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1. (WO2005100302) SOLID STATE FORMS OF (-)-(1R,2S)-2-AMINO-4-METHYLENE-CYCLOPENTANECARBOXYLIC ACID
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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.