DESC:TECHNICAL FIELD:
Disclosed herein are novel pharmaceutical compounds comprising abiraterone acetate and organic acids, a process for the preparation thereof and use thereof for the preparation of a pharmaceutical composition.

BACKGROUND:
Abiraterone acetate, chemically termed as (3ß)-17-(3-pyridinyl)androsta-5, 16-dien-3-yl acetate specifically shown in formula (I),

is the prodrug of abiraterone of the formula (II)

It was first reported in WO9320097A and its synthesis method.
Abiraterone acetate (ZYTIGA) is transferred to abiraterone in vivo, which is an oral cytochrome P450 (CYP450) oxidase c17 inhibitor and inhibits biosynthesis of androgen by inhibiting CYP450 c17 enzyme which is a key enzyme to hormone synthesis in testis and other part of a body. It selectively inhibits the enzyme 17a-hydroxylase/C17, 20-lyase (CYP17), which catalyses the conversion of pregnenolone and progesterone to the precursors of testosterone, DHEA, or androstenedione by 17 a-hydroxylation and cleaving of the C17,20 bond. Abiraterone acetate is used together with prednisone or prednisolone for treatment of metastatic castration resistant prostate cancer in adult men.

Preparation of salts of abiraterone acetate and tartaric acid, acetic acid, malic acid, methanesulfonic acid, ditoluoyl tartaric acid, hydrochloric acid and sulphuric acids is described in the US 7700766 B2 patent. Further disclosed is a method for the preparation of abiraterone acetate or its pharmaceutically acceptable salt, comprising isolation of the abiraterone acetate salt, e.g. methanesulfonate salt, from methyl tert-butyl ether thereby removing most of the impurities including dehydroepiandrosterone acetate.

A method of purification of abiraterone acetate using the trifluoromethanesulfonate salt of
abiraterone acetate is further described in the patent document CN102030798 A.

US 9,522,934 B2 discloses abiraterone acetate trifluoroacetate, a preparation method and an application of same.

US 1000458998 B2 discloses molecular crystal comprises abiraterone acetate and an organic acid selected from the group consisting of citric acid. ascorbic acid, methyl-4-hydroxy benzoate. Saccharin and, vanillic acid, adipic acid, maleic acid, malic acid and tartaric acid.

It has now been found that the aqueous solubility of abiraterone acetate, especially the solubility in a gastric or intestinal environment may be distinctly enhanced by combining this prodrug with certain organic acids.

It has further been found that certain salts and certain co-crystals, of abiraterone acetate show advantageous properties for use as medical application forms of abiraterone acetate. Preferred ones among these solid forms are those comprising abiraterone acetate and the organic acid
within the same crystalline phase (i.e, the organic acid forming a crystalline salt or co-crystal with abiraterone acetate, such organic acids are also recalled as "co-former” in the following).

In view of the foregoing, it would be desirable to provide new forms of abiraterone acetate. Further, it would be desirable to have reliable processes for producing these forms of abiraterone acetate. Additionally, the various forms of abiraterone acetate could be used to prepare improved pharmaceutical compositions

SUMMARY:
The present invention is directed to novel pharmaceutical compounds comprising abiraterone acetate and organic acids, methods of preparing such pharmaceutical compounds, and methods of treating androgen or oestrogen dependent disorders with such pharmaceutical compounds. The pharmaceutical compound may be a salt, or a crystalline form of a salt or a co-crystal.

A “Pharmaceutical Compound” according to the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure. Pharmaceutical Compounds consist of a fixed ratio of atoms that are held together in a defined spatial arrangement by ionic, covalent, hydrogen bonds, van der Waals forces or p- p interactions. According to the present invention the elements of a Pharmaceutical Compound comprise abiraterone acetate and organic acids, water, ions, solvents, or co-formers.
In addition, the pharmaceutical compounds according to the present invention represent a” drugable form of abiraterone acetate with organic acids”. A” drugable form” as used herein is defined as any form (salt, amorphous, crystal (of a salt), co-crystal, solution, dispersion, mixture, etc.) that abiraterone acetate with organic acids might take which still can be formulated into a pharmaceutical formulation usable as a medicament to treat a disease or a symptom.

Accordingly, the present invention provides novel synergistic pharmaceutical compounds of abiraterone acetate with group of organic acids also recalled as “co-former”.

The novel pharmaceutical compounds are relatively stable towards the moisture and humidity, thereby representing an amorphous or a crystalline form of pharmaceutical compound, thus enhancing the efficacy of the parent molecule in lower doses.

In a first aspect, a salt and/or a co-crystal of abiraterone acetate and succinic acid, pharmaceutical compositions containing the salt and/or a co-crystal, and methods of administering the salt and/or a co-crystal to a patient for treating a disease, are provided.

In a second aspect, a salt and/or a co-crystal of abiraterone acetate and glutaric acid, pharmaceutical compositions containing the salt and/or a co-crystal, and methods of administering the salt and/or a co-crystal to a patient for treating a disease, are provided.

In a third aspect, a salt and/or a co-crystal of abiraterone acetate and 4-hydroxybenzoic acid, pharmaceutical compositions containing the salt and/or a co-crystal, and methods of administering the salt and/or a co-crystal to a patient for treating a disease, are provided.

In a fourth aspect, a salt and/or a co-crystal of abiraterone acetate and 3,5-dihydroxybenzoic acid, pharmaceutical compositions containing the salt and/or a co-crystal, and methods of administering the salt and/or a co-crystal to a patient for treating a disease, are provided.

In a fifth aspect, a salt and/or a co-crystal of abiraterone acetate and 2,5-dihydroxybenzoic acid, pharmaceutical compositions containing the salt and/or a co-crystal, and methods of administering the salt and/or a co-crystal to a patient for treating a disease, are provided.

The salt and/or co-crystals of the present invention could be either in a crystalline or amorphous form.

The salt and/or co-crystal of abiraterone acetate of the present invention have been characterized by means of Powder X-ray diffraction pattern (PXRD), differential scanning calorimetry (DSC), ORTEP diagram and powder dissolution. A variety of other solid state spectroscopic techniques can be used including, but not limited to,, Raman spectroscopy, FTIR spectroscopy, vibrational spectroscopy, polarized light microscopy (PLM), and solid state NMR, the 13C NMR and 1H NMR (in a suitable solvent, e.g., in D2O or DMSO-d6) to evaluate the chemical structure, Dynamic Gravimetric Vapor Sorption (DVS) to evaluate the hygroscopicity, and thermogravimetric analysis (TGA) to evaluate the thermal properties, and/or chromatography (e.g., HPLC) in a suitable solvent to evaluate the purity. Products as described herein can be further analysed via Karl Fischer Titration (KF) to determine the water content.

The salt and/or co-crystals of the present invention could be used for the preparation of abiraterone acetate in the free base form or in the form of any other co-crystals of abiraterone acetate.

These and other features, aspects, and advantages of the disclosure will be apparent from a reading of the following detailed description together with the accompanying drawings, which are briefly described below. The invention includes any combination of the above-noted embodiments as well as combinations of any features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined in a specific embodiment description herein.

BRIEF DESCRIPTION OF THE DRAWINGS:
FIG. 1 is an X-ray powder diffractogram of a co-crystal of abiraterone acetate and succinic acid.

FIG. 2 is a DSC curve of a co-crystal of abiraterone acetate and succinic acid.

FIG. 3 is an X-ray powder diffractogram of a co-crystal of abiraterone acetate and glutaric acid.

FIG. 4 is a DSC curve of a co-crystal of abiraterone acetate and glutaric acid.

FIG. 5 is a crystal structure (ORTEP diagram) of a co-crystal of abiraterone acetate and glutaric acid. The non-hydrogen atoms are represented by 50% probability anisotropic atomic thermal displacement ellipsoids

FIG. 6 is an X-ray powder diffractogram of a co-crystal of abiraterone acetate and 4-hydroxybenzoic acid

FIG. 7 is a DSC curve of a co-crystal of abiraterone acetate and 4-hydroxybenzoic acid

FIG. 8 is a crystal structure (ORTEP diagram) of a co-crystal of abiraterone acetate and 4-hydroxybenzoic acid. The non-hydrogen atoms are represented by 50% probability anisotropic atomic thermal displacement ellipsoids

FIG. 9 is an X-ray powder diffractogram of a co-crystal of abiraterone acetate and 3,5-dihydroxybenzoic acid

FIG. 10 is a DSC curve of a co-crystal of abiraterone acetate and 3,5-dihydroxybenzoic acid

FIG. 11 is an X-ray powder diffractogram of a salt of abiraterone acetate and 2,5-dihydroxybenzoic acid

FIG. 12 is a DSC curve of a salt of abiraterone acetate and 2,5-dihydroxybenzoic acid

FIG. 13 is an overlay of powder dissolution profiles of a salt/co-crystals of abiraterone acetate

DETAILED DESCRIPTION OF INVENTION:
Abiraterone acetate is a prodrug of abiraterone. Once administered, the compound is metabolized in vivo into an active metabolite, namely, abiraterone.

By co-crystallizing the abiraterone acetate with a co-former, a new solid form is created having different properties from the abiraterone acetate or the conformer. For example, a co-crystal may have a different melting point, dissolution, solubility, hygroscopicity, bioavailability, toxicity, crystal morphology, density, loading volume, compressibility, physical stability, chemical stability, shelf life, taste, production costs, and/or manufacturing method than the prodrug.

The term "co-former" refers to a compound other than abiraterone acetate that is also a component of the co-crystal. Thus, the co-former is part of the co-crystalline lattice. The co-former is typically a GRAS (generally regarded as safe) compound and need not exhibit any therapeutic or pharmacological activity of its own. The Registry of Toxic Effects of Chemical Substances (RTECS) database is a useful source for toxicology information, and the GRAS list maintained by the RTECS contains about 2,500 relevant compounds that may be used in the generation of one or more co-crystals.

In an embodiment “co-former” is selected from one or more pharmaceutically acceptable organic acids.

For a list of pharmaceutically acceptable organic acids, see Handbook of Pharmaceutical Salts - Properties, Selection, and Use, P. Heinrich Stahl, CamiUe G. Wermuth (Eds.) VHCA (Verlag Helvetica Chemica Acta -Ziirich), Wiley-VCH (New York) 2002, which is incorporated herein by reference. For example, certain co-formers useful for reaction with the abiraterone acetate, which may result in the formation of a salt, co-crystal, or salt co-crystal include, but are not limited to: acetic acid; capric (decanoic) acid; D-glucuronic acid; D-gluconic acid; DL-lactic acid; L-lactic acid; galactaric (mucic) acid; hippuric (N-benzoylglycine) acid; hydrochloric acid; L-aspartic acid; L-glutamic acid; L-glutaric acid; glycerophosphoric acid; glycolic acid; lauric acid; palmitic acid; phosphoric acid; sebacic (1,8-octanedicarboxylic) acid; stearic (octadecanoic) acid; succinic acid; sulfuric acid; and thiocyanic acid (HS-CN). Other exemplary co-formers for reaction with the abiraterone acetate, which may result in the formation of a salt, co-crystal, or salt co-crystal include, but are not limited to, (+)-camphoric acid; 1,5-naphthalenedisulfonic acid; 1-hydroxy-2 -naphthoic (xinafoic) acid; 3,5- dihydroxybenzoic acid, 2,5- dihydroxybenzoic (gentisic) acid; benzenesulfonic acid; benzoic acid; caprylic (octanoic) acid; cyclamic acid; ethanesulfonic acid; fumaric acid; D-glucoheptonic acid; 4-hydroxybenzoic acid; isobutyric acid; ketoglutaric (2-oxo-glutaric) acid; 2-ketobutyric acid; lactobionic acid; malonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic (Z-octadecenoic) acid; orotic acid; oxalic acid; pamoic acid; pivalic acid; propionic acid; L-pyroglutamic acid; and p-toluenesulfonic acid.

Organic acids are preferably selected from but not limited to the group comprising of succinic acid, glutaric acid, 4-hydroxybenzoic acid, 3,5- dihydroxybenzoic acid and 2,5- dihydroxybenzoic acid. Other abiraterone acetate salts, co-crystals, and salt co-crystals are also encompassed by the present disclosure.

The present solid forms, in the following summarized as multicomponent molecular crystal, thus may be classified as co-crystals or crystalline salts of abiraterone acetate. The present multi-component molecular crystal typically comprises abiraterone acetate and the organic acid within the same crystalline phase in a molar ratio ranging from 2 :1 to 1:2.
As crystalline forms are reliably characterized by peak positions in the X-ray diffractogram, the crystals of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the crystalline form and is able to distinguish it from all other crystalline and amorphous forms of abiraterone acetate. Measurements of 2? values are accurate to within ± 0.2 degrees. All the powder diffraction patterns were measured on a PANalytical X’Pert3 X-ray powder diffractometer with a copper-K-a radiation source.

In a first aspect of the invention is provided a co-crystals or crystalline salt of abiraterone acetate and succinic acid. In some embodiments, the co-crystal is a hemi -succinic acid co-crystal. The hemi- succinic acid co-crystal can, in certain embodiments, be in hydrated or solvated form. In some embodiments, the co-crystal is a mono- succinic acid co-crystal. Preferably, the co-crystals comprises abiraterone acetate and the succinic acid within the same crystalline phase in a molar ratio ranging from 2 :1.

Advantageously, in some embodiments, a given percentage of the co-crystal is in crystalline form. For example, in various embodiments at least about 50% of the co-crystal is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the co-crystal is in crystalline form.

In an embodiment, the succinate co-crystals of abiraterone acetate can, in some embodiments, be characterized as having particular peaks in X-ray powder diffraction patterns obtained therefrom. For example, co-crystals can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 5.06, 7.62, 14.80, 15.40 and 23.12 ±0.2°2?.

In another embodiment, the succinate co-crystals of abiraterone acetate is characterized by having an XRD pattern as shown in Figure 1.

The succinate co-crystals of abiraterone acetate may also be characterized as having a DSC spectrum exhibiting a significant peak at around 123.47°C.

In an embodiment, succinate co-crystals of abiraterone acetate may be characterized by having a DSC spectrum as shown in Figure 2.

According to another aspect of the present invention, there is provided a process for preparing salt or co-crystals of abiraterone acetate and succinic acid, the process comprising,

1. dissolving abiraterone acetate and succinic acid in a suitable solvent selected from the group comprising of acetone, methanol, ethanol, isopropyl alcohol (IPA) or a mixture thereof;
2. removing the solvent under reduced pressure to obtain a residue;
3. cooling the reaction mass to a temperature ranging from about 20°C to 30°C;
4. stirring the residue in a solvent or a solvent mixture selected from the group comprising of dimethyl ether, diethyl ether, di-isopropyl ether, hexane, heptane and pentane, for at about 20 hours to about 50 hours; and
5. isolating the precipitated salts or co-crystals of abiraterone acetate and succinic acid and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.

In a second aspect of the invention is provided a co-crystals or crystalline salt of abiraterone acetate and glutaric acid. In some embodiments, the co-crystal is a bis-glutaric acid co-crystal. The bis- glutaric acid co-crystal can, in certain embodiments, be in hydrated or solvated form. In some embodiments, the co-crystal is a mono- glutaric acid salt. Preferably, the co-crystals comprises abiraterone acetate and the glutaric acid within the same crystalline phase in a molar ratio ranging from 1 :1.

Advantageously, in some embodiments, a given percentage of the co-crystal is in crystalline form. For example, in various embodiments at least about 50% of the co-crystal is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the co-crystal is in crystalline form.

In an embodiment, the glutarate co-crystals can, in some embodiments, be characterized as having particular peaks in X-ray powder diffraction patterns obtained therefrom. For example, co-crystals can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 5.74, 7.20, 9.81, 11.56, 15.87, 16.40 and 21.90 ±0.2°2?.

As another example, co-crystals can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 14.51, 14.92 and 18.85 ±0.2°2?.
In another embodiment, the glutarate co-crystals of abiraterone acetate is characterized by having an XRD pattern as shown in Figure 3.
The glutarate co-crystals of abiraterone acetate may also be characterized as having a DSC spectrum exhibiting significant endothermic peaks at around 75.37°C and 92.33°C.

In an embodiment, glutarate co-crystals of abiraterone acetate may is characterized by having a DSC spectrum as shown in Figure 4.

Single crystal structure determination on solids crystallized from methanol confirmed that the co-crystal of abiraterone acetate and glutaric acid is 1:1 co-crystal. Oak Ridge Thermal Ellipsoid Plot (ORTEP) of the co-crystal of abiraterone acetate and glutaric acid was drawn with ORTEP-3, v.2.02. The ellipsoids are at 50% probability.

In an embodiment, Figure 5 shows an ORTEP drawing of co-crystal of abiraterone acetate and glutaric acid.

According to another aspect of the present invention, there is provided a process for preparing salts or co-crystals of abiraterone acetate and glutaric acid, the process comprising,

1. dissolving abiraterone acetate and glutaric acid in a suitable solvent selected from the group comprising of acetone, methanol, ethanol, isopropyl alcohol (IPA) or a mixture thereof;
2. removing the solvent under reduced pressure to obtain a residue;
3. cooling the reaction mass to a temperature ranging from about 20°C to 30°C;
6. stirring the residue in a solvent or a solvent mixture selected from the group comprising of dimethyl ether, diethyl ether, di-isopropyl ether, hexane, heptane and pentane, for at about 20 hours to about 50 hours; and
4. isolating the precipitated salts or co-crystals of abiraterone acetate and glutaric acid and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.

In a third aspect of the invention is provided a co-crystals or crystalline salt of abiraterone acetate and 4- hydroxybenzoic acid. In some embodiments, the co-crystal is a bis-4- hydroxybenzoic acid co-crystal. The bis-4-hydroxybenzoic acid co-crystal can, in certain embodiments, be in hydrated or solvated form. In some embodiments, the co-crystal is a mono 4- hydroxybenzoic acid salt. Preferably, the co-crystal comprises abiraterone acetate and the 4- hydroxybenzoic acid within the same crystalline phase in a molar ratio ranging from 1 :1.

Advantageously, in some embodiments, a given percentage of the co-crystal is in crystalline form. For example, in various embodiments at least about 50% of the co-crystal is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the co-crystal is in crystalline form.

In an embodiment, the 4- hydroxybenzoate co-crystals of abiraterone acetate can, in some embodiments, be characterized as having particular peaks in X-ray powder diffraction patterns obtained therefrom. For example, co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 15.98, 17.83, 20.53, and 23.76 ±0.2°2?.

As another example, co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 14.10, 19.80, 21.3 and 24.81 ±0.2°2?.

In another embodiment, the 4- hydroxybenzoate co-crystals of abiraterone acetate is characterized by having an XRD pattern as shown in Figure 6.

The 4- hydroxybenzoate co-crystals of abiraterone acetate may also be characterized as having a DSC spectrum exhibiting significant endothermic peaks at around 169.02°C and 185.51°C.

In an embodiment, 4- hydroxybenzoate co-crystals of abiraterone acetate may be characterized by having a DSC spectrum as shown in Figure 7.

Single crystal structure determination on solids crystallized from methanol confirmed that the co-crystal of abiraterone acetate and 4-hydroxybenzoic acid is 1:1 co-crystal. ORTEP of the salt of abiraterone acetate and 4-hydroxybenzoic acid was drawn with ORTEP-3, v.2.02. The ellipsoids are at 50% probability.

In an embodiment, Figure 8 shows an ORTEP drawing of co-crystal of abiraterone acetate and 4-hydroxybenzoic acid.

According to another aspect of the present invention, there is provided a process for preparing salts or co-crystals of abiraterone acetate and 4-hydroxybenzoic acid, the process comprising,

1. dissolving abiraterone acetate and 4-hydroxybenzoic acid in a suitable solvent selected from the group comprising of methanol, ethanol, isopropyl alcohol (IPA), n-propanol, t-butanol, or a mixture thereof;
2. removing the solvent under reduced pressure to obtain a residue;
3. cooling the reaction mass to a temperature ranging from about 20°C to 30°C;
4. stirring the residue in a solvent or a solvent mixture selected from the group comprising of dimethyl ether, diethyl ether, di-isopropyl ether, hexane, heptane and pentane, for at about 15 hours to about 30 hours; and
5. isolating the precipitated salts or co-crystals of abiraterone acetate and 4-hydroxybenzoic acid and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.
In a fourth aspect of the invention is provided a co-crystals or crystalline salt of abiraterone acetate and 3,5- dihydroxybenzoic acid. In some embodiments, the co-crystal is a bis-3,5- dihydroxybenzoic acid salt-co-crystal. The bis-3,5-dihydroxybenzoic acid co-crystal can, in certain embodiments, be in hydrated or solvated form. In some embodiments, the co-crystal is a mono 3,5- dihydroxybenzoic acid salt. Preferably, the co-crystal comprises abiraterone acetate and the 3,5-dihydroxybenzoic acid within the same crystalline phase in a molar ratio ranging from 1 :1.

Advantageously, in some embodiments, a given percentage of the co-crystal is in crystalline form. For example, in various embodiments at least about 50% of the co-crystal is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the co-crystal is in crystalline form.

In an embodiment, the 3,5-dihydroxybenzoate co-crystals of abiraterone acetate can, in some embodiments, be characterized as having particular peaks in X-ray powder diffraction patterns obtained therefrom. For example, co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 5.78, 13.53, 17.35, 21.96, and 27.57 ± 0.2°2?.

As another example, co-crystal can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 11.51, 12.19, 18.88, 19.81 and 20.47 ± 0.2°2?.

In another embodiment, the 3,5-dihydroxybenzoate co-crystals of abiraterone acetate is characterized by having an XRD pattern as shown in Figure 9.

The 3,5-dihydroxybenzoate co-crystals of abiraterone acetate may also be characterized as having a DSC spectrum exhibiting significant endothermic peak at around 177.17°C.
In an embodiment, 3,5-dihydroxybenzoate co-crystals of abiraterone acetate may is characterized by having a DSC spectrum as shown in Figure 10.

According to another aspect of the present invention, there is provided a process for preparing salts or co-crystals of abiraterone acetate and 3,5- dihydroxybenzoic acid, the process comprising,

1. dissolving abiraterone acetate and 3,5-dihydroxybenzoic acid in a suitable solvent selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, t-butanol, or a mixture thereof;
2. removing the solvent under reduced pressure to obtain a residue;
3. cooling the reaction mass to a temperature ranging from about 20°C to 30°C;
4. stirring the residue in a solvent or a solvent mixture selected from the group comprising of dimethyl ether, diethyl ether, di-isopropyl ether, hexane, heptane and pentane, for at about 10 hours to about 30 hours; and
5. isolating the precipitated salts or co-crystals of abiraterone acetate and 3,5- dihydroxybenzoic acid and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.

In a fifth aspect of the invention is provided a crystalline salt of abiraterone acetate and 2,5- dihydroxybenzoic acid. In some embodiments, the salt is a bis-2,5- dihydroxybenzoic acid salt. The bis-3,5-dihydroxybenzoic acid salt can, in certain embodiments, be in hydrated or solvated form. In some embodiments, the salt is a mono 2,5-dihydroxybenzoic acid salt. Preferably, the crystalline salt comprises abiraterone acetate and the 2,5-dihydroxybenzoic acid within the same crystalline phase in a molar ratio ranging from 1 :1.

Advantageously, in some embodiments, a given percentage of the salt is in crystalline form. For example, in various embodiments at least about 50% of the salt is in crystalline form. In other embodiments, at least about 80 or at least about 90% of the salt is in crystalline form.

In an embodiment, the 2,5-dihydroxybenzoate salts of abiraterone acetate can, in some embodiments, be characterized as having particular peaks in X-ray powder diffraction patterns obtained therefrom. For example, one salt can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 13.78, 14.72, 16.22, and 19.43 ± 0.2°2?.

As another example, one salt can be characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 6.04, 20.19, 21.50, 24.25, 25.30 and 26.92 ± 0.2°2?.

In another embodiment, the 2,5-dihydroxybenzoate salts of abiraterone acetate is characterized by having an XRD pattern as shown in Figure 11.

The 2,5-dihydroxybenzoate salts of abiraterone acetate may also be characterized as having a DSC spectrum exhibiting significant endothermic peak at around 154.28°C.

In an embodiment, 2,5-dihydroxybenzoate salts of abiraterone acetate may is characterized by having a DSC spectrum as shown in Figure 12.

According to another aspect of the present invention, there is provided a process for preparing 2,5- dihydroxybenzoate salts of abiraterone acetate, the process comprising,

1. dissolving abiraterone acetate and 2,5-dihydroxybenzoic acid in a suitable solvent selected from the group comprising of methanol, ethanol, isopropyl alcohol, n-propanol, t-butanol, or a mixture thereof;
2. removing the solvent under reduced pressure to obtain a residue;
3. cooling the reaction mass to a temperature ranging from about 20°C to 30°C;
4. stirring the residue in a solvent or a solvent mixture selected from the group comprising of dimethyl ether, diethyl ether, di-isopropyl ether, hexane, heptane and pentane, for at about 2 hours to about 20 hours; and
5. isolating the precipitated 2,5-dihydroxybenzoate salts of abiraterone acetate and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.

In yet another embodiment, salts or co-crystals of abiraterone acetate of the present invention are further characterised by the powder dissolution profiles.

POWDER DISSOLUTION:
In vitro powder dissolution studies were conducted for Abiraterone acetate (ABI), Abiraterone acetate-succinic acid (ABI-SA) (2:1) co-crystal, Abiraterone acetate-Glutaric acid (ABI-GA) (1:1) co-crystal, Abiraterone acetate-4-hydroxy benzoic acid (ABI-4HBA) (1:1) co-crystal, and Abiraterone acetate-3,5 Di hydroxy benzoic acid (ABI-35DHBA) (1:1) co-crystal at pH-1.2 over different time intervals (5, 10, 20, 30, 60 and 120 minutes). The corresponding results were compared with Abiraterone acetate free base.

It is interesting to note that, ABI-GA co-crystal showed about 31 folds higher drug release when compared to its parent Abiraterone acetate free base at 120 mins.

ABI-SA co-crystal showed about 4.7 folds higher drug release when compared to Abiraterone acetate.

ABI-35DHBA co-crystal showed initially higher drug release at 5 min and less drug release at 20 mins when compared to its parent Abiraterone acetate free base. Dissolution profiles for ABI-35DHBA indicate a polymorph transformation takes place at 10 mins during dissolution. The initial solid form of ABI-35DHBA co-crystal converted to the less soluble polymorph of ABI-35DHBA co-crystal.

On the other hand, the drug release tendency of ABI-4HBA co-crystal did not changed from initial to 120 min and it showed 0.03 folds lower drug release when compared to its parent Abiraterone acetate free base. This could be due to strong hydrogen bonding in cocrystal. It is also supported by high melting point in DSC (Figure 7) when compared to parent Abiraterone acetate free base.

From the above data it is evident that, ABI-GA co-crystal has highest dissolution advantage (about 31 folds) over parent Abiraterone acetate.

In an embodiment, Figure 13 shows an overlay of the In Vitro powder dissolutions of salts or co-crystals of abiraterone acetate prepared by the present invention with abiraterone acetate.

The abiraterone acetate used in the processes of the present invention as well as for the powder dissolution studies, may be in any polymorphic form or in a mixture of any polymorphic forms. The starting material can be obtained by any method known in the art, such as the one described in the PCT application publication No. WO9320097A which is incorporated herein by reference.

The process of invention may be used as a method for purifying any form of abiraterone acetate, as well as for the preparation of the new forms.

In another embodiment, the present invention provides a pharmaceutical composition comprising solid forms of abiraterone acetate prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc.

According to yet another aspect of the present invention there is provided use of solid forms of abiraterone acetate as described above, in the preparation of a medicament useful in treating or preventing androgen- or oestrogen-dependent disorders.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

EXAMPLES:

Example 1
Process to prepare abiraterone acetate-succinic acid (2:1) co-crystal:
1g of abiraterone acetate and 150 mg of succinic acid (2:1 mole/mole) were dissolved in 30 ml acetone at room temperature. The reaction mass was concentrated in a Bauchi rotavapor at 45°C, to get the residue. The residue was cooled to room temperature and stirred in 20 ml of pentane for 24 hrs. The solids were isolated by vacuum filtration and dried.

H-NMR reveals a molar ratio of abiraterone acetate to succinic acid of about 2:1. The powder X-ray diffraction pattern is depicted in Fig 1 and DSC in Fig 2.

Example 2
Process to prepare abiraterone acetate-succinic acid (2:1) co-crystal:
1g of abiraterone acetate and 150 mg of succinic acid (2:1 mole/mole) were dissolved in 30 ml methanol at room temperature. The reaction mass was concentrated in a Bauchi rotavapor at 45°C, to get the residue. The residue was cooled to room temperature and stirred in 20 ml of pentane for 24 hrs. The solids were isolated by vacuum filtration and dried.

H-NMR reveals a molar ratio of abiraterone acetate to succinic acid of about 2:1. The powder X-ray diffraction pattern is depicted in Fig 1 and DSC in Fig 2.
Example 3
Process to prepare abiraterone acetate-glutaric acid (1:1) co-crystal:
1g of abiraterone acetate and 340 mg of glutaric acid (1:1 mole/mole) were dissolved in 40ml methanol at 55°c. The reaction mass was concentrated in a Bauchi rotavapor at 55°C, to get the residue. The residue was cooled to room temperature and stirred in 20 ml of pentane for 24 hrs. The solids were isolated by vacuum filtration and dried.

H-NMR reveals a molar ratio of abiraterone acetate to glutaric acid of about 1:1. The powder X-ray diffraction pattern is depicted in Fig 3, DSC in Fig 4 and an ORTEP diagram in Fig 5.

Example 4
Process to prepare abiraterone acetate-4-hydroxybenzoic acid (1:1) co-crystal:
1g of abiraterone acetate and 354 mg of 4-hydroxybenzoic acid (1:1 mole/mole) were dissolved in 30ml methanol at 60 to 65°C. The reaction mass was concentrated in a Bauchi rotavapor at 65°C, to get the residue. The residue was cooled to room temperature and stirred in 20 ml of pentane for 18 hrs. The solids were isolated by vacuum filtration and dried.

H-NMR reveals a molar ratio of abiraterone acetate to 4-hydroxybenzoic acid of about 1:1. The powder X-ray diffraction pattern is depicted in Fig 6, DSC in Fig 7 and an ORTEP diagram in Fig 8.

Example 5
Process to prepare abiraterone acetate-3,5-dihydroxybenzoic acid (1:1) co-crystal:
1g of abiraterone acetate and 394 mg of 3,5-dihydroxybenzoic acid (1:1 mole/mole) were dissolved in 30ml methanol at 60 to 65°C. The reaction mass was concentrated in a Bauchi rotavapor at 65°C, to get the residue. The residue was cooled to room temperature and stirred in 20 ml of pentane for 24 hrs. The solids were isolated by vacuum filtration and dried.

H-NMR reveals a molar ratio of abiraterone acetate to 3,5-dihydroxybenzoic acid of about 1:1. The powder X-ray diffraction pattern is depicted in Fig 9 and DSC in Fig 10.

Example 6
Process to prepare abiraterone acetate-3,5-dihydroxybenzoic acid (1:1) co-crystal:
1g of abiraterone acetate and 394 mg of 3,5-dihydroxybenzoic acid (1:1 mole/mole) were dissolved in 30ml isopropanol at 60 to 65°C. The reaction mass was concentrated in a Bauchi rotavapor at 65°C, to get the residue. The residue was cooled to room temperature and stirred in 20 ml of pentane for 17 hrs. The solids were isolated by vacuum filtration and dried.

H-NMR reveals a molar ratio of abiraterone acetate to 3,5-dihydroxybenzoic acid of about 1:1. The powder X-ray diffraction pattern is depicted in Fig 9 and DSC in Fig 10.

Example 7
Process to prepare abiraterone acetate-2,5-dihydroxybenzoic acid (1:1) salt:
1g of abiraterone acetate and 394 mg of 2,5-dihydroxybenzoic acid (1:1 mole/mole) were dissolved in 30ml methanol at 60 to 65°C. The reaction mass was concentrated in a Bauchi rotavapor at 65°C, to get the residue. The residue was cooled to room temperature and stirred in 20 ml of pentane for 3 hrs. The solids were isolated by vacuum filtration and dried.

H-NMR reveals a molar ratio of abiraterone acetate to 2,5-dihydroxybenzoic acid of about 1:1. The powder X-ray diffraction pattern is depicted in Fig 11 and DSC in Fig 12.
Example 8
Comparative Powder Dissolution Study
Excess amount of sample was added in to pH 1.2 media and the samples were shaken for 2 hrs at 37°C in a horizontal orbital shaker (n = 3) at 200 RPM speed. After the requisite time the supernatant was filtered through 0.45 mm filter and the filtrate was assayed spectrophotometrically by HPLC at 252 nm using Zorbax C8 (75 mm x 4.6 mm, 3.5 µm) column.

The percentage of abiraterone released from salts or co-crystals of abiraterone acetate as well as from the abiraterone acetate were plotted against time as shown in figure 13. The powder dissolution rate was derived from the slope of this curve.

The above data shows that, the salts or co-crystals of abiraterone acetate have more advantage over abiraterone acetate.

These results further proved that salts or co-crystals of abiraterone acetate have been formed after this technique.
,CLAIMS:1. A salt or co-crystal of abiraterone acetate and an organic acid selected from the group consisting of succinic acid, glutaric acid, 4-hydroxy benzoic acid, 3,5-dihydroxy benzoic acid and 2,5-dihydroxybenzoiac acid.

2. The salt or co-crystal of abiraterone acetate and an organic acid according to claim 1, wherein molar ratio of abiraterone acetate to the organic acid within the same crystalline phase ranges from 2 :1 to 1:2.

3. A salt or co-crystal of abiraterone acetate and glutaric acid.

4. The salt or co-crystal of claim 3, wherein the co-crystal is a mono- glutaric acid co-crystal, having a molar ration of abiraterone acetate to glutaric acid of about 1:1.

5. The salt or co-crystal of claim 4, wherein the mono- glutaric acid co-crystal is in anhydrous form.

6. The salt or co-crystal of claim 3, wherein at least about 50% of the salt or co-crystal is in crystalline form.

7. The salt or co-crystal according to any one of claims 3 to 6, characterized by an X-ray powder diffraction pattern having peaks at one or more of the following 2-theta diffraction angles: 5.74, 7.20, 9.81, 11.56, 15.87, 16.40 and 21.90 ±0.2°2?.

8. The salt or co-crystal according to claim 7, characterized by an X-ray powder diffraction pattern having further peaks at one or more of the following 2-theta diffraction angles: 14.51, 14.92 and 18.85 ±0.2°2?.

9. The salt or co-crystal according to any one of claims 7 or 8, characterized by having an XRD pattern as shown in Figure 3.

10. The salt or co-crystal according to any one of claims 3 to 6, characterized as having a DSC spectrum exhibiting a significant peak at around 75.37°C and 92.33°C.
11. The salt or co-crystal of claim 10, characterized by having a DSC spectrum as shown in Figure 4.

12. The salt or co-crystal according to any one of claims 3 to 6, characterized by ORTEP diagram as shown in Figure 5.

13. A process for preparing a salt or co-crystal of abiraterone acetate and glutaric acid, as claimed in any one of claims 3 to 12, wherein, the process comprises:

5. dissolving abiraterone acetate and glutaric acid in a suitable solvent selected from the group comprising of acetone, methanol, ethanol, isopropyl alcohol (IPA) or a mixture thereof;
6. removing the solvent under reduced pressure to obtain a residue;
7. cooling the reaction mass to a temperature ranging from about 20°C to 30°C;
7. stirring the residue in a solvent or a solvent mixture selected from the group comprising of dimethyl ether, diethyl ether, di-isopropyl ether, hexane, heptane and pentane, for at about 20 hours to about 50 hours; and
8. isolating the precipitated salts or co-crystals of abiraterone acetate and glutaric acid and drying under reduced pressure at 25-50°C, preferably at 25-30°C for at least 5 hrs.

14. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a salt or co-crystal of abiraterone acetate and an organic acid according to claim 1; and (b) at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient; wherein the pharmaceutical composition can be useful for the treatment or prevention of prostate cancer.

15. A method for the prevention or treatment of prostate cancer which method comprises administering therapeutically effective amounts to a patient in need a salt or co-crystal of abiraterone acetate and an organic acid according to claim 1.