CROSS REFERENCE TO RELATED PATENT APPLICATION

[0001] This patent application claims the benefit of U.S. Provisional Patent

Application No. 61/498,818, filed June 20, 2011, the disclosures of which are hereby incorporated by reference.

FIELD OF INVENTION

[0002] The present invention is directed to Paliperidone oleate, solid state forms thereof, and methods of preparation thereof.

BACKGROUND OF THE INVENTION

[0003] Paliperidone, 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l-piperidyl]- ethyl]-7-hydroxy-4-methyl-l,5-diazabicyclo[4.4.0]deca-3,5-di en-2-one, is a 5-HT antagonist belonging to the chemical class of benzisoxazole derivatives. It is a racemic mixture having the following structural formula:

Paliperidone

[0004] Paliperidone is a metabolite of Risperidone. It is marketed under the trade name, Invega®. Paliperidone is an anti-psychotropic agent approved in the United States for the treatment of schizophrenia.

[0005] Processes for the synthesis of Paliperidone, are described in U.S.

Patent No. 5,158,952 ("US '952") and PCT application No. WO 96/23784 ("WO '784"). US '952 and WO '784 also describe a process for the synthesis of a precursor of Paliperidone, (3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2- a]- pyrimidine-4-one).

[0006] Paliperidone palmitate ((9R,S)-3-[2-[4-(6-Fluoro-l,2-benzisoxazol-

3-yl)piperidin- 1 -yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1 ,2-a]- pyrimidin-9-yl hexadecanoate) suspension for injection was developed as a monthly intramuscular injectible suspension for the treatment of schizophrenia. The extremely low solubility of paliperidone palmitate allows the formulation of an extended release product where the isotonic aqueous buffer solvent penetrates the muscle tissue and the undissolved paliperidone palmitate particles are localized at the site as a poorly soluble agglomerate. Paliperidone palmitate purportedly dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation.

SUMMARY OF THE INVENTION

[0007] The present invention provides paliperidone oleate, a solid state form thereof, and processes for preparing paliperidone oleate and a solid state form of paliperidone oleate.

[0008] The invention further provides pharmaceutical compositions comprising the below described paliperidone oleate. This pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable excipient.

[0009] The invention further provides the use of the paliperidone oleate described below for the manufacture of a medicament for the treatment of schizophrenia.

BRIEF DESCRIPTION OF THE FIGURES

[00010] Figure 1 shows a DSC thermogram of Paliperidone oleate, as obtained in Example 2.

[00011] Figure 2 shows a DSC thermogram of Paliperidone oleate, as obtained in Example 3. [00012] Figure 3 shows an XRD diffractogram of Paliperidone oleate, as obtained in Example 2.

[00013] Figure 4 shows an XRD diffractogram of Paliperidone oleate, as obtained in Example 3.

[00014] Figure 5 shows a 1H NMR spectrum of Paliperidone oleate.

DETAILED DESCRIPTION OF THE INVENTION

[00015] A solid state form may be referred to herein as being characterized by graphical data "as shown in" a Figure. Such data include, for example, powder X-ray diffractograms (XRD) and solid state nuclear magnetic resonance (NMR) spectra. The skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which factors are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirming whether the two sets of graphical data characterize the same solid state form or two different solid state forms. The skilled person would understand that a solid state form referred to herein as being characterized by graphical data "as shown in" a Figure would include any solid state form of the same chemical characterized by graphical data substantially similar to the Figure except for such small variations, the potential occurrence of which is well known to the skilled person.

[00016] The present invention provides paliperidone oleate, as shown in the following formula:

[00017] The paliperidone oleate of the present invention can be in a solid state form.

[00018] The paliperidone oleate and the solid state form of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

[00019] The present invention also provides a crystalline form of

Paliperidone oleate designated Form A. Form A can be characterized by data selected from: a powder XRD pattern with peaks at 4.8°, 7.2°, 19. F, 19.4°, 20. F, 20.8°, and 24.0° ± 0.2° 2Θ; a powder XRD pattern as shown in figures 2.1 or 2.2; and combinations thereof.

[00020] Form A may have a melting point of between about 84 and 88°C.

The mp of the oleate is substantially lower than that of the palmitate and if the particle size of both esters is reduced to <1 μιη, the trend of particle agglomeration is much more pronounced for the oleate compared to the palmitate. The

agglomeration tendency together with the lower mp suggest that the oleate will not have to be micronized in order to achieve the required bioavailability.

[00021] The above described Paliperidone oleate and the crystalline form can be used to prepare Paliperidone or Paliperidone palmitate, for example by hydrolyzing the oleate group, for example by reacting Paliperidone oleate with an aqueous solution, for example, an aqueous solution of acid. [00022] The present invention provides a process for preparing Paliperidone

or Paliperidone palmitate comprising preparing the above describes Paliperidone

oleate by the process of the present invention, and converting it to Paliperidone or

Paliperidone palmitate.

[00023] The present invention further encompasses 1) a pharmaceutical

composition comprising Paliperidone oleate, as described above, and at least one

pharmaceutically acceptable excipient and 2) the use of the above described

Paliperidone oleate, in the manufacture of a pharmaceutical composition. The

pharmaceutical composition can be useful for the treatment of schizophrenia.

[00024] 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

composition 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.

1H-NMR Spectroscopy

Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS, 400 MHz

Differential Scanning Calorimetry (DSC)

Apparatus: Mettler Toledo DSC 822E coupled with a Mettler Toledo Gas-Flow-

Controller TS0800GC1 (Mettler-Toledo GmbH, Giessen, Germany)

Aluminum crucible: 40 μΐ.

Lid: perforated

Temperature range: 30 °C to 300 °C

Heating rate: 10°C/ min

Nitrogen flush: 40 mL / min

Software: ST ARe Version. 8.10

Interpretation: Endothermic modus X-Ray Powder Diffraction

The sample was analyzed on a D8 Advance X-ray powder diffractometer (Bruker-AXS, Karlsruhe, Germany). The sample holder was rotated in a plane parallel to its surface at 20 rpm during the measurement. Further conditions for the measurements are summarized below. The raw data were analyzed with the program EVA (Bruker-AXS, Germany).

EXAMPLES

Crystalline paliperidone oleate was prepared and characterized by means of HPLC/UV, ¹ H-NMR spectroscopy, differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD).

The crystal form is characterized by a m.p. of from 84 to 88°C (peak in DSC) and by the following characteristic X-ray powder diffraction (XRPD) angles (°2Θ): 4.85, 7.28, 19.11, 19.45, 20.12, 20.85 and 23.95 (± 0.2).

Example 1 : Preparation of Paliperidone Oleate Form A

Paliperidone (50 g, 117.2 mmol) was dissolved in 500 ml tetrahydrofuran and 20 ml pyridine. While the solution was heated to reflux, 83.01 g (234.5 mmol, 2 eq.) were added dropwise and the mixture was refluxed for 20 h. The mixture was allowed to cool to r.t. followed by addition of 400 ml water and 100 ml brine. The aqueous phase was removed and the organic phase was washed with (3 X 700 ml). The organic layer was then dried over MgS0 ₄ and the solvent was evaporated to provide a residue. To the residue, 30 ml isopropanol and 30 ml diisopropyl ether were added and the resulting solution was kept overnight at 4°C. A solid precipitated and was dissolved in n-hexane and purified by flash chromatography using an Interchim puriflash Uptiprep silica 50 μιη cartridge.

Example 2: Preparation of Paliperidone Oleate Form A

Oleic acid (4.2 g, 14.87 mmol) and N,N'-dicyclohexylcarbodiimide (3 g, 14.5 mmol) were dissolved in 230 ml dichloromethane and the solution was stirred at r.t. After 10 minutes, 5 g paliperidone (11.7 mmol) and 180 mg N,N-dimethylamino- pyridine was added, and the mixture was stirred at r.t. for 24 h. The mixture was then washed sequentially with 100 ml water, with a solution of 30 ml saturated NaHCC"3 in 70 ml of water. The combined aqueous phase was extracted with dichloromethane (2 x 50 ml). The organic extracts were combined, dried over MgS0 ₄ and the solvent was evaporated. To the oily residue, 80 ml diethylether was added and the solution was stored at 4°C overnight. A white solid (2.49 g, chemical purity: 88%) precipitated and was dissolved in n-hexane and purified by flash chromatography using an

Interchim puriflash Uptiprep silica 50 μιη cartridge.

Example 3: Preparation of Paliperidone Oleate Form A

Paliperidone (5 g, 11.7 mmol) and 3.5 g oleic acid were dissolved in 120 ml tetrahydrofuran and the solution was stirred at r.t. for 10 min. Benzoylchloride (1.43 ml) was added dropwise, followed by triethylamine and Ν,Ν-dimethylaminopyridine . The mixture was stirred for 22 h at r.t. Thereafter 250 ml water was added and the mixture was extracted with dichloromethane (3 x 150 ml). The organic layers were combined and dried over NaS0 ₄ . The solvent was evaporated and the oily residue was dissolved in 20 ml diethylether and stirred at 40°C. After addition of 30 ml n-hexane, the solution was cooled to 0°C and 7.3 g of a white solid precipitated and was isolated by filtration.