CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority of United States Provisional Application No. 61/197,493, filed October 27, 2008; United States Provisional Application No. 61/199,324, filed November 13, 2008; United States Provisional Application No. 61/210,890, filed March 23, 2009; and United States Provisional Application No. 61/167,408, filed April 7, 2009; the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to polymorphs of Vorinostat and Vorinostat potassium salts.

BACKGROUND OF THE INVENTION

Vorinostat, suberoylanilide hydroxamic acid ("SAHA"), has the following structure:

SAHA

Vorinostat, which is marketed under the trade name Zolinza® by Merck, is a histone deacetylase inhibitor ("HDI") used for the treatment of cutaneous T cell lymphoma and Sezary's lymphoma.

Vorinostat is disclosed in US patent No. 5,369,108 as a member of a family of compounds that selectively induce terminal differentiataion of neoplastic cells. It can be prepared by the process described by the following scheme: C-OIf

Suberic acid aniline Suberanilic acid

Methyl suberanilate

]

Sυberoylanilide hydoxamic acid

Processes for preparation of Vorinostat are also disclosed in WO2009098515.

US patent No. 7,456,219 discloses Vorinostat form I and describes 4 other polymorphs of Vorinostat, refered herein as forms II, III, IV and V.

The present invention discloses new polymorph of Vorinostat and of Vorinostat potassium salt.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") as well as by content of solvent in the crystalline form, which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solutions, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

SUMMARY OF THE INVENTION

In one embodiment, the present invention encompasses a crystalline Vorinostat potassium salt characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 4.9 and 7.4 ± 0.2 degrees 2-theta and any 3 peaks selected from the list consisting of: 12.3, 19.8, 20.9, 22.1, 22.8, 28.7 and 29.5 ± 0.2 degrees 2-theta; a powder XRD pattern having peaks at about 4.9, 7.4, 12.3, 20.9 and 22.8 ± 0.2 degrees 2- theta; the PXRD pattern depicted in Figure 1, and combinations thereof.

In another embodiment, the present invention encompasses a process for preparing Vorinostat comprising preparing the above described polymorph of Vorinostat potassium salt according to the process of the present invention, and converting it to Vorinostat. hi yet another embodiment the present invention provide the use of the above described polymorph of Vorinostat potassium salt to prepare Vorinostat.

In one embodiment, the present invention encompasses crystalline Vorinostat characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 14.3, 14.8, 17.6, 21.4 and 23.1 ± 0.2 degrees 2-theta; the PXRD pattern depicted in Figure 4, and the combination thereof.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat potassium salt designated form A.

Figure 2 illustrates TGA results obtained for pure crystalline Vorinostat potassium salt designated form A.

Figure 3 illustrates a DSC pattern of polymorphically pure crystalline Vorinostat potassium salt designated form A.

Figure 4 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat designated form VI.

Figure 5 illustrates TGA results obtained for crystalline Vorinostat designated form VI.

Figure 6 illustrates a DSC pattern of crystalline Vorinostat designated form VI.

Figure 7 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat designated form I.

Figure 8 illustrates a powder X-ray diffraction pattern of crystalline Vorinostat designated form HI.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to polymorphs of Vorinostat and Vorinostat potassium salts.

As used herein, the term Vorinostat form I refers to crystalline Vorinostat characterized by data selected from a group consisting of: an X-ray powder diffraction pattern having peaks at about 9.1, 10.8, 12.3, 17.2, 19.2, 19.8, 23.7, 25.7, 26.8 and 27.7 ± 0.2 degrees two-theta; a powder XRD pattern as depicted in figure 7; and the combination thereof.

As used herein, the term Vorinostat form III refers to crystalline Vorinostat characterized by data selected from a group consisting of: an X-ray powder diffraction pattern having peaks at about 11.9, 17.5, 18.4, 18.7 and 24.4 ± 0.2 degrees rwo-theta; a powder XRD pattern as depicted in figure 8; and the combination thereof.

In one embodiment, the present invention encompasses a crystalline Vorinostat potassium salt characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 4.9 and 7.4 ± 0.2 degrees 2-theta and any 3 peaks selected from the list consisting of: 12.3, 19.8, 20.9, 22.1, 22.8, 28.7 and 29.5 ± 0.2 degrees 2-theta; a powder XRD pattern having peaks at about 4.9, 7.4, 12.3, 20.9 and 22.8 ± 0.2 degrees 2- theta; the PXRD pattern depicted in Figure 1, and combinations thereof.

The above-described polymorph of potassium salt of Vorinostat can be designated form A.

The above-described crystalline form A of Vorinostat potassium salt can be further characterized by data selected from a group consisting of: a powder XRD pattern having peaks at about 19.8, 22.1, 28.7 and 29.5 ± 0.2 degrees 2-theta; a weight loss of less than about 0.5% by weight as measured by TGA; a TGA pattern depicted in Figure 2; a DSC pattern having an exothermic peak at about 195 ⁰ C ± 0.5 ⁰ C; a DSC pattern depicted in Figure 3, and combinations thereof.

In preferred embodiments, the above form A of Vorinostat potassium salt is polymorphically pure.

As used herein, the term "polymorphically pure" in relation to Vorinostat potassium salt form A, relates to Vorinostat potassium salt containing less than about 10% by weight of crystalline Vorinostat form I; preferably less than about 5%, more preferably less than 1% by weight crystalline Vorinostat form I.

Typically, the amount of Vorinostat form I in the crystalline Vorinostat potassium salt form A of the present invention is measured by PXRD using any peak from the following list of peaks at about: 9.1, 10.8, 19.2, 24.1 and 26.8 ± 0.2 degrees two theta.

Preferably, the above polymorphically pure Vorinostat potassium salt form A is a composition which comprises about 0% to about 10% Vorinostat form I and about 100% to about 90% Vorinostat potassium salt form A, based on the combined weight of Vorinostat form I and Vorinostat potassium salt form A. More preferably, the composition comprises about 0% to about 5% Vorinostat form I and about 100% to about 95% Vorinostat potassium salt form A. Most preferably, the composition comprises about 0% to about 1% Vorinostat form I and about 100% to about 99% Vorinostat potassium salt form A.

More preferably, the polymorphically pure Vorinostat potassium salt form is a composition which contains essentially Vorinostat form I and Vorinostat potassium salt form A in the above described amounts.

The above form A of Vorinoatat potassium salt can be prepared by a process comprising reacting Suberanilic acid methyl ester ("SAME") of the following formula:

Suberanilic acid methyl ester with hydroxylamine in methanol at a pH of at least about 13 to obtain a suspension comprising the said crystalline Vorinostat potassium salt form A.

In certain embodiments, SAME is reacted with hydroxylamine in other alcohols such as ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or 3-butanol, or combinations thereof, or combinations of the other alcohols with methanol.

Preferably, a solution of hydroxylamine in methanol is reacted with a solution of SAME in methanol.

The above solution of hydroxylamine in methanol can be prepared by reacting hydroxylamine hydrochloride with a base in methanol, to obtain a suspension comprising free hydroxylamine, and filtering the suspension to obtain the said solution.

Preferably the said base is inorganic base, more preferably an alkali base, most preferably the base is potassium hydroxide.

Preferably, the reaction between hydroxylamine hydrochloride and the base is performed at a temperature of about O ⁰ C to about 5 ⁰ C. The reaction can proceed at 18-22 ⁰ C.

After the said suspension is formed, it is preferably maintained, prior to the filtration. Preferably, maintaining is with stirring. Preferably maintaining is performed at a temperature of about O ⁰ C to about 5 ⁰ C. Preferably maintaining is for a period of about 15 minutes to about 60 minutes; more preferably about 15 minutes to about 30 minutes. The solution comprising hydroxylamine obtained after the filtration is then used to produce Vorinostat potassium salt crystalline form A by reacting the said solution with a solution of SAME in methanol at a pH of at least about 13.

Obtaining a pH of at least about 13 can be done by reacting SAME and hydroxylamine in the presense of a base. Preferably, the base is an inorganig base, more preferably an alkali base, most preferably the base is potassium hydroxide, hi certain embodiments, the base is sodium hydroxide or tetrabutylammoniurn hydroxide.

Preferably the said reaction is done by adding SAME to the solution of hydroxylamine in methanol. One non-limiting possibility is to add SAME as a solid to the hydroxylamine solution. The SAME container can then be rinsed with methanol and the rinsings added to the SAME/hydroxylamine solution. Then a solution of potassium hydroxide in methanol can be added.

Preferably, the above reaction is done at a temperature of about 0 ⁰ C to about 5 ⁰ C.

The process for preparing crystalline form A of Vorinostat potassium salt may further comprise recovering the said crystalline form. The recovery may be done, for example, by filtering the suspension, washing and drying. Preferably, washing is done with water. Preferably, drying is done under vacuum. Preferably, drying is performed for a period of about 1 hour to about 12 hours, more preferably drying is for a period of about 1 hour.

In one embodiment, the present invention encompasses crystalline Vorinostat characterized by data selected from the group consisting of: a powder XRD pattern having peaks at about 14.3, 14.8, 17.6, 21.4 and 23.1 ± 0.2 degrees 2-theta; the PXRD pattern depicted in Figure 4, and the combination thereof. This crystalline form of Vorinostat can be designated form VI.

The above form VI of Vorinostat can be further characterized by data selected from a group consisting of: a powder XRD pattern having peaks at about 9.1, 10.5, 19.8 and 28.3 ± 0.2 degrees 2-theta; a double diffraction peak at about 14.3 and 14.8 ± 0.2 degrees 2-theta; a weight loss of less than about 0.2% by weight at a temperature of about 30° to about 140 ⁰ C as measured by TGA; a TGA pattern depicted in Figure 5; a DSC pattern having an endothermic melting peak at about 159 ⁰ C ± 2 ⁰ C; a DSC pattern depicted in Figure 6; and combinations thereof.

The above form VI of Vorinostat is an anhydrous form. As used herein, the term "anhydrous form" in relation to Vorinostat form VI refers to a substance containing water and/or any other solvent in an amount of less than 0.2 % (w/w)as measured by TGA.

Melting of this crystalline material is followed by its decomposition as indicated by the exothermic DSC peak and also by the significant weight loss starting at about 160 °C visible in the TGA thermogram.

The above described crystalline Vorinostat form VI can be prepared by a process comprising heating crystalline Vorinostat form III to a temperature of about 133°C to about 137 ⁰ C, preferably to a temperature of about 135 ⁰ C.

In another embodiment, the present invention encompasses a process for preparing Vorinostat comprising preparing the above described polymorph of Vorinostat potassium salt according to the process of the present invention, and converting it to Vorinostat.

Li another embodiment the present invention provide the use of the above described polymorph of Vorinostat potassium salt to prepare Vorinostat.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the compositions and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

PXRD

Vorinostat potassium salt form A:

XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8

Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions were as follows:

Scan range: 2-55 ° 2-theta;

Scan mode: continuous;

Step size: 0.0190 °; Time per step: 60 seconds; Sample spin: 15 rpm; Sample holder: glass. Radiation: CuK _-03 λ = 1.541874 A

Vorinostat forms III and VI:

X-Ray powder diffractometer Philips X'pert Pro, CuK _n radiation, λ = 1.541874 A, X'Celerator detector active length = 2.122mm, laboratory temperature 22-25 °C, using the analysis conditions as follows:

Scan range: 4 - 40° 2-theta;

Scan mode: continuous;

Step size: 0.0167 °;

Time per step: 21 seconds;

Sample spin: 16 rpm;

Sample holder: stainless steel sample holder with zero-background silicon plate.

Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

DSC

DSC measurements were performed on Differential Scanning Calorimeter DSC823e (Mettler

Toledo). Al crucibles 40 μl with PIN were used for sample preparation. Usual weight of sample was 1.5 - 3.5 mg.

Parameters: temperature range at least 25 ⁰ C - 250°C, heating rate 10°C/min, nitrogen flow 50 ml/min.

TGA

TGA measurements were performed on Thermo gravimetric analyzer TGA851e (Mettler

Toledo). Alumina crucibles 70 μl were used for sample preparation. Usual weight of sample was 7 - 13 mg.

Parameters: temperature range at least 25°C - 250 ⁰ C, 10°C/min; nitrogen flow 50°C/min. Example 1 : Preparation of Vorinostat potassium salt form A

A solution of Potassium hydroxide (5.3 g, 0.095 mol, 5.0 eq.) in methanol (15 mL, 3 vol.) (flask A) was added to a stirred solution of Hydroxylamine hydrochloride (6.6 g, 0.095 mol, 5.0 eq.) in methanol (30 mL, 6 vol) at 0°C-5°C (flask B). The flask A was rinsed with methanol (5 mL, 1 vol.) and added to the suspension in flask B. The suspension was stirred for 15-30 min at 0°C-5°C; the salts were filtered and washed with methanol (10 mL, 2 vol.).

Suberanilic acid methyl ester (5 g, 0.019 mol, 1.0 eq.) was added to the filtrate followed by a solution of Potassium hydroxide (2.5 g, 0.045 mol, 2.35 eq.) in methanol (15 mL, 3 vol.), maintaining the temperature at 0°C-5°C while the measured pH was 12.8. The flask was rinsed with methanol (5 mL, 1 vol.) and maintained at 0°C-5°C until completion. The suspension was filtered at 0°C-5°C. The solid was washed with water (5 mL, 1 vol.) and was allowed to drain under vacuum for 1 hour.

Example 2: Preparation of Vorinostat form III

A solution of Potassium hydroxide (2.7 g, 0.048 mol, 2.5 eq.) in methanol (10 mL, 2 vol.) (flask A) was added to a stirred solution of Hydroxylamine hydrochloride (3.3 g, 0.048 mol, 2.5 eq.) in methanol (20 mL, 4 vol) at 0°C-5°C (flask B). The flask A was rinsed with Methanol (5 mL, 1 vol.) and added to the suspension in flask B. The suspension was stirred for 15-30 min at 0°C-5°C; the salts were filtered and washed with Methanol (5 mL, 1 vol.). 8- oxo-8-(phenylamino)octanoic acid methyl ester ("OPO") (5 g, 0.019 mol, 1.0 eq.) was added to the filtrate followed by a solution of Potassium hydroxide (1.3 g, 0.023 mol, 1.5 eq.) in Methanol (10 mL, 2 vol.) maintaining temperature at 0°C-5°C. The flask was rinsed with Methanol (5 mL, 1 vol.) and the reaction mixture was stirred at the same temperature until completion. The suspension was added to cold water (75 mL, 15 vol.) at 0-5 ⁰ C over 1-2 min and was stirred for 10-15 min at 18-22 ⁰ C. IN Hydrochloric acid was slowly added until pH 7.4, the suspension was cooled to 0-5 ⁰ C and was stirred for 0.5-1.5 h at the same temperature. The solid was filtered and washed twice with water, (10 mL, 10 vol. each) The white to light orange solid was allowed to drain under vacuum for 1 hour

Example 3: Preparation of Vorinostat form VI

Vorinostat form III was heated at 135 ± 2 °C for 1 hour in a drying oven.