WO2009100723A2 - Formes cristallines d’une substance antibiotique - Google Patents

Formes cristallines d’une substance antibiotique Download PDF

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WO2009100723A2
WO2009100723A2 PCT/DK2009/000039 DK2009000039W WO2009100723A2 WO 2009100723 A2 WO2009100723 A2 WO 2009100723A2 DK 2009000039 W DK2009000039 W DK 2009000039W WO 2009100723 A2 WO2009100723 A2 WO 2009100723A2
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spectrum
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fourier transform
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WO2009100723A3 (fr
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Jan Jensen
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Leo Pharma AS
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Leo Pharma AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
    • 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
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to crystalline forms of 24-bromofusidic acid, to their preparation, pharmaceutical compositions containing them, and to the use of said crystalline 24-bromofusidic acid forms as medicaments in the treatment of infectious diseases.
  • 24-Bromofusidic acid (Br-FA) (WO 2005/007669) represents a new promising antibiotic for the treatment of bacterial infections with a broad range of antimicrobial activity.
  • Br-FA gram positive bacteria
  • Staphylococcus Aureus S. Pyogenes
  • oxacillin oxacillin
  • methicillin resistant strains of S. Aureus oxacillin and methicillin resistant strains of S. Aureus.
  • Skin infections caused by Staphylococcus aureus species present a major problem for treating physicians today; greater than 80% of skin infections are complicated by S. aureus.
  • S. aureus can cause various infections of the skin (impetigo, dermatitis, folliculitis, etc.) and other organs.
  • S. aureus can cause various infections of the skin (impetigo, dermatitis, folliculitis, etc.) and other organs.
  • aureus infections are common in people with frequent skin injury, particularly if the skin is dry. Staphylococcal skin infections are seen most commonly in pre-pubertal children and certain occupational groups such as healthcare workers. Several skin conditions, particularly atopic dermatitis, are exacerbated by Staphylococcus aureus, but most staphylococcal infections will be in normal individuals.
  • Br-FA having excellent skin-penetration properties, therefore represents a promising new chemical entity which is presently in clinical development for topical treatment of skin and mucosa/soft tissue infections, such as for the topical treatment of impetigo and secondarily infected traumatic lesions (SITL). More particularly, Br-FA may also be useful for the treatment of secondary infected dermatoses (SID).
  • SID secondary infected dermatoses
  • the solid form, such as the crystal form, of a drug substance or active pharmaceutical ingredient used in a pharmaceutical formulation or medicament is important based on solubility, dissolution rate, hygroscopicity, bioavailability, e.g. skin-penetration properties, and stability differences between the different solid forms.
  • solubility solubility
  • dissolution rate e.g. hygroscopicity
  • bioavailability e.g. skin-penetration properties
  • stability differences between the different solid forms e.g. skin-penetration properties
  • various solid forms such as polymorphism or pseudo polymorphism can affect the properties of the quality of the drug product.
  • a specific crystal form including solvates and hydrates, might be preferable over another one.
  • certain forms may be preferable depending on the specific formulation and/or application.
  • the properties of a drug such as the dissolution rate of the active ingredient, may be tuned by the proper choice of a certain crystal form, or mixtures thereof.
  • a crystalline form of an active pharmaceutical ingredient is usually preferred over a non-crystalline form, e.g. an amorphous form, in a drug formulation or during processing.
  • Crystalline forms have inter alia the advantage of greater chemical stability (heat and light), easier processability and handling.
  • the provision of a crystalline form is an important advantage during drug synthesis, especially on an industrial scale, since crystals are generally easier isolated from a reaction mixture.
  • the crystallisation of a specific crystalline form of a compound in a particular solvent may result in an advantageous purification of the compound which would not be achieved by crystallisation of another form in a different solvent (partly due to differences in solubility properties of impurities in different solvents).
  • Various crystalline forms also differ in melting point, density, hardness, grinding properties, etc. and as a consequence a particular polymorphic form is preferred over another one depending on the specific application.
  • Different crystalline forms have different stabilities in pharmaceutical formulations which depend on the excipients, vehicles, and other additives present in the dosage form.
  • the instability of amorphous compounds represents in particular a problem when the drug substance is in suspension.
  • crystalline forms are generally preferred over non-crystalline forms of a drug substance, a specific crystalline form of a compound will be preferred depending on the various circumstances, such as its application or the process in which it is being used. Sometimes a thermodynamically more stable form is preferred over a metastable form, sometime a metastable form which may have an increased dissolution rate is preferred.
  • WO 2005/007669 describes the synthesis of Br-FA and salts of Br-FA, but is silent about crystalline forms of the compound or the preparation of such forms.
  • WO 2007/087806 describes topical formulations of derivatives of fusidic acid including such formulations containing Br-FA as disclosed in WO 2005/007669.
  • the present invention surprisingly provides for the first time crystalline Br-FA, i.e. crystalline forms of Br-FA, i.e. polymorphs and pseudo-polymorphs, such as anhydrates, a hemihydrate and a hydrate of Br-FA, and processes for their preparation.
  • crystalline Br-FA i.e. crystalline forms of Br-FA, i.e. polymorphs and pseudo-polymorphs, such as anhydrates, a hemihydrate and a hydrate of Br-FA
  • the present invention relates to 24-bromofusidic acid (Br-FA) in crystalline form.
  • this invention relates to a crystalline form C (hydrate), D (hemihydrate), E (anhydrate), G (anhydrate), H (anhydrate), or I (anhydrate), of Br- FA, respectively; essentially exhibiting one or more of the features, or characteristic lines, shapes, or patterns depicted in Figures 1-32 respectively; or having one ore more of the values listed therein, e.g. wavenumbers in cm “1 ( ⁇ 3, ⁇ 4 or ⁇ 8 cm “1 depending on the method used), or angles of reflection in degrees 2 ⁇ ( ⁇ 0.1); or being represented by a spectrum/diffractogram substantially similar to that shown in said Figures.
  • this invention relates to an isolated crystalline form of Br-FA of the present invention as defined above which has a polymorphic purity of at least 80%, such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.
  • this invention relates to an isolated crystalline form of Br-FA of the present invention as defined above which has a degree of crystallinity of at least 80%, such as %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.
  • this invention relates to a mixture or composition of crystalline forms Br-FA, including pseudopolymorphs of Br-FA, comprising a crystalline form of Br-FA of the present invention as defined herein, e.g. a mixture of Br-FA anhydrates form E and G.
  • this invention relates to the use of a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, for the manufacture of Br-FA form H (anhydrate).
  • this invention relates to a method for the preparation of a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, said method comprising the step of crystallising a crystalline form of Br-FA of the present invention as defined herein in a suitable solvent or mixture of solvents.
  • this invention relates to a crystalline form of Br-FA of the present invention, or mixtures thereof, as defined herein for use in therapy.
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, together with a pharmaceutically acceptable excipient or vehicle.
  • this invention relates to a method of treating, preventing or ameliorating infections in a patient, the method comprising administering to said patient an effective amount of a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, and optionally further comprising concomitant or sequential administration of one or more other therapeutically active compounds.
  • this invention relates to the use of a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, for the manufacture of a medicament for the treatment, amelioration or prophylaxis of infections.
  • this invention relates to the use of a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, for the manufacture of a medicament for the treatment, amelioration or prophylaxis of bacterial infections.
  • this invention relates to the use of a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, for controlling microbial growth.
  • this invention relates to the use of a crystalline form of Br-FA of the present invention as defined herein, or mixtures thereof, for the prevention or prophylaxis of bacterial infections during animal breeding.
  • this invention relates to a method for the preparation of Br-FA form E (anhydrate) or G (anhydrate), as described above, such as a mixture of the two forms, said method comprising the steps of a) dissolving Br-FA in a mixture of ethanol and/or methanol, and water, optionally with heating; b) optionally cooling and/or concentrating of the solution obtained in step a); c) allowing crystalline Br-FA form E (anhydrate) or G (anhydrate) of the present invention, such as a mixture of the two forms, to crystallise; d) isolating the crystalline Br-FA form E (anhydrate) or G (anhydrate), or a mixture thereof, of the present invention.
  • this invention relates to a method for the preparation of Br-FA form H (anhydrate), as described above, said method comprising the steps of a) suspending crystalline Br-FA form E (anhydrate) or G (anhydrate) of the present invention, such as a mixture of the two forms, in ethyl formate, optionally with heating; b) optionally cooling and/or concentrating of the suspension obtained in step a); c) allowing crystalline Br-FA form H (anhydrate) of the present invention to crystallise; d) isolating the crystalline Br-FA form H (anhydrate) of the present invention.
  • this invention relates to a method for the preparation of Br-FA form H (anhydrate), as described above, said method comprising the steps of a) dissolving crystalline Br-FA form E (anhydrate) or G (anhydrate) of the present invention, such as a mixture of the two forms, in acetonitrile, optionally with heating; b) optionally cooling and/or concentrating of the solution obtained in step a); c) allowing crystalline Br-FA form H (anhydrate) of the present invention to crystallise; d) isolating the crystalline Br-FA form H (anhydrate) of the present invention.
  • this invention relates to a method for the preparation of Br-FA form C (hydrate), as described above, said method comprising the steps of a) dissolving Br-FA in a mixture of ethyl acetate and water, optionally with heating; b) optionally cooling and/or concentrating of the solution obtained in step a); c) allowing crystalline Br-FA form C (hydrate) of the present invention to crystallise; d) isolating the crystalline Br-FA form C (hydrate) of the present invention.
  • this invention relates to a method for the preparation of Br-FA form D (hemihydrate), as described above, said method comprising the steps of a) dissolving Br-FA in toluene saturated with water, optionally with heating; b) optionally cooling and/or concentrating of the solution obtained in step a), such as cooling to 0-10 0 C for 1-2 days; c) allowing crystalline Br-FA form D (hemihydrate) of the present invention to crystallise; d) isolating the crystalline Br-FA form D (hemihydrate) of the present invention.
  • this invention relates to a method for the preparation of Br-FA form I (anhydrate), as described above, said method comprising the steps of a) suspending Br-FA of the present invention, in hexane, optionally with heating; b) optionally cooling and/or concentrating of the suspension obtained in step a); c) allowing crystalline Br-FA form I (anhydrate) of the present invention to crystallise; d) isolating the crystalline Br-FA form I (anhydrate) of the present invention.
  • this invention relates to method of preparing a pharmaceutical formulation, said method comprising the step of mixing a crystalline Br-FA as anywhere defined herein with a pharmaceutically acceptable excipient or carrier.
  • this invention relates to a mixture or composition of crystalline forms of 24-bromofusidic acid (Br-FA), including pseudopolymorphs of 24- bromofusidic acid, comprising crystalline form E of 24-bromo-fusidic acid (Br-FA) according to the invention and crystalline form G of 24-bromo-fusidic acid (Br-FA) according to the invention.
  • Br-FA 24-bromofusidic acid
  • this invention relates to the use of a mixture or composition of crystalline forms of 24-bromofusidic acid (Br-FA), including pseudopolymorphs of 24- bromofusidic acid, comprising crystalline form E of 24-bromo-fusidic acid (Br-FA) according to the invention and crystalline form G of 24-bromo-fusidic acid (Br-FA) according to the invention as an intermediate for the preparation of crystalline form H of 24-bromofusidic acid (Br-FA).
  • Br-FA 24-bromofusidic acid
  • Br-FA 24-bromofusidic acid
  • Figure 1 is a graph showing the infrared spectrum (FTIR-MIKRO-ATR) of the crystalline Br-FA form C (hydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm '1 ).
  • Figure 2 is a graph showing the infrared spectrum (0.3% in KBr) of the crystalline Br-FA form C (hydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 3 is a graph showing the near infrared spectrum (FT-NIR) of the crystalline Br-FA form C (hydrate) of the present invention.
  • the Y-axis shows the absorbance and the X-axis the wavenumber (cm 1 ).
  • Figure 4 is a graph showing the Raman spectrum (FT-NIR-Raman) (neat) of the crystalline Br-FA form C (hydrate) of the present invention.
  • the Y-axis shows the Raman intensity and the X-axis the wavenumber (cm "1 ).
  • Figure 5 is a graph showing the infrared spectrum (FTIR-MIKRO-ATR) of the crystalline Br-FA form D (hemihydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 6 is a graph showing the infrared spectrum (0.3% in KBr) of the crystalline Br-FA form D (hemihydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 7 is a graph showing the near infrared spectrum (FT-NIR) of the crystalline Br-FA form D (hemihydrate) of the present invention.
  • the Y-axis shows the absorbance and the X-axis the wavenumber (cm 1 ).
  • Figure 8 is a graph showing the Raman spectrum (FT-NIR-Raman) (neat) of the crystalline Br-FA form D (hemihydrate) of the present invention.
  • the Y-axis shows the Raman intensity and the X-axis the wavenumber (cm 1 ).
  • Figure 9 is a graph showing the infrared spectrum (FTIR-MIKRO-ATR) of the crystalline Br-FA form E (anhydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 10 is a graph showing the near infrared spectrum (FT-NIR) (fiber neat) of the crystalline Br-FA form E (anhydrate) of the present invention.
  • the Y-axis shows the absorbance and the X-axis the wavenumber (cm "1 ).
  • Figure 11 is a graph showing the Raman spectrum (FT-NIR-Raman) (neat) of the crystalline Br-FA form E (anhydrate) of the present invention.
  • the Y-axis shows the Raman intensity and the X-axis the wavenumber (cm 1 ).
  • Figure 12 is a graph showing the infrared spectrum (0.3% in KBr) of the crystalline Br-FA form G (anhydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm "1 ).
  • Figure 13 is a graph showing the near infrared spectrum (FT-NIR) (fiber neat) of the crystalline Br-FA form G (anhydrate) of the present invention.
  • the Y-axis shows the absorbance and the X-axis the wavenumber (cm 1 ).
  • Figure 14 is a graph showing the Raman spectrum (FT-NIR-Raman) (neat) of the crystalline Br-FA form G (anhydrate) of the present invention.
  • the Y-axis shows the Raman intensity and the X-axis the wavenumber (cm 1 ).
  • Figure 15 is a graph showing the infrared spectrum (0.3% in KBr) of the crystalline Br-FA form H (anhydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 16 is a graph showing the near infrared spectrum (FT-NIR) (fiber neat) of the crystalline Br-FA form H (anhydrate) of the present invention.
  • the Y-axis shows the absorbance and the X-axis the wavenumber (cm 1 ).
  • Figure 17 is a graph showing the Raman spectrum (FT-NIR-Raman) (neat) of the crystalline Br-FA form H (anhydrate) of the present invention.
  • the Y-axis shows the Raman intensity and the X-axis the wavenumber (cm 1 ).
  • Figure 18 is a graph showing the infrared spectrum (FTIR-MIKRO-ATR) of the crystalline Br-FA form I (anhydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 19 is a graph showing the near infrared spectrum (FT-NIR) (fiber neat) of the crystalline Br-FA form I (anhydrate) of the present invention.
  • the Y-axis shows the absorbance and the X-axis the wavenumber (cm 1 ).
  • Figure 20 is a graph showing the Raman spectrum (FT-NIR-Raman) (neat) of the crystalline Br-FA form I (anhydrate) of the present invention.
  • the Y-axis shows the Raman intensity and the X-axis the wavenumber (cm "1 ).
  • Figure 21 shows the X-ray powder diffractogram (XRPD) of the crystalline Br-FA form C (hydrate) of the present invention.
  • the Y-axis shows the absolute intensity and the X-axis the angle in degrees 2 ⁇ .
  • Figure 22 shows the X-ray powder diffractogram (XRPD) of the crystalline Br-FA form D (hemihydrate) of the present invention.
  • XRPD X-ray powder diffractogram
  • the Y-axis shows the absolute intensity and the X-axis the angle in degrees 2 ⁇ .
  • Figure 23 shows the X-ray powder diffractogram (XRPD) of the crystalline Br-FA form E (anhydrate) of the present invention.
  • the Y-axis shows the absolute intensity and the X-axis the angle in degrees 2 ⁇ .
  • Figure 24 shows the X-ray powder diffractogram (XRPD) of the crystalline Br-FA form G (anhydrate) of the present invention.
  • the Y-axis shows the absolute intensity and the X-axis the angle in degrees 2 ⁇ .
  • Figure 25 shows the X-ray powder diffractogram (XRPD) of the crystalline Br-FA form H (anhydrate) of the present invention.
  • the Y-axis shows the absolute intensity and the X-axis the angle in degrees 2 ⁇ .
  • Figure 26 shows the X-ray powder diffractogram (XRPD) of the crystalline Br-FA form I (anhydrate) of the present invention.
  • the Y-axis shows the absolute intensity and the X-axis the angle in degrees 2 ⁇ .
  • Figure 27 is a graph showing the infrared spectrum (FTIR-MIKRO-ATR) of the crystalline Br-FA form H (anhydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 28 is a graph showing the infrared spectrum (FTIR-MIKRO-ATR) of the crystalline Br-FA form C (hydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 29 is a graph showing the infrared spectrum (FTIR-MIKRO-ATR) of the crystalline Br-FA form G (anhydrate) of the present invention.
  • the Y-axis shows absorbance units and the X-axis the wavenumber (cm 1 ).
  • Figure 30 shows the solid-state 13 C NMR spectrum of the crystalline Br-FA form H (anhydrate) of the present invention.
  • the Y-axis shows the relative intensity and the X-axis the chemical shift (ppm).
  • Figure 31 shows the solid-state 13 C NMR spectrum of the crystalline Br-FA form C (hydrate) of the present invention.
  • the Y-axis shows the relative intensity and the X- axis the chemical shift (ppm).
  • Figure 32 shows the solid-state 13 C NMR spectrum of the crystalline Br-FA form I
  • the Y-axis shows the relative intensity and the X-axis the chemical shift (ppm).
  • Crystallisation is a well known technique for the purification of chemical compounds and for obtaining a desired crystalline form of chemical compounds.
  • crystallisation of polymorphs is affected by a number of effects and the mechanism of these effects is not known and the quantitative relationship between the operational factors and the crystallisation characteristics of the polymorphs is not clearly understood.
  • the crystallisation process of polymorphous crystals is composed of competitive nucleation, growth, and the transformation from a metastable to a stable form.
  • the mechanism of each elementary step in the crystallisation process needs to be in clear relation to the operational conditions and the key controlling factors [Crystal Growth & Design, 2004, Vol. 4, No.6, 1153- 1159].
  • An embodiment of the invention is crystalline form H of 24-bromofusidic acid (Br- FA), characterised by exhibiting one or more of the following features a)-e) : a) an X-ray powder diffractogram (XRPD) exhibiting an angle of reflection, expressed in degrees 2 ⁇ ( ⁇ 0.1), at approximately 16.5, 11.1 and/or 5.3; b) an attenuated total reflectance Fourier transform infrared (FTIR-ATR) spectrum exhibiting attenuated total reflectance peaks at approximately 3520 and/or 1183 cm “ 1 ( ⁇ 3 cm “1 ); c) a near infrared (FT-NIR) spectrum exhibiting absorbance peaks at approximately 5820 cm "1 ( ⁇ 8 cm “1 ); d) a Fourier transform (FT-NIR) Raman spectrum exhibiting intensity peaks at approximately 1654 and/or 1454 cm “1 ( ⁇ 4 cm “1 ) or e) a 13 C CP/MAS solid-state NMR spectrum exhibiting one or more of
  • Another embodiment of the invention is crystalline form H of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-k) :
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting the following intensity peaks at approximately 1720, 1676, 1654, 1454 and/or 591 cm “1 ( ⁇ 4 cm “1 ), respectively
  • FT-NIR Fourier transform Raman spectrum substantially similar to that shown in Figure 17
  • FTIR-ATR an attenuated total reflectance Fourier transform infrared
  • FTIR-ATR an attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form H of 24-bromofusidic acid (Br-FA), further characterised by exhibiting one or more of the following features a)- k):
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting one or more of the following intensity peaks at approximately 2927 , 1720, 1676, 1654, 1454, 1338, 756, 688, 591, 535, 349 and/or 192 cm “1 ( ⁇ 4 cm '1 ), respectively
  • FT-NIR Fourier transform
  • FT-ATR attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form C of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-e):
  • XRPD X-ray powder diffractogram
  • FTIR-ATR attenuated total reflectance Fourier transform infrared
  • FT-NIR near infrared
  • Raman spectrum exhibiting intensity peaks at approximately 1713 cm "1 ( ⁇ 4 cm “1 ); or e) a 13 C CP/MAS solid-state NMR spectrum exhibiting one or more of the following resonances at approximately 155.8 ppm ( ⁇ 0.5 ppm), respectively.
  • Another embodiment of the invention is crystalline form C of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-j):
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting the following intensity peaks at approximately 1713, 1286, 1151, 1067, 1002 and/or 797 cm “1 ( ⁇ 4 cm “1 ), respectively
  • FT-NIR Fourier transform
  • FT-ATR attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form C of 24-bromofusidic acid (Br-FA), further characterised by exhibiting one or more of the following features a)- j):
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting one or more of the following intensity peaks at approximately 2940, 1713, 1660, 1459, 1380, 1338, 1286, 1151, 1067, 1002, 797, 697, 537 and/or 188 cm " ( ⁇ 4 cm 1 ), respectively
  • FT-NIR Fourier transform
  • FT-ATR attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form I of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-e) :
  • XRPD X-ray powder diffractogram
  • FTIR-ATR attenuated total reflectance Fourier transform infrared
  • FT-NIR near infrared
  • Raman spectrum exhibiting intensity peaks at approximately 1694 cm " '( ⁇ 4 cm “1 ); or e) a 13 C CP/MAS solid-state NMR spectrum exhibiting one or more of the following resonances at approximately 147.6 ppm ( ⁇ 0.5 ppm), respectively.
  • Another embodiment of the invention is crystalline form I of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-j):
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting the following intensity peaks at approximately 3015, 2943, 2910, 1694, 1329 and/or 990 cm “1 ( ⁇ 4 cm “1 ), respectively
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum substantially similar to that shown in Figure 20
  • FTIR-ATR an attenuated total reflectance Fourier transform infrared
  • FTIR-ATR attenuated total reflectance Fourier transform infrared
  • FTIR-ATR attenuated total reflectance Fourier transform infrared
  • FTIR-ATR an attenuated total reflectance Fourier transform infrared (FTIR-ATR) spectrum spectrum substantially similar to that shown in Figure 18
  • FT-NIR near infrared
  • Another embodiment of the invention is crystalline form I of 24-bromofusidic acid (Br-FA), further characterised by exhibiting one or more of the following features a)- j):
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting one or more of the following intensity peaks at approximately 3015, 2943, 2910, 1694, 1459, 1329, 990, 757, 697, 687, 535, 190 and/or 105 cm '1 ( ⁇ 4 cm “1 ), respectively
  • FT-NIR Fourier transform
  • FT-ATR attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form E of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-d):
  • FTIR-ATR attenuated total reflectance Fourier transform infrared
  • FT-NIR near infrared
  • FT-NIR Fourier transform
  • Another embodiment of the invention is crystalline form E of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-h):
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform
  • Figure 11 a Fourier transform
  • FT-NIR Fourier transform
  • Figure 11 an attenuated total reflectance Fourier transform infrared (FTIR-ATR) spectrum exhibiting the following attenuated total reflectance peaks at approximately 3649, 3608, 3558 and/or 1443 cm “1 ( ⁇ 3 cm “1 ), respectively
  • FTIR-ATR an attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form E of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-h), respectively:
  • FT-NIR Fourier transform
  • Another embodiment of the invention is crystalline form G of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-d) :
  • XRPD X-ray powder diffractogram
  • FTIR-ATR attenuated total reflectance Fourier transform infrared
  • FT-NIR near infrared
  • Raman spectrum exhibiting intensity peaks at approximately 186 cm “1 ( ⁇ 4 cm “1 ), respectively.
  • Another embodiment of the invention is crystalline form G of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-h) :
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting the following intensity peaks at approximately 1723, 1704, 1460, 944, 928, 754 and/or 186 cm “1 ( ⁇ 4 cm “ x ), respectively
  • FT-NIR Fourier transform
  • FT-ATR attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form G of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-h), respectively:
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting one or more of the following intensity peaks at approximately 2980, 2938, 1723, 1704, 1660, 1460, 1442, 1337, 944, 928, 754, 698, 687, 641, 546, 537, 337 and/or 186 cm '1 ] ( ⁇ 4 cm " 1 J, respectively;
  • FT-NIR Fourier transform
  • FT-ATR an attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form D of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-d) :
  • XRPD X-ray powder diffractogram
  • FTIR-ATR attenuated total reflectance Fourier transform infrared
  • FT-NIR near infrared
  • Raman spectrum exhibiting intensity peaks at approximately 1741 and/or 203 cm “1 ( ⁇ 4 cm “1 ), respectively.
  • Another embodiment of the invention is crystalline form D of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-h):
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum exhibiting the following intensity peaks at approximately 1741, 879, 702, 689, 625, 251 and/or 203 cm “1 ( ⁇ 4 cm “1 ), respectively
  • FT-NIR Fourier transform
  • FT-NIR Fourier transform Raman spectrum substantially similar to that shown in Figure 8
  • FTIR-ATR an attenuated total reflectance Fourier transform infrared
  • Another embodiment of the invention is crystalline form D of 24-bromofusidic acid (Br-FA), characterised by exhibiting one or more of the following features a)-h), respectively: a) a Fourier transform (FT-NIR) Raman spectrum exhibiting one or more of the following intensity peaks at approximately 2937, 1741, 1659, 1460, 1441, 994, 879, 755, 702, 689, 625, 534, 251 and/or 203 cm “1 ( ⁇ 4 cm “1 ), respectively; b) a Fourier transform (FT-NIR) Raman spectrum substantially similar to that shown in Figure 8; c) an attenuated total reflectance Fourier transform infrared (FTIR-ATR) spectrum exhibiting one or more of the following attenuated total reflectance peaks at approximately 3436, 1745, 1687, 1443, 1379, 1230, 1188, 1052, 1031, 974, 950, 934, 917 and/or 755 cm “1 ( ⁇ 3 cm “1 ), respectively
  • An embodiment of the invention is a mixture or composition of crystalline forms of 24-bromofusidic acid (Br-FA), including pseudopolymorphs of 24-bromofusidic acid, comprising crystalline form H, form C, form I, form E, Form G and/or form D of 24- bromofusidic acid (Br-FA) according to the invention.
  • Br-FA 24-bromofusidic acid
  • the mixture of crystalline forms of 24- bromofusidic acid essentially consists of form H, form C, form I, form E, Form G, or form D of 24-bromofusidic acid (Br-FA) anhydrate.
  • the mixture of crystalline forms of 24- bromofusidic acid consists of 90-99.9 (mol) % of form H, form C, form I, form E, Form G, or form D of 24-bromofusidic acid (Br-FA) anhydrate.
  • An embodiment of the invention is a method for the preparation of crystalline form H of 24-bromofusidic acid (Br-FA), said method comprising:
  • step a) suspending or dissolving optionally with heating 24-bromofusidic acid (Br-FA) in a suitable solvent or mixture of solvents; b) optionally cooling and/or concentrating the solution/suspension in step a) allowing crystallisation of form H of 24-bromofusidic acid (Br-FA) according to the invention; and c) isolating the crystalline Br-FA form H anhydrate.
  • said solvent is selected from the group consisting of a ketone, a Ci-C 4 alkyl ester of formic acid, an ether, a nitrile, water and mixtures thereof.
  • said solvent is selected from the group consisting of ethyl formate, acetonitrile, water, tert-butyl methyl ether, diisopropyl ether, acetone and mixtures thereof.
  • said solvent is ethyl formate.
  • said solvent is acetonitrile.
  • said solvent is acetone
  • said solvent is a mixture of acetone and water.
  • said solvent is tert-butyl methyl ether.
  • said solvent is diisopropyl ether.
  • An embodiment of the invention is a method for the preparation of crystalline form C of 24-bromofusidic acid (Br-FA), said method comprising:
  • step a) suspending or dissolving optionally with heating 24-bromofusidic acid (Br-FA) in a suitable solvent or mixture of solvents; b) optionally cooling and/or concentrating the solution/suspension in step a) allowing crystallisation of form C of 24-bromofusidic acid (Br-FA) according to the invention; and c) isolating the crystalline Br-FA form C.
  • said solvent is selected from the group consisting of Ci-C 4 alkyl esters of C 2 -C 3 carboxylic acids, water and mixtures thereof.
  • said solvent is selected from the group consisting of ethyl acetate, water and mixtures thereof.
  • said solvent is water.
  • said solvent is a mixture of ethyl acetate and water.
  • An embodiment of the invention is a method for the preparation of crystalline form E, form G or mixtures thereof of 24-bromofusidic acid (Br-FA), said method comprising :
  • step a) suspending or dissolving optionally with heating 24-bromofusidic acid (Br-FA) in a suitable solvent or mixture of solvents; b) optionally cooling and/or concentrating the solution/suspension in step a) allowing crystallisation of form E, form G or mixtures thereof of 24-bromofusidic acid (Br-FA) according to the invention, and c) isolating the crystalline Br-FA form E, form G or mixtures thereof.
  • said solvent is selected from the group consisting of an alcohol, water and mixtures thereof.
  • said solvent is selected from the group consisting of methanol, ethanol, water and mixtures thereof.
  • said solvent is methanol.
  • said solvent is a mixture of methanol and water. In an embodiment of the invention said solvent is a mixture of ethanol and water.
  • said solvent is a mixture of propan-2-ol and water.
  • An embodiment of the invention is a method for the preparation of crystalline form I of 24-bromofusidic acid (Br-FA), said method comprising:
  • step a) suspending or dissolving optionally with heating 24-bromofusidic acid (Br-FA) in a suitable solvent or mixture of solvents; b) optionally cooling and/or concentrating the solution/suspension in step a) allowing crystallisation of form I of 24-bromofusidic acid (Br-FA) according to the invention; and c) isolating the crystalline Br-FA form I.
  • said solvent is selected from the group consisting of aliphatic hydrocarbons and mixtures thereof.
  • said solvent is hexane
  • An embodiment of the invention is a method for the preparation of crystalline form D of 24-bromofusidic acid (Br-FA), said method comprising:
  • step a) suspending or dissolving optionally with heating 24-bromofusidic acid (Br-FA) in a suitable solvent or mixture of solvents; b) optionally cooling and/or concentrating the solution/suspension in step a) allowing crystallisation of form D of 24-bromofusidic acid (Br-FA) according to the invention; and c) isolating the crystalline Br-FA form D.
  • said solvent is selected from the group consisting of aromatic hydrocarbons, water and mixtures thereof. In an embodiment of the invention said solvent is selected from the group consisting of toluene, water and mixtures thereof.
  • said solvent is a mixture of toluene and water.
  • the crystalline Br-FA forms of the present invention may be useful for treating, preventing or ameliorating infections in a patient, including a mammalian, and in particular, a human patient.
  • Animals that may be treated with a compound of the invention include, more specifically, domestic animals such as horses, cows, pigs, sheep, poultry, fish, cats, dogs and zoo animals.
  • the crystalline Br-FA forms of the present invention may be particularly useful in the treatment of bacterial infections, such as skin infections or secondary skin infections, or eye infections.
  • the crystalline Br-FA forms of the present invention may be furthermore useful in the treatment of simple abscesses, impetiginous lesions, furuncles, or cellulites.
  • the crystalline Br-FA forms of the present invention may be particularly useful for the treatment, e.g. the topical treatment, of contagious superficial infections of the skin, such as non-bullous impetigo (or impetigo contagiosa) or bullous impetigo.
  • the present invention provides a method of treating, preventing or ameliorating bacterial infections, the method comprising administering to a patient an effective amount of the crystalline Br-FA forms, optionally together with another therapeutically active compound.
  • antibiotics such as ⁇ -lactams, such as penicillins (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, flucloxacillin, piperacillin and mecellinam), cefalosporins (cefalexin, cefalotin, cefepim, cefotaxim, ceftazidim, ceftriazon and cefuroxim), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclins (tetracycline, doxycyclin, oxytetracyclin and lymecyclin); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinol, such as penicillins (phenoxy
  • a compound of the invention especially for topical treatment
  • corticosteroids such as hydrocortisone, betamethasone- 17-valerate and triamcinolone acetonid.
  • the crystalline Br-FA forms and the other compounds may either be administered concomitantly or sequentially.
  • the crystalline Br-FA forms of the present invention are further useful for the prevention or prophylaxis of bacterial infections in animals and are therefore useful during the breeding of domestic animals, such as mammals, such as horses, cows, pigs, sheep, poultry, fish, cats, dogs and zoo animals.
  • the crystalline Br-FA forms of the present invention are typically in the form of a pharmaceutical composition.
  • the invention therefore relates to a pharmaceutical composition comprising crystalline Br-FA described herein, optionally together with other therapeutically active compounds, together with a pharmaceutically acceptable excipient or vehicle.
  • the excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the active ingredient comprises from 0.05-99.9% by weight of the formulation.
  • the formulations include e.g.
  • formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, e.g. as disclosed in Remington, The Science and Practice of Pharmacy, 20 th ed., 2000. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients.
  • formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • oils may be edible oils, such as e.g. cottonseed oil, sesame oil, coconut oil or peanut oil.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers and polyvinylpyrrolidone.
  • the active ingredients may also be administered in the form of a bolus, electuary or paste.
  • a tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed by a binder, such as e.g. lactose, glucose, starch, gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes or the like; a lubricant such as e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as e.g.
  • a binder such as e.g. lactose, glucose, starch, gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes or the like
  • Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.
  • Formulations for rectal administration may be in the form of suppositories in which the compound of the present invention is admixed with low melting water soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oils, polyethylene glycol or fatty acids esters of polyethylene glycols, while elixirs may be prepared using myristyl palmitate.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution.
  • the formulation may be conveniently sterilised by for instance filtration through a bacteria retaining filter, addition of sterilising agent to the formulation, irradiation of the formulation or heating of the formulation.
  • Liposomal formulations as disclosed in e.g. Encyclopedia of Pharmaceutical Technology, vol.9, 1994, are also suitable for parenteral administration.
  • the crystalline 24-bromofusidic acid may be presented as a sterile, solid preparation, e.g.
  • Transdermal formulations may be in the form of a plaster or a patch.
  • Formulations suitable ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredients, which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension.
  • Liposomal formulations or biodegradable polymer systems e.g. as disclosed in Encyclopedia of Pharmaceutical Technology, vol.2, 1989, may also be used to present the active ingredient for ophthalmic administration.
  • Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
  • Formulations suitable for nasal or buccal administration include powder, self- propelling and spray formulations, such as aerosols and atomisers. Such formulations are disclosed in greater detail in e.g. Modern Pharmaceutics. 2 nd ed., G. S. Banker and CT. Rhodes (Eds.), page 427-432, Marcel Dekker, New York; Modern Pharmaceutics. 3 th ed., G. S. Banker and CT.
  • the formulations of a compound of crystalline 24-bromofusidic acid may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • parenteral formulations are in particular useful in the treatment of conditions in which a quick response to the treatment is desirable.
  • the tablets or capsules may be the appropriate form of pharmaceutical preparation owing to the prolonged effect obtained when the drug is given orally, in particular in the form of sustained-release tablets.
  • the composition may contain other therapeutically active components, which can appropriately be administered together with the compounds of the invention in the treatment of infectious diseases, such as other suitable antibiotics, in particular such antibiotics which may enhance the activity and/or prevent development of resistance.
  • antibiotics such as other suitable antibiotics, in particular such antibiotics which may enhance the activity and/or prevent development of resistance.
  • Corticosteroids may also beneficially be included in the compositions of the present invention.
  • said other active component may include ⁇ -lactams, such as penicillins (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, flucloxacillin, piperacillin and mecellinam), cefalosporins (cefalexin, cefalotin, cefepim, cefotaxim, ceftazidim, «ceftriazon and cefuroxim), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclins (tetracycline, doxycyclin, oxytetracyclin and lymecyclin); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (n-l
  • the other therapeutically active compound may be in the same or separate containers adapted for concomitant or sequential administration of said therapeutically active compounds.
  • the treatment of infectious diseases often involves determining whether said disease is resistant or refractory to the treatment, before the treatment is, in fact, initiated.
  • samples containing the infectious microbe may be taken from the patient, e.g. blood or urine, after which the sample is cultured and exposed to the treatment to determine whether said infectious organism responds to the treatment.
  • the present invention also provides a method for identifying compounds effective against a micro organism, the method comprising administering crystalline Br-FA of the present invention as described above, optionally together with other therapeutically active agents, to a micro organism, and determining whether said compound or mixture of compounds has a toxic or static effect on the micro organism in question.
  • compositions of the present invention are not limited to pharmaceuticals, but may also be used in a non-therapeutic context to control microbial growth.
  • compositions or compounds of the present invention be useful as additives which inhibit microbial growth, such as during fermentation processes.
  • the selectivity of antimicrobial agents renders them useful to enhance growth of particular micro organisms at the expense of others in a multi- species culture.
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline Br-FA form of the present invention as described above together with a pharmaceutically acceptable excipient or vehicle further comprising another therapeutically active compound is selected from the group consisting of antibiotics and corticosteroids.
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Br-FA of the present invention as described above together with a pharmaceutically acceptable excipient or vehicle further comprising another therapeutically active compound selected from the group consisting of penicillins (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, flucloxacillin, piperacillin and mecellinam), cefalosporins (cefalexin, cefalotin, cefepim, cefotaxim, ceftazidim, ceftriazon and cefuroxim), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclins (tetracycline, doxycyclin, oxytetracyclin and lymecyclin);
  • this invention relates to a method of treating, preventing or ameliorating infections in a patient, the method comprising administering to said patient an effective amount of crystalline Br-FA of the present invention as described above, and optionally further comprising concomitant or sequential administration of one or more other therapeutically active compounds, wherein said other therapeutically active compound is selected from the group consisting of antibiotics and corticosteroids.
  • this invention relates to a method of treating, preventing or ameliorating infections in a patient, such as a bacterial infection the method comprising administering to said patient an effective amount of crystalline Br-FA of the present invention as described above, and optionally further comprising concomitant or sequential administration of one or more other therapeutically active compounds, wherein said other therapeutically active compound is selected from the group consisting of penicillins (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, flucloxacillin, piperacillin and mecellinam), cefalosporins (cefalexin, cefalotin, cefepim, cefotaxim, ceftazidim, ceftriazon and cefuroxim), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin);
  • this invention relates to the use of crystalline Br- FA of the present invention as described above for the manufacture of a medicament for the treatment, amelioration or prophylaxis of infections, such as a bacterial infection, wherein said medicament further comprises another therapeutically active compound in the same or separate containers adapted for concomitant or sequential administration of said therapeutically active compounds.
  • this invention relates to the use of crystalline Br- FA of the present invention as described above for the manufacture of a medicament for the treatment, amelioration or prophylaxis of infections, such as a bacterial infection, wherein said medicament further comprises another therapeutically active compound in the same or separate containers adapted for concomitant or sequential administration of said therapeutically active compounds, wherein said other therapeutically active compound is selected from the group consisting of penicillins (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, flucloxacillin, piperacillin and mecellinam), cefalosporins (cefalexin, cefalotin, cefepim, cefotaxim, ceftazidim, ceftriazon and cefuroxim), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and
  • polymorphic purity includes the purity relative to other polymorphic and pseudopolymorphic crystal forms.
  • Non- limiting examples thereof include acetone, methyl ethyl ketone etc.
  • CrC 4 alkyl esters of C 2 -C 3 carboxylic acids relates to esters formed from C 1 -C 4 alcohols and C 2 -C 3 carboxylic acids.
  • the term includes, but is not limited to, methyl acetate, ethyl acetate, propyl acetate, butyl acetate etc.
  • ether relates to compounds of the general formula ROR ' .
  • Non-limiting examples thereof include dimethyl ether, diethyl ether, tert-butyl methyl ether, diisopropyl ether etc.
  • nitrile relates to compounds of the general formula RCN. Non-limiting examples thereof include acetonitrile, propionitrile etc.
  • alcohol relates to compounds of the general formula ROH.
  • Non-limiting examples thereof include methanol, ethanol, n-propanol (propan-1-ol), isopropanol (propan-2-ol), butanol etc.
  • aliphatic hydrocarbon refers to compounds of the formula C x H y .
  • Non- limiting examples thereof include pentane, hexane, heptane etc.
  • aromatic hydrocarbon refers to compounds having at least one aromatic ring. Non-limiting examples thereof include benzene, toluene, xylene (ortho, meta, para) etc.
  • ethanol in the context of the present invention includes but is not limited to all commercially available grades of ethanol, such as anhydrous ethanol or ethanol from obtained from azeotropic distillation containing water, typically containing 4-5% water, commonly named alcohol.
  • polymorph encompasses all solid forms, e.g. amorphous solids or solid crystal forms, including solvates with stoichiometric or non-stoichiometric amounts of solvent and hydrates with stoichiometric or non stoichiometric amounts of water.
  • hexane includes but is not limited to all commercially available grades of hexane such as pure hexane isomers, e.g. n-hexane, or mixtures of hexane isomers, optionally in mixture with other aliphatic hydrocarbons.
  • crystalline forms encompasses crystalline polymorphs in all degrees of crystallinity.
  • crystalline types encompasses crystalline polymorphs in all degrees of crystallinity.
  • crystalline forms encompasses crystalline polymorphs in all degrees of crystallinity. The term is used interchangeably in this context with the term “crystalline forms”.
  • X-ray powder diffraction The diffractogram was obtained in the range 3-30 degrees 2 ⁇ on a STADI-P instrument from STOE&CIE GmbH.
  • XRPD X-ray powder diffraction
  • the 13 C solid-state NMR spectrum was acquired on a Varian Unity-INOVA NMR spectrometer with a magnetic field strength of 7.04 T.
  • a 5 mm homebuilt CP/MAS TLT probe using a spinning frequency of 5.0 kHz was used.
  • the spectrum was acquired with a standard cross-polarization pulse sequence and referenced to an external of TMS.
  • FTIR-ATR spectroscopy attenuated total reflectance fourier transform infrared spectroscopy: The spectrum was recorded on a FTIR instrument, Equinox 55 or Tensor 27 from Bruker equipped with a GoldenGate ATR unit from SPECAC. A spectral resolution of 3 cm "1 was used.
  • Raman spectroscopy The spectrum was recorded on a FT-NIR-Raman instrument, RFS 100/S from Bruker. A spectral resolution of 4 cm "1 was used.
  • FT-NIR reflection spectroscopy (diffuse reflection mode): The spectrum was recorded using a fiber optic probe coupled to a FTIR instrument, Equinox 55 from Bruker. Measurements were conducted either directly on the sample or through a glass container. A spectral resolution of 8 cm "1 was used.
  • IR spectroscopy (KBr disc): The spectra were recorded on a FTIR instrument, Equinox 55 from Bruker. A spectral resolution of 3 cm "1 was used.
  • the given error ranges in this application for the X-ray diffractographic and spectroscopic characteristics may be more or less depending on factors well known to a person skilled in the art of spectroscopy and diffractography and may for example depend on sample preparation, such as particle size distribution, or if the crystal form is part of a formulation, on the composition of the formulation, as well as instrumental fluctuations, and other factors.
  • An error range of ⁇ 5 includes, but is not limited to variations of ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, ⁇ 1, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, and ⁇ 0.1;
  • an error range of ⁇ 3 includes, but is not limited to variations of ⁇ 3, ⁇ 2, ⁇ 1, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, and ⁇ 0.1;
  • an error range of ⁇ 1 includes, but is not limited to variations of ⁇ 0.9, ⁇ 0.8, ⁇ 0.7, ⁇ 0.6, ⁇ 0.5, ⁇ 0.4, ⁇ 0.3, ⁇ 0.2, and ⁇ 0.1;
  • an error range of ⁇ 0.2 includes, but is not limited to variations of ⁇ 0.2, ⁇ 0.15, ⁇ 0.1, ⁇ 0.09, ⁇ 0.08, ⁇ 0.07, ⁇ 0.06, ⁇ 0.05, ⁇ 0.04, ⁇ 0.03, ⁇ 0.02, and ⁇ 0.01.
  • the present invention includes embodiments, where one or more steps in a procedure are omitted, one or more additional steps are added, and/or where the order of steps is modified or reversed. All examples described herein shall be considered to be non-limiting.
  • Example 1 Br-FA form E (anhydrate) and/or G (anhydrate) : 10 g Br-FA, e.g. form H (anhydrate) or crude Br-FA, is suspended in a mixture of ethanol (80 ml_) and purified water (20 ml_). The resulting suspension is heated to 50 0 C and stirred for 1 h. The resulting solution is cooled on an ice bath to 0-10 0 C, filtered and dried using vacuum to yield Br-FA form E (anhydrate) and/or G (anhydrate).
  • Br-FA form E anhydrate
  • G anhydrate
  • Br-FA form E (anhydrate) and/or G (anhydrate) 10 g Br-FA, e.g. form H (anhydrate) or crude Br-FA, is suspended in a mixture of methanol (80 ml_) and purified water (20 ml_). The resulting suspension is heated to 50 0 C and stirred for 1 h. The resulting solution is cooled on an ice bath to 0-10 0 C, filtered and dried using vacuum to yield Br-FA form E (anhydrate) and/or G (anhydrate).
  • methanol 80 ml_
  • purified water 20 ml_
  • Br-FA form H (anhydrate) : 10 g mixture of Br-FA forms E (anhydrate) and G (anhydrate) was suspended in ethyl formate (50 ml_). The resulting suspension is heated to reflux temperature and stirred for 3-4 h. The suspension is cooled on an ice bath to 0-10 0 C, filtered and dried using vacuum to give Br-FA form H (anhydrate).
  • Br-FA form H (anhydrate): 0.3 g Br-FA as a mixture of Br-FA forms E (anhydrate) and G (anhydrate) was suspended in acetonitrile (6 ml_). The suspension is heated until a clear solution was obtained. The Br-FA form H (anhydrate) crystallised by cooling to 0-10 0 C and was collected by filtration and dried using vacuum.
  • Br-FA form C (hydrate) 1.0 g Br-FA, such as anhydrous Br-FA, was suspended in a mixture of ethyl acetate (10 mL) and purified water (1.0 ml_). The suspension was heated until a clear solution was obtained. The Br-FA form C (hydrate) was crystallised by cooling to 0-10 0 C, collection by filtration and drying using vacuum.
  • Example 6 1.0 g Br-FA, such as anhydrous Br-FA, was suspended in a mixture of ethyl acetate (10 mL) and purified water (1.0 ml_). The suspension was heated until a clear solution was obtained. The Br-FA form C (hydrate) was crystallised by cooling to 0-10 0 C, collection by filtration and drying using vacuum.
  • Example 6 1.0 g Br-FA, such as anhydrous Br-FA, was suspended in a mixture of ethyl acetate (10 mL) and purified water (1.0 ml_). The suspension was heated until
  • Br-FA form D (hemihydrate): Br-FA (0.3 g) was added to toluene (20 mL) saturated with water. The resulting suspension was heated until a clear solution is obtained. The Br-FA form D (hemihydrate) was crystallised by cooling to 0-10 0 C, optionally stirring for 1-2 day(s), collected by filtration and dried using vacuum.
  • Br-FA form I (anhydrate): 1 g Br-FA was suspended in hexane (10 mL). The resulting suspension was heated to reflux temperature and stirred for 3-4 h. The suspension was cooled on an ice bath to 0-10 0 C, filtrated and dried using vacuum to yield Br-FA form I (anhydrate).
  • Example 8 Br-FA form H (anhydrate): The same procedure was used as in example 3, except that the starting Br-FA was from example 45 of WO 2005/007669.
  • Br-FA form H (anhydrate) : The same procedure was used as in example 4, except that the starting Br-FA was from example 45 of WO 2005/007669.
  • Br-FA form H (anhydrate): 0.2985 g Br-FA was suspended in 6 ml acetonitrile and heated to 70 0 C for 3 hours. The suspension was filtered through a 0.2 ⁇ m poly(tetrafluoroethylene) (PTFE) filter and the filtrate was stored at 6°C for 1 day. The precipitate was isolated by centrifugal filtration as a slightly humid sample to yield Br-FA form H (anhydrate).
  • PTFE poly(tetrafluoroethylene)
  • Example 11 Br-FA form H (anhydrate): 0.1039 g Br-FA was suspended in 0.2 ml acetone at room temperature for 7 days. An aliquot of the solid was isolated as Br-FA form H (anhydrate).
  • Example 12
  • Br-FA form H (anhydrate): 0.0970 g Br-FA was suspended in 0.2 ml acetonitrile at room temperature for 7 days. An aliquot of the solid was isolated as Br-FA form H (anhydrate).
  • Br-FA form H (anhydrate): 0.1049 g Br-FA was suspended in 0.2 ml tert-butyl methyl ether at room temperature for 7 days. An aliquot of the solid was isolated as Br-FA form H (anhydrate).
  • Br-FA form H (anhydrate): 0.1063 g Br-FA was suspended in 0.2 ml diiso- propylether at room temperature for 7 days. An aliquot of the solid was isolated as Br-FA form H (anhydrate).
  • Br-FA form H (anhydrate): 0.0718 mg Br-FA was suspended for 5 days in 0.6 ml of acetone/H 2 O (1/1) at 25°C. After further 11 days an aliquot was isolated and dried for 1 hour under rotary oil pump vacuum to yield Br-FA form H (anhydrate).
  • Br-FA form C (hydrate) 0.9969 g Br-FA was suspended in 10 ml ethyl acetate/H 2 O (20/1) and heated to 70 0 C for 2 hours. The solution was put in the fridge. No solid had formed after 15 days of storage. The solution was brought to room temperature and evaporated under a slight N 2 flow. White crystals were obtained as a residue (slightly humid) to yield Br-FA form C (hydrate).
  • Br-FA form C (hydrate) 0.0374 g from Example 16 was stored open at 85% relative humidity and room temperature for 33 days and isolated as Br-FA form C (hydrate).
  • Br-FA form C (hydrate) 0.1107 g Br-FA was suspended for 7 days in 0.2 ml ethyl acetate (saturated with H 2 O) at 25°C. A sample was isolated and dried for 15 minutes under rotary pump vacuum. The remaining solid was dried for 5 days under rotary oil pump vacuum to yield Br-FA form C (hydrate).
  • Br-FA form C (hydrate) 0.1211 g Br-FA was suspended for 7 days in 0.2 ml ethyl acetate/H 2 O (9/1) at 5°C. A sample was isolated as a humid and dried for 15 minutes under a rotary pump vacuum to yield Br-FA form C (hydrate).
  • Example 22 Br-FA form C (hydrate) 0.4 g Br-FA was suspended in 10 ml ethyl acetate/H 2 O (9/1) and stirred for 1 hour at 70 0 C and the solution was brought to room temperature. After 10 minutes a slight turbidity was visible and the sample was stored at 6°C for 15 days. The solid was isolated and dried for 5 minutes under a rotary oil pump vacuum to yield Br-FA form C (hydrate).
  • Br-FA as a mixture of forms E and G (anhydrates): 1.0 g Br-FA was dissolved in 10 ml methanol and filtered through a 0.22 ⁇ m filter. The solution was frozen with liquid nitrogen and the sample was lyophilized (0.0070 mbar, -82°C, 18 hours) to yield a mixture of Br-FA forms E and G (anhydrates).
  • Br-FA as a mixture of forms E and G (anhydrates) 0.0110 g from Example 24 was stored open as a powder at 80 0 C for 1 day to yield a mixture of Br-FA forms E and G (anhydrates).
  • Br-FA as a mixture of forms E and G (anhydrates) 0.0204 g from Example 23 was stored open at 85% relative humidity and room temperature for 33 days to yield a mixture of Br-FA forms E and G (anhydrates).
  • Example 28 Br-FA form D (hemihydrate): 0.0992 g from Example 24 was dissolved in 7 ml toluene (saturated with H 2 O) at 80 0 C (10 minutes) and stored for 15 days at 6°C. An aliquot was isolated to yield Br-FA form D (hemihydrate).
  • Br-FA form H (anhydrate): The same procedure was used as in example 4, except that the starting Br-FA was Br-FA form C such as that obtainable from any of the examples 5 or 16-22. ⁇ _
  • Br-FA form H (anhydrate): 10 g Br-FA were suspended in 100 ml acetone and 5 ml purified water and stirred to obtain a clear solution. The suspension was filtered and the filtrate was heated to 50 0 C. To the solution was added 150 ml purified water.
  • Example 32 Br-FA as a mixture of forms E and G (anhydrates) 10 g Br-FA were suspended in 100 ml isopropanol and 5 ml purified water and stirred to obtain a clear solution. The suspension was filtered and the filtrate was heated to 50 0 C. To the solution was added 150 ml purified water. Crystallisation took place, and the crystal suspension was kept at a constant temperature at 50 0 C. After 1 hour an aliquot of the crystal suspension was filtered to yield a mixture of Br-FA forms E and G (anhydrates).
  • Br-FA as a mixture of forms E and G (anhydrates) : 10 g Br-FA were suspended in 100 ml methanol and 5 ml purified water and stirred to obtain a clear solution. The suspension was filtered. To the solution was added 150 ml purified water. Crystallisation took place
  • HCI q.s. Water, purified up to Ig Part of the aqueous phase was heated to about 70 0 C and mixed with the melted oil phase (glyceryl myristate and glyceryl laurate) with homogenization. Part of the aqueous phase was mixed with citric acid monohydrate, sodium citrate, glycerol 85% and diazolidinyl urea and added to the cream blend with homogenization. The cream blend was cooled to room temperature with stirring. The 24-bromo-fusidic acid, hydrate C was added to the cream vehicle by means of a mortar and pestle. A stable cream formulation was obtained.
  • Citric acid monohydrate 0.9 mg HCI q.s.
  • a formulation containing 24-bromo-fusidic acid, anhydrate H was prepared analogously to the procedure disclosed in Example 34. A stable cream formulation was obtained.
  • Glyceryl laurate 70 mg Glycerol 85% 60 mg Diazolidinyl urea 5 mg
  • a formulation containing 24-bromo-fusidic acid, anhydrate I was prepared analogously to the procedure disclosed in Example 34. A stable cream formulation was obtained.

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Abstract

La présente invention concerne des formes cristallines de l’acide 24-bromofusidique, leur préparation , des compositions pharmaceutiques les contenant, et l’utilisation desdites formes de l’acide 24-bromofusidique en tant que médicaments dans le traitement de maladies infectieuses.
PCT/DK2009/000039 2008-02-14 2009-02-13 Formes cristallines d’une substance antibiotique Ceased WO2009100723A2 (fr)

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