded to the DSC thermogram of the solid state form β of icofungipen obtained according to Example 6.
Example 8 (Form βl) Solid state form β of icofungipen (0.15 g) was heated above 176 °C by methods known in the art using a Philips X'PertPRO powder diffractometer with an Anton Paar
TTK-450 Low-Temperature Camera. The temperature of the sample was controlled with an Anton Paar Temperature Control Unit TCU 100. This process resulted in forming high temperature solid state form β 1 of icofungipen. X-ray powder diffraction patterns were collected using CuKα radiation.
Example 9 (Form βl) Solid state form β of icofungipen (0.05 g) was heated above 85 °C by methods known in the art using a DSC Mettler Toledo 822 Star6, and yielded high temperature solid state form βl of icofungipen. The temperature range of the scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μL aluminum crucibles with pierced lids were used.
Example 10 (Form δ) Icofungipen (1.00 g) was suspended in chloroform (200 mL). Suspension was stirred for 5 hours at boiling temperature and then stirred at the room temperature for 18 hours to yield solid state form δ of icofungipen. The x-ray powder diffraction patterns were obtained by x-ray diffraction on a powder sample by the methods known in the art. X-ray powder diffraction patterns were collected at Philips X'PertPRO powder diffractometer using CuKα radiation. The differential scanning calorimeter thermograms were obtained by methods known in the art using DSC Mettler Toledo 822 Star6. The weight of the samples was about 5 mg. The temperature range of scans was 25 °C - 250 °C at a rate of 10 °C/min.
Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μL aluminum crucibles with pierced lids were used. Example 11 (Form δl) Solid state form δ of icofungipen (0.20 g) was heated above 158 °C by methods known in the art using Philips X'PertPRO powder diffractometer with Anton Paar TTK-
450 Temperature Camera. The temperature of the sample was controlled with Anton Paar Temperature Control Unit TCU 100. This process results in forming high temperature solid state form δl of icofungipen.
Example 12 (Form δl) Solid state form δ of icofungipen (0.005 g) was heated above 158 °C by methods known in the art using DSC Mettler Toledo 822 Star6 yielded high temperature solid state form δl. The temperature range of scans was 25 °C - 250 °C at a rate of 10 °C/min.
Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μL aluminum crucibles with pierced lids were used.
Example 13 (Form ε) Solid state form δ of icofungipen (0.10 g) was heated above about 158 °C by methods known in the art, and then cooled below about 78 °C, yielded solid state form ε. The differential scanning calorimeter thermograms were obtained by methods known in the art using DSC Mettler Toledo 822 Star6. The weight of the samples was about 5 mg. The temperature range of scans was 25 °C - 250 °C at a rate of 10 °C/min.
Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μL aluminum crucibles with pierced lids were used. Example 14 (Form ε) Solid state form δ of icofungipen (O.005 g) was heated above about 158 °C and then cooled below about 78 °C by methods known in the art using DSC Mettler Toledo
822 Star6 yielded solid state form ε. The temperature range of scans was 25 °C - 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min.
Standard 40 μL aluminum crucibles with pierced lids were used.
Example 15 (Form ζ) Icofungipen (0.125 g) was treated to heating in vacuum sublimation apparatus at oil bath temperature of about 170 °C and pressure of 0.05 mm Hg for 1 hour to yield solid state form ζ of icofungipen. The differential scanning calorimeter thermograms were obtained by methods known in the art using DSC Mettler Toledo 822 Star6. The weight of the samples was about 5 mg. The temperature range of scans was 25 °C — 250 °C at a rate of 10 °C/min. Samples were purged with nitrogen gas at a flow rate of 80 mL/min. Standard 40 μL aluminum crucibles with pierced lids were used.

Claims

WHAT CLAIMED IS:
1. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized by the monoclmic space group P 2\, and displaying unit cell parameters comprising: crystal axis lengths of a = 6.38(18) A, b = 5.98 (18) A, and c — 9.69 (19) A, and an angle between the crystal axes of β= 96.60(1)°.
2. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having characteristic x-ray powder diffraction peaks, designated by 2© and expressed in degrees, at 9.2+0.2°, 14.0+0.2°, 15.8+0.2°, 17.5+0.2, 20.4+0.2°, 21.7+0.2°, 28.6+0.2°, and 32.0+0.2°.
3. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having a characteristic DSC endothermic maximum at about 176 °C (onset at about 174 °C) (heating rate of 10 °C/min).
A. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having characteristic FT-Raman absoφtion bands at 3076, 2979, 2921, 2900, 1542, 1427, 826, 545, and 403 cm"1.
5. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized in that when heated above about 176 °C, transfer to high temperature solid state form αl is characterized by the following data: x-ray powder diffraction peaks, designated by 2© and expressed in degrees, at 8.2+0.2°, 14.0±0.2°, 14.4+0.2°, 15.3+0.2°, 17.4+0.2°, 20.4±0.2°, 28.2+0.2°, and 30.9+0.2°; and a DSC characteristic endothermic maximum at about 237 °C (onset at about 233 °C) at heating rate of 10 °C/mm.
6. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized in that when cooled to about -173 °C, transfer to low temperature solid state form α2 characterized by the following data: monoclmic space group P2 with unit cell parameters comprising: crystal axis lengths of a = 6.34(1) A, b = 5.95 (1) A, and c = 9.51 (1) A, and an angle between the crystal axes of β= 96.5 (1)°.
7. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, characterized in that it does not contain water.
8. A solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, characterized in that it does not contain solvent.
9. A process for the preparation of the solid state form α of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid according to claims 1 to 6, characterized in that a solution of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid and organic solvents or mixtures of organic solvents is subjected to crystallization at a temperature of -20 °C to 80 °C.
10. A process for the preparation of the solid state form o of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid according to claims 1 to 6, characterized in that a solution of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid and organic solvents or mixtures of organic solvents and water is subjected to crystallization at a temperature of -20 °C to 80 °C.
11. A process for the preparation of the solid state form oc of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid according to claims 1 to 6, characterized in that (-)-(li<-JS)-2-amino-4-methylene-cyclopentanecarboxylic acid is subjected to a sublimation.
12. The solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a polymoφhic purity greater than 95.0 %.
13. The solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a polymoφhic purity greater than 99.0 %.
14. The solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a polymoφhic purity greater than 99.5 %.
15. T-he solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a polymoφhic purity greater than 99.9 %.
16. T_he solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, which is polymoφhic pure.
17. T-he solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a purity of greater than about 90.0 %.
18. T-he solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a purity of greater than about 95.0 %.
19. T-he solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a purity of greater than about 99.0 %.
20. Trie solid state form α (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, having a purity of greater than about 99.9 %.
21. A pharmaceutical composition comprising the solid state form oc (-)-(lR,lS)-2- amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, and one or more pharmaceutically acceptable carriers or excipients.
22. A method of treating fungal infections in a human, comprising administering to a patient in need of such treatment an effective amount of the solid state form α of (-)- (lR,l»S -2-amino-4-methylene-cyclopentatιecarboxylic acid according to claims 1 to 6.
23. A solid state form β of (-)-(lR3lS)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized by the orthorhombic space group P 212121, and displaying unit cell parameters comprising: crystal axis lengths of a = 6.04(1) A, b = 6.42(1) A, and c - 18.720) A.
24. A solid state form β of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid -having characteristic x-ray powder diffraction peaks, designated by 2© and expressed in degrees, at 9.0+0.2°, 14.4+0.2°, 15.6+0.2°, 17.5+0.2°, 20.3+0.2°, 20.8+0.2°, 22.2+0.2°, 23.6+0.2°, 27.3+0.2°, 28.9+0.2°, and 30.5+0.2°.
25. A solid state form β of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having a characteristic DSC endothermic maximmn at about 85 °C (onset at about 83 °C) (heating rate of 10 °C/min).
26. A solid state form β of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having characteristic FT-Raman absoφtion bands at 3074, 2981, 2950, 2911, 1658, 1431, 1315, 818, 605, 541, and 422 cm"1.
27. A solid state form β of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized in that when heated above about 85 °C, transfer to high temperature solid state form βl is characterized "by the following data: x-ray powder diffraction peaks, designated by 2© and expressed in degrees, at 5.9+0.2°, 8.6(2) +0.2°, 14.4+0.2°, 15.6+0.2°, 16.2+0.2°, 17.4+0.2°, 18.9+0.2°, 20.4±0.2°, 20.8+0.2°, 22.2+0.2°, 28.9+0.2°, and 30.6(2)+0.2°; and a DSC characteristic endothermic maximum at about 236 °C (onset at about 232 °C) at heating rate of 10 °C/min.
28. A solid state form β of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, c-haracterized in that it does not contain water.
29. A solid state form β of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, c-haracterized in that it does not contain solvent.
30. A process for the preparation of the solid state form β of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid according to claims 23 to 27, characterized in that (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid is subjected to spray drying.
31. A process for the preparation of the solid state form β of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid according to claims 23 to 27, characterized in that a frozen solution of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid and water is subjected to a lyophilization.
32. The solid state form β (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a polymoφhic purity greater than 95.0 %.
33. The solid state form β (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a polymoφhic purity greater than 99.0 %.
34. The solid state form β (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a polymoφhic purity greater than 99.5 % .
35. The solid state form β (-)-(lR,lS)-2-an-tino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a polymoφhic purity greater than 99.9 %.
36. The solid state form β (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, which is polymoφhic pure.
37. The solid state form β (-)-(lR,lS)-2-anιino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a purity of greater than about 90.0 %.
38. The solid state form β (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a purity of greater than about 95.0 %.
39. The solid state form β (-)-(lR,l/-S)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a purity of greater than about 99.0 %.
40. The solid state form β (-)-(lR,l<S)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, having a purity of greater than about 99.9 %.
41. A pharmaceutical composition comprising the solid state form β (-)-(lR,lS)-2- amino-4-methylene-cyclopentanecarbox lic acid according to claims 23 to 27, and one or more pharmaceutically acceptable carriers or excipients.
42. A method of treating fungal infections in a human, comprising administering to a patient in need of such treatment an effective amount of the solid state form β of (-)- (lR,lS)-2-amino-4-methylene-cyclopenta.necarboxylic acid according to claims 23 to 27.
43. A pharmaceutical composition comprising any mixture of the solid state form α of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 1 to 6, and the solid state form β of (-)-(lR,l<S)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 23 to 27, and one or more pharmaceutically acceptable carriers or excipients.
44. A method of treating fungal infections in a human, comprising aα-tninistering to a patient in need of such treatment an effective amount of any mixture of the solid state form α of (-)-(lR,lS)-2-amino-4-rα.ethylene-cyclopentanecarboxylic acid of claim 1 to claim 6, and the solid state form β of (-)-(lR,lS)-2-amino-4-methylene- cyclopentanecarboxylic acid according to claims 23 to 27.
45. Solid state form δ of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having characteristic x-ray powder diffraction peaks, designated by 2Θ and expressed in degrees, at 7.6+0.2°, 8.2.0+0.2°, 9.2+0.2°, 18.4+0.221.2+0.2° and 29.7+0.2°.
46. Solid state form δ of (-)-( lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having characteristic DSC endothermic maximum at about 147 °C (onset at about 145 °C) and another one at about 158 °C (onset at about 150 °C) (heating rate of 10 °C/min).
47. Solid state form δ of (-)-(lR,lS)-2-aιrιino-4-methylene-cyclopentanecarboxylic acid characterized in that when is heating above about 158 °C transfer to high temperature solid state form δl of (-)-(lR,l-?)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized by the following data: X-ray powder diffraction peaks, designated by 2© and expressed in degrees, at 8.5±0.2°, 14.3+0.2°, 18.2+0.2°, 19.7-t0.2°, 20.8+0.2°, and 29.3+0.2° and DSC characteristic endothermic maximum at about 211 °C (onset at about 202 °C) and exothermic maximum at about 232 °C (onset at about 230 °C) at heating rate of 10 °C/min.
48. Process for the preparation of the solid state form δ of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid according to claims 45 to 47, characterized in that suspension of (-)-(lR3lS)-2-amino-4-methylene-cyclopentanecarboxylic acid and chloroform is stirred at about 61 °C.
49. A pharmaceutical composition comprising the solid state form δ of (-)- -(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 45 to 47 , and one or more pharmaceutically acceptable carriers or excipients.
50. A method of treating fungal infections in a human which comprises adrninistering to a patient in need of such treatment an effective amount of the solid state form δ of (-)- (lR,lS)-2-amirιo-4-methylene-cyclopentanecarboxylic acid according to claims 45 to 47 .
51. Solid state form ε of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having characteristic DSC endothermic maximum at about 81 °C (onset at about 79 °C) (heating rate of 10 °C/min).
52. Solid state form ε of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized in that when is heating above about 81 °C transfer to high temperature solid state form δl of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid characterized by the following data: X-ray powder diffraction peaks, designated by 2© and expressed in degrees, at 8.5+0.2°,
14.3+0.2°, 18.2+0.2°, 19.7+0.2°, 20.8+0.2°, and 29.3±0.2° and DSC characteristic endothermic maximum at about 210 °C (onset at about 204 °C) and exothermic maximum at about 232 °C (onset at about 230 °C) at heating rate of 10
°C/min.;
53. Process for the preparation of the solid state form ε of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid that includes heating of solid state form δ of (-)- (lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid up to about 158 °C and cooling to about 75 °C.
54. Process for the preparation of the solid state form ε of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid that includes heating of solid state form δ of (-)- (lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid up to about 158 °C and cooling to room temperature.
55. A pharmaceutical composition comprising the solid state form ε of (-)-(lR,lS)-2- ammo-4-memylerre-cyclopentanecarboxylic acid according to claims 51 to 52, and one or more pharmaceutically acceptable carriers or excipients.
56. A method of treating fungal infections in a human which comprises adm-tnistering to a patient in need of such treatment an effective amount of the solid state form ε of (-)- (lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid according to claims 51 to 52 .
57. Solid state form ζ of (-)-(lR,lS)-2-amino-4-methylene-cyclopentanecarboxylic acid having characteristic DSC endothermic maximum at about 234 °C (onset at about 229 °C) (heating rate of 10 °C/min).
58. Process for the preparation of the solid state form ζ of (-)-(lR,lS)-2-amino-4- methylene-cyclopentanecarboxylic acid that includes sublimation of icofungipen at about oil bath temperature 170 °C and pressure of about 0.05 mm Hg for 1 hour.
59. The solid state form ζ of (-)-(lR,lS)-2-amino-4-methylene- cyclopentanecarboxylic acid according to claim 57, having a polymoφhic purity greater than about 95.0 %.
60. The solid state form ζ of (-)-(lR,lS)-2-amino-4-mefhylene- cyclopentanecarboxylic acid according to claim 57, having a polymoφhic purity greater than about 99.0 %.
61. The solid state form ζ of (-)-(lR,lS)-2-amino-4-methylene- cyclopentanecarboxylic acid according to claim 57, having a polymoφhic purity greater than about 99.5 %.
62. A pharmaceutical composition comprising the solid state form ζ of (-)-(lR,lS)-2- amino-4-methylene-cyclopentanecarboxyhc acid according to claim 57, and one or more pharmaceutically acceptable carriers or excipients.
63. A method of treating fungal infections in a human which, comprises administering to a patient in need of such treatment an effective amount of the solid state form ζ of (-)- (lR,l-S}-2-amino-4-methylene-cyclopentanecarboxylic acid according to claim 57.
64. A pharmaceutical composition comprising at least two solid state forms of (-)- (lR,lΛS)-2-amino-4-methylene-cyclopentanecarboxylic acid and one or more pharmaceutically acceptable carriers or excipients, wherein said solid state forms of (-)- (lR,l-S}-2-amino-4-methylene-cyclopentanecarboxylic acid are selected from the solid state form α according to claims 1 to 6, the solid state form β according to claims 23 to 27, the solid state form δ according to claims 45 to 47, the solid state form ε according to claims 51 to 52, and the solid state form ζ according to clai 57.
PCT/IB2005/000971 2004-04-16 2005-04-13 Solid state forms of (-)-(1r,2s)-2-amino-4-methylene-cyclopentanecarboxylic acid WO2005100302A1 (en)

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US60/563,265 2004-04-16
US60817604P 2004-09-07 2004-09-07
US60/608,176 2004-09-07

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J.MITTENDORF: "Efficient Asymetric Synthesis of beta-Amino Acid BAY 10-8888/PLD-118, a Novel Antifungal for the Treament of Yeast Infections", SYNTHESIS, no. 1, 2003, pages 136 - 140, XP002344848 *
MITTENDORFJ ET AL: "NOVEL ANTIFUNGAL BETA-AMINO ACIDS: SYNTHESIS AND ACTIVITY AGAINST CANDIDA ALBICANS", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 13, no. 3, 10 February 2003 (2003-02-10), pages 433 - 436, XP002317979, ISSN: 0960-894X *

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