WO2012063246A1

WO2012063246A1 - Amorphous form of lurasidone hydrochloride

Info

Publication number: WO2012063246A1
Application number: PCT/IL2011/050009
Authority: WO
Inventors: Ehud Marom; Shai Rubnov
Original assignee: Mapi Pharma Ltd
Current assignee: Mapi Pharma Ltd
Priority date: 2010-11-11
Filing date: 2011-11-10
Publication date: 2012-05-18
Anticipated expiration: 2013-05-11

Abstract

The present invention provides novel amorphous form of lurasidone HC1, pharmaceutical compositions comprising same, methods for their preparation and use thereof as an antipsychotic agent.

Description

properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.

There still remains an unmet need for solid state forms of lurasidone having good physicochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.

SUMMARY OF THE INVENTION

The present invention provides a new amorphous form of lurasidone HCl, pharmaceutical compositions comprising this form, methods for its preparation and use thereof in treating schizophrenia and bipolar disorder.

The present invention is based in part on the unexpected finding that the new amorphous form disclosed herein possesses advantageous physicochemical properties which render its processing and use as a medicament beneficial. The new amorphous form has a higher maximal solubility value in water and acidic media, indicating improved bioavailability as compared with the known crystalline form. Moreover, the amorphous form dissolves more rapidly than the crystalline form in 0.1N HCl, which is of significant pharmaceutical advantage, as lurasidone HCl is typically formulated into an immediate release dosage form, in which the lurasidone active ingredient is mainly absorbed in the acidic medium of the stomach. The new form of the present invention thus has good solubility, bioavailability as well as adequate stability characteristics enabling its incorporation into a variety of different formulations particularly suitable for pharmaceutical utility.

According to one aspect, the present invention provides an amorphous form of lurasidone HCl. In one embodiment, the present invention provides an amorphous form of lurasidone HCl characterized by an X-ray diffraction (XRD) profile substantially as shown in any of Figures 1A, IB, 1C, ID, IE, 2A, 2B, 2C, 3A, 3B, 9A, 9B, 15A, 21A, 27A, 27B, 27C, 28A, 28B, 28C, 28D or 34. Each possibility represents a separate embodiment of the invention. In another embodiment, the present invention provides an amorphous form of lurasidone HCl characterized by a DSC profile substantially as shown in any of Figures 4, 10, 16, 22, 29 or 35. Each possibility represents a separate embodiment of the invention. In yet another embodiment, the amorphous form of lurasidone HCl has a glass transition temperature between about 40°C and about 115°C, for example about 43°C, about 61°C, about 110°C, about 112°C, or about 113°C. Each possibility represents a separate embodiment of the invention. In another embodiment, the amorphous form of lurasidone is characterized by a TGA profile substantially as shown in any of Figures 5, 11, 17, 23, 30 or 36. Each possibility represents a separate embodiment of the invention. In other embodiments, the amorphous form is characterized by an IR spectrum substantially as shown in any of Figures 6, 12, 18, 24 or 31. Each possibility represents a separate embodiment of the invention. In some embodiments, the IR spectrum of the amorphous form of lurasidone HCl comprises characteristic peaks at about 738±4, 776±4, 963±4, 1143±4, 1181±4, 1288±4, 1314±4, 1367±4, 1381±4, 1423±4, 1493±4, 1687±4, 1761±4, 2848±4, 2879±4, 2929±4, and 3417±4 cm^"1. In certain embodiments, the amorphous form of lurasidone HCl is characterized by a Raman spectrum substantially as shown in any of Figures 7, 13, 19, 25, or 32. Each possibility represents a separate embodiment of the invention. In particular embodiments, the Raman spectrum of the amorphous lurasidone HCl comprises characteristic peaks at about 429±4, 518±4, 649±4, 715±4, 916±4, 1028±4, 1135±4, 1185±4, 1274±4, 1326±4, 1386±4, 1455±4, 1565±4, 1765±4, 2884±4, 2944±4, 3072±4, and 3480±4 on \ In certain embodiments, the amorphous form of lurasidone HCl is characterized by an 1H- NMR spectrum substantially as shown in any of Figures 8, 14, 20, 26, 33 or 37. Each possibility represents a separate embodiment of the invention.

In one embodiment, the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:

(a) dissolving lurasidone HCl in a solvent or a mixture of solvents selected from MeOH, DCM:MeOH, EtOH:acetone, MeOH:ACN, MeOH:l,4 dioxane,

MeOH:EtOAc, MeOH:EtOH, MeOH:MEK, MeOH:MTBE and MeOH:THF; and

(b) evaporating the solvent or mixture of solvents so as to precipitate amorphous lurasidone HCl.

In one embodiment, when a mixture of solvents is used, the solvents in the mixture of solvents are at a volume ratio of about 1:1. In other embodiments, the evaporation in step (b) is performed at a room temperature or at a temperature below the boiling point of the solvent or mixture of solvents. In another embodiment, the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:

(a) heating lurasidone HCl to melt under vacuum; and

(b) cooling the melted lurasidone obtained in step (a), so as to provide amorphous lurasidone HCl.

In one embodiment, the cooling in step (b) is selected from fast cooling and slow cooling. Each possibility represents a separate embodiment of the present invention.

In some embodiments, the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the step of grinding crystalline lurasidone HCl with forces sufficient to induce the transformation of crystalline lurasidone HCl to amorphous lurasidone HCl.

In yet another embodiment, the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:

(a) dissolving lurasidone HCl in water, wherein the water further comprises about 5% MeOH; and

(b) removing the water by freeze drying (so as to provide amorphous lurasidone HCl).

In additional embodiments, the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:

(a) dissolving lurasidone HCl in a solvent or mixture of solvents selected from DCM,

DCM:ACN, DCM:MEK, MeOH, MeOH:DCM, MeOH:acetone and MeOH:EtOAc; and

(b) evaporating the solvent or mixture of solvents under vacuum so as to provide amorphous lurasidone HCl.

In one embodiment, when a mixture of solvents is used, the solvents in the mixture of solvents are at a volume ratio of about 1 : 1. In another embodiment, step (b) is performed using rotary evaporator.

In certain embodiments, the present invention provides a pharmaceutical composition comprising the amorphous lurasidone HCl of the present invention as an active ingredient, and a pharmaceutically acceptable carrier. In a particular embodiment, the pharmaceutical composition is in the form of a tablet, suitable for any mode of administration, such as immediate release, slow release, extended release, sustained release, delayed release, controlled release of various orders, and the like. Each possibility represents a separate embodiment of the present invention.

In various embodiments, the present invention provides a pharmaceutical composition comprising the amorphous lurasidone HC1 of the present invention as an active ingredient, and a pharmaceutically acceptable carrier for use in treating schizophrenia or bipolar disorder.

In some embodiments, the present invention provides a method of treating schizophrenia or bipolar disorder comprising administering to a subject in need thereof an effective amount of the amorphous lurasidone HC1 of the present invention, or a pharmaceutical composition comprising the amorphous lurasidone HC1 of the present invention.

In additional embodiments, the present invention provides the use of the amorphous lurasidone HC1 of the present invention for the preparation of a medicament for treating schizophrenia or bipolar disorder.

In various embodiments, the subject is a mammal, such as a human.

Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HC1, obtained by method I using MeOH: 1 ,4 dioxane = 1:1 (panel A), MeOH:ACN =1:1 (panel B), MeOH (panel C), EtOH:acetone = 1:1 (panel D), or DCM:MeOH = 1:1 (panel E). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HC1 Form I (Lurasidone API, panel F).

Figure 2 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HC1, obtained by method I using MeOH:MEK= 1:1 (panel A), MeOH:EtOH =1:1 (panel B), or MeOH:EtOAc = 1:1 (panel C). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HC1 Form I (Lurasidone API, panel D). Figure 3 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by method I using MeOH:THF = 1:1 (panel A) or MeOH:MTBE =1: 1 (panel B). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl Form I (Lurasidone API, panel C).

Figure 4 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous form of lurasidone HCl, obtained by method I from MeOH:EtOAc = 1 :1 (v/v).

Figure 5 illustrates characteristic Thermogravimetric analysis (TGA) profile of an amorphous form of lurasidone HCl, obtained by method I from MeOH:EtOAc = 1:1 (v/v).

Figure 6 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of an amorphous form of lurasidone HCl obtained by method I from MeOH:EtOAc = 1 :1 (v/v).

Figure 7 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous form of lurasidone HCl obtained by method I from MeOH:EtOAc = 1:1 (v/v).

Figure 8 illustrates a characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous form of lurasidone HCl obtained by method I from MeOH:EtOAc = 1:1 (v/v).

Figure 9 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone

HCl, obtained by method II with slow (panel A) or fast (panel B) cooling. Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl From I (Lurasidone API, panel C).

Figure 10 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of amorphous lurasidone HCl, obtained by method II with fast cooling.

Figure 11 illustrates a characteristic Thermogravimetric analysis (TGA) profile of amorphous lurasidone HCl, obtained by method II with fast cooling.

Figure 12 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method II with fast cooling.

Figure 13 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method II with fast cooling.

Figure 14 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method II with fast cooling.

Figure 15 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min; panel A). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl Form I (Lurasidone API, panel E) and lurasidone HCl Form I after milling at 200 rpm for 10, 20 and 30 min (panels D, C and B).

Figure 16 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).

Figure 17 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).

Figure 18 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).

Figure 19 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).

Figure 20 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).

Figure 21 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by method IV (panel A). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl Form I (Lurasidone API, panel B).

Figure 22 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by method IV.

Figure 23 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by method IV.

Figure 24 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method IV

Figure 25 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method IV.

Figure 26 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method IV.

Figure 27 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by method V using the following solvents or mixture of solvents: DCM:MEK = 1:1 (panel A), DCM:ACN = 1:1 (panel B), or DCM (panel C). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl Form I (Lurasidone API, panel D).

Figure 28 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone

HCl, obtained by method V using the following solvents or mixture of solvents: MeOH:EtOAc = 1 : 1 (panel A), MeOH:acetone = 1 :1 (panel B), MeOH:DCM = 1 : 1 (panel C), or MeOH (panel D). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl Form I (Lurasidone API, panel E).

Figure 29 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by method V using MeOH.

Figure 30 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by method V using MeOH.

Figure 31 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method V using MeOH.

Figure 32 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method V using MeOH.

Figure 33 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method V using MeOH.

Figure 34 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.

Figure 35 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.

Figure 36 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.

Figure 37 illustrates characteristic 1H-Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.

Figure 38 shows intrinsic dissolution curves of Form I and amorphous lurasidone HCl in water.

Figure 39 shows intrinsic dissolution curves of Form I and amorphous lurasidone HCl in 0. IN HCl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel amorphous form of 3aR,45^,,7R,7aS)-2- [(( \R,2R)-2- { [4-( 1 ,2-benzisothiazol-3-yl)-piperazin- 1 -yljmethyl} cyclohexyl)methyl] hexahydro-lH-4,7-methanisoindol-l,3-dione hydrochloride. The present invention is further directed to pharmaceutical compositions comprising the amorphous form of the present invention and a pharmaceutically acceptable carrier and its use in treating schizophrenia or bipolar disorder.

The present invention is further directed to methods of preparing the novel amorphous form of the present invention.

Polymorphs are two or more solid state phases of the same chemical compound that possess different arrangement and/or conformation of the molecules. Different polymorphs of an active pharmaceutical compound can exhibit different physical and chemical properties such as color, stability, processability, dissolution and even bioavailability.

One of the important physical properties of a compound used as an active ingredient of a medicament is its solubility in aqueous media, e.g. gastric and intestinal fluids. This may bear consequences on the absorption ability of the compound and hence on its bioavailability. The identification and characterization of various morphic or amorphic forms of a pharmaceutically active compound is therefore of great significance in obtaining medicaments with desired properties including a specific dissolution rate, milling property, bulk density, thermal stability or shelf-life. The novel form of lurasidone HCl disclosed herein possess improved physicochemical properties. For example, the new amorphous form has a higher maximal solubility value in water and acidic media, indicating improved bioavailability as compared with the known crystalline form. Moreover, the amorphous form dissolves more rapidly than the crystalline form in 0.1N HCl, which is of significant pharmaceutical advantage, as lurasidone HCl is typically formulated into an immediate release dosage form, in which the Lurasidone active ingredient is mainly absorbed in the acidic medium of the stomach.

In one embodiment, the present invention provides an amorphous form of lurasidone HCl which is characterized by an X-ray diffraction pattern having a single broad peak expressed between about 15 and about 35 degrees two theta [2Θ°] as is shown in any of Figures 1A, IB, 1C, ID, IE, 2A, 2B, 2C, 3A, 3B, 9A, 9B, 15A, 21A, 27A, 27B, 27C, 28A, 28B, 28C, 28D or 34. Each possibility represents a separate embodiment of the present invention. In some embodiments, the amorphous form is further characterized by its glass transition temperature and by using various techniques including infrared spectroscopy, Raman spectrometry, and thermal analysis (e.g. thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)).

In one embodiment, the amorphous form of lurasidone HCl of the present invention is characterized by a DSC profile substantially as shown in any of Figures 4, 10, 16, 22, 29 or 35. Each possibility represents a separate embodiment of the present invention. In another embodiment, the amorphous form of lurasidone HCl of the present invention is further characterized by a TGA profile substantially as shown in any of Figures 5, 11, 17, 23, 30 or 36. Each possibility represents a separate embodiment of the present invention. In other embodiments, the amorphous form has a glass transition temperature between about 40°C and about 115°C. In some embodiments, the glass transition temperature of amorphous lurasidone HCl is about 43°C. In other embodiments, the glass transition temperature of amorphous lurasidone HCl is about 61°C. In yet other embodiments, the glass transition temperature of amorphous lurasidone HCl is about 110°C. In particular embodiments, the glass transition temperature of amorphous lurasidone HCl is about 112°C. In further embodiments, the glass transition temperature of amorphous lurasidone HCl is about 113°C. In another embodiment, the amorphous lurasidone HCl is characterized by an infrared spectrum substantially as shown in any of Figures 6, 12, 18, 24 or 31 with characteristic peaks at the following wavenumbers: about 738, about 776, about 963, about 1 143, about 1181, about 1288, about 1314, about 1367, about 1381, about 1423, about 1493, about 1687, about 1761, about 2848, about 2879, about 2929, and about 3417 cm^"1. In other embodiments, the amorphous form of lurasidone HCl is characterized by a Raman spectrum substantially as shown in any of Figures 7, 13, 19, 25 or 32 with characteristic peaks at the following wavenumbers: about 429, about 518, about 649, about 715, about 916, about 1028, about 1135, about 1185, about 1274, about 1326, about 1386, about 1455, about 1565, about 1765, about 2884, about 2944, about 3072, and about 3480 cm^"1. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the amorphous form of lurasidone HCl is characterized by an IH-NMR spectrum substantially as shown in any of Figures 8, 14, 20, 26, 33 or 37. Each possibility represents a separate embodiment of the invention.

In other embodiments, the present invention further provides processes for the preparation of amorphous lurasidone HCl. The processes include thermal precipitations by fast or slow cooling, precipitations from saturated solutions, precipitations under high pressure, and precipitations using freeze-drying. Any type of lurasidone can be used as the starting material in the methods Of the present invention. In one embodiment, these processes involve the use of lurasidone, such as crystalline lurasidone HCl (Form I, designated herein "API") as the starting material or any other lurasidone prepared by any methods known in the art, including, for example, the methods described in JP2004224764 (SUMITOMO PHARMA, 2004); WO 2005/009999 (US 7,605,260); JP-A-5-17440 (US 5,532,372 and US 5,780,632) or any other synthetic method. The contents of all of the aforementioned references are hereby incorporated by reference in their entirety. According to one embodiment, the lurasidone HCl starting material is heated until fully melted, preferably under vacuum followed by controlled precipitation by slow/fast cooling. According to another embodiment, the lurasidone HC1 starting material is dissolved in water comprising about 5% MeOH. The water is then removed using freeze drying (lyophilization). According to an alternative embodiment, the lurasidone HC1 starting material is dissolved in a suitable solvent or a mixture of solvents, e.g., at room temperatures or at temperatures below the solvent boiling point. The solvent is then removed by slow or fast evaporation. Suitable solvents include, but are not limited to, acetone, methanol (MeOH), ethanol (EtOH), methylene chloride ((¾(¾), dichloromethane (DCM), acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (EtOAc), methyl ethyl ketone (MEK), methyl t- butyl ether (MTBE), 1,4 dioxane and mixtures thereof including, but not limited to, DCM:MeOH (1:1), EtOH:acetone (1:1), MeOH:ACN (1:1), MeOH:l,4 dioxane (1 :1), MeOH:EtOAc (1:1), MeOH:EtOH (1 :1), MeOH:MEK (1:1), MeOH:MTBE (1:1), MeOH:THF (1 :1), DCM:ACN (1 :1), DCM:MEK (1:1), MeOH:DCM (1:1), MeOH:acetone (1:1) and MeOH:EtOAc (1:1). Each possibility represents a separate embodiment of the invention. In yet another embodiment, the lurasidone starting material is ground using e.g. mortar and pestle until transformation to the amorphous form occurs.

Several non-limiting processes used to prepare amorphous lurasidone HC1 are provided herein.

Methods for "precipitation from solution" include, but are not limited to, evaporation of a solvent or solvent mixture, a concentration method, a slow cooling method, a fast cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, a fusing agent method, and so forth. The solution can be a saturated solution or supersaturated solution, optionally heated to temperatures below the solvent boiling point. The recovery of the forms can be done for example, by filtering the suspension and drying. Alternatively, the solvents may be removed by rotary evaporation at desired temperatures. Techniques for precipitation from a solvent or solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, or freeze drying the solvent mixture.

Within the scope of the present invention are high pressure techniques where the active ingredient is compressed using various forces (e.g. grinding) as is known in the art. Further encompassed by the present invention is a process for preparing amorphous lurasidone HC1 comprising heating crystalline lurasidone HC1 to a melt followed by fast or slow cooling of the melt to obtain amorphous lurasidone HC1.

The novel amorphous form of the present invention is useful as an antipsychotic pharmaceutical for treating schizophrenia or bipolar disorder. The present invention thus provides pharmaceutical compositions comprising the novel amorphous form disclosed herein and a pharmaceutically acceptable carrier. The pharmaceutical amorphous form can be safely administered orally or non-orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual. Typically, the lurasidone HC1 amorphous form of the present invention is administered orally. The pharmaceutical compositions can be formulated as tablets (including e.g. film-coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, and sustained-release preparations as is well known in the art.

Pharmacologically acceptable carriers that may be used in the context of the present invention include various organic or inorganic carriers including, but not limited to, excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts. The pharmaceutical compositions of the present invention may further include additives such as, but not limited to, preservatives, antioxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings.

Suitable excipients include e.g. lactose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride and titanium oxide. Suitable lubricants include e.g. magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc and stearic acid. Suitable binders include e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, a- starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substitutional hydroxypropyl cellulose. Suitable disintegrants include e.g. crosslinked povidone (any crosslinked 1 -ethenyl-2-pyrrolidinone homopolymer including polyvinylpyrrolidone (PVPP) and l-vinyl-2-pyrrolidinone homopolymer), crosslinked carmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cornstarch and the like. Suitable water-soluble polymers include e.g. cellulose derivatives such as hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like. Suitable basic inorganic salts include e.g. basic inorganic salts of sodium, potassium, magnesium and/or calcium. Particular embodiments include the basic inorganic salts of magnesium and/or calcium. Basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogen carbonate, disodiumhydrogenphosphate, etc. Basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogen carbonate, etc. Basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite, aluminahydroxidemagnesium and the like. Basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium hydroxide, etc.

Suitable preservatives include e.g. sodium benzoate, benzoic acid, and sorbic acid.

Suitable antioxidants include e.g. sulfites, ascorbic acid and a-tocopherol. Suitable coloring agents include e.g. food colors such as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2 and the like. Suitable sweetening agents include e.g. dipotassium glycyrrhetinate, aspartame, stevia and thaumatin. Suitable souring agents include e.g. citric acid (citric anhydride), tartaric acid and malic acid. Suitable bubbling agents include e.g. sodium bicarbonate. Suitable flavorings include synthetic substances or naturally occurring substances, including e.g. lemon, lime, orange, menthol and strawberry.

The lurasidone HCl amorphous form of the present invention is particularly suitable for oral administration in the form of tablets, capsules, pills, dragees, powders, granules and the like. A tablet may be made by compression or molding, optionally with one or more excipients as is known in the art. For example, molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

The tablets and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices and the like. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

The present invention provides a method of treating schizophrenia or bipolar disorder comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising the amorphous lurasidone HCl disclosed herein.

"A therapeutically effective amount" as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one embodiment, the therapeutic benefit is inducing an antipsychotic effect thus treating disorders such as schizophrenia and bipolar disorder. In additional embodiments, the lurasidone HCl amorphous form of the present invention are used for the preparation of an antipsychotic medicament. The present invention further provides the administration of the lurasidone HC1 amorphous form of the present invention in combination therapy with one or more other active ingredients. The combination therapy may include the two or more active ingredients within a single pharmaceutical composition as well as the two or more active ingredients in two separate pharmaceutical compositions administered to the same subject simultaneously or at a time interval determined by a skilled artisan.

The principles of the present invention are demonstrated by means of the following non- limiting examples.

EXAMPLES

Example 1: General Preparation Methods of Lurasidone HC1 Amorphous Form

1. Reagents

Acetonitrile, HPLC grade, Sigma, Lot No.07278PH;

Ethanol, HPLC grade, Sigma, Lot No.11085CH;

Dichloride methane, Alfa Aesar, HPLC grade, Lot No. C27S008;

Methanol, AR, SCRC, Lot No. T20090912; or HPLC grade, Merck, Lot No. SF1SF61611;

Ethyl Acetate, AR, Yixing Secondary Chemical Company, Lot No.090607 or 070501;

Isopropyl alcohol, AR, Sinopharm Chemical Reagent Co. Ltd, Lot No.T20090813;

Acetone, AR, Sinopharm Chemical Reagent Co. Ltd, Lot No.090104;

tert-Butyl methyl ether, HPLC grade, Fluka, Lot No. 1359496;

THF, AR, Yixing Secondary Chemical, Lot No. 090901;

1-Butanol, AR, SCRC, Lot No. T20080818;

MEK, AR, SCRC, Lot No. T20090724;

HC1, AR, Sinopharm Chemical Reagent Co. Ltd, Lot No. 10011018;

KH2PO4, AR, Sigma, Lot No. 0001394691;

NaOH, AR, Shanghai LingFeng Chemical Reagent Co. Ltd, Lot No. 081118;

NaCl, AR, Shanghai LingFeng Chemical Reagent Co. Ltd, Lot No. 090113.

2. Instruments Sartorius CP 225D Balance

ELGA Water Purification Equipment

Mettler Toledo DSC 1

Mettler Toledo TGA/DSC 1

Rigaku D/MAX 2200 X-ray powder diffractometer

Thermo Nicolet 380 FT-IR

Nikon LV100 Polarized Light Microscopy

Eyela FDU-1100 freeze dryer

NMR Varian 400

Fritsch Planetary mono mill Pulverisette-6

Jobin Yvon LabRam-lB FT-RamanAgilent 1260 series HPLC

Mettler-Toledo MX5 Balance

TA Q5000 TGA

SOTAX Dissolution Testing System

DVS Advantage 1

Shanghai ShanYue Scientific Instrument Co., Ltd, YP-2 Hydraulic Press 3. XRPD, DSC, and TGA methods

3.1 XRPD method

Details of XRPD method used in the tests are mentioned below:

- X-ray Generator: Cu, ka,

- Tube Voltage: 40 kV, Tube Current: 40 mA.

- DivSlit: 1 deg.

- DivH.L.Slit: 10 mm

- SctSlit: 1 deg.

- RecSlit: 0.15 mm

- Monochromator: Fixed Monochromator

- Scanning Scope: 2-40 deg. - Scanning Step: 10 deg/min

3.2 DSC and TGA methods

Details of DSC method used in the tests are mentioned below:

- Heat from 30 °C to 350 °C at 10 °C /min

Details of DSC (Topem) method used in the tests are mentioned below:

- Heat from 0 °C to 270 °C at 2 °C /min

Details of TGA method used in the tests are mentioned below:

- Heat from 30 °C to 400 °C at 10 °C /min

3.3 Polarized light microscope

Details of polarized light microscope method used in the tests are mentioned below:

- Nikon L V 100POL equipped with 5 megapixel CCD

- Physical Lens: 50 X

3.4 FT-IR and FT-Raman method

Details of FT-IR method used in the tests are mentioned below:

- No. of scan: 32

- Time for collection: 38 s

- Scan Range: 400-4000 cm^"1

- Resolution: 4

Details of FT-Raman method used in the tests are mentioned below:

- Laser wave: 632.8 nm

- Power: 1 mW

- Resolution: 1 cm^"1

- Time for integration: 50 s

3.5 HPLC method

The HPLC method used in the present studies is detailed in the Table below. Typical retention time of Lurasidone HC1 is 10.9 min. Instrument Agilent 1260 HPLC Series

Column X Bridge CI S (4.6 x 250 mm) 5μιη

Time(min) A B

0 10 90

Mobile phase gradient

3 10 90

A: ACN

8 90 10

B: 0.1 %TFA iu water

18 90 10

20 10 90

Colmim temperature Ambient

Flow rate 0.8 mL/aiin

Run time 20 min

Post time 10 min

Diluents: ACN : 0.1 % TFA in water = 1: 1 (v v)

Detector wavelength 232 run

4. General Preparation Methods

4.1 Method I: Slow precipitation from saturated solutions

Solutions of lurasidone HCl (Batch No. B174-065A1) in different solvents were prepared and filtered through 0.22 μηι filter into clean vessels. Solvent was then evaporated at 25 °C or 50 °C. Amorphous lurasidone HCl was identified by this method, as set forth in the Examples below.

4.2. Method II: Thermal heating/cooling

Lurasidone HCl (Batch No. B174-065A1) was heated to melt under vacuum. The lurasidone melt was then rapidly or slowly cooled. Amorphous lurasidone HCl was identified by this method, as set forth in the Examples below.

4.3 Method III: Grinding

Lurasidone HCl (Batch No. B 174-06 A 1) was milled by using planetary mono mill at 200 rpm for 200 min. Amorphous lurasidone HCl was identified by this method, as set forth in the Examples below.

4.4 Method IV: Lyophilization

Lurasidone HCl (Batch No. B174-065A1) was dissolved in water with 5 % MeOH. The water was then removed by freeze drying. Amorphous lurasidone HCl was identified by this method, as set forth in the Examples below. 4.5 Method V: Fast precipitation from saturated solutions

Saturated solutions of lurasidone HC1 (Batch No. B174-065A1) in different solvents/mixture of solvents were prepared at room temperatures. The solvents/mixture of solvents were then removed by rotary evaporator below 50 °C. Amorphous lurasidone HC1 was identified by this method, as set forth in the Examples below.

Example 2: Amorphous Lurasidone HC1 (Method I)

General method I was performed. Thus, Lurasidone HC1 (Batch No. B174-065A1) was dissolved in DCM:MeOH = 1:1 (v/v), EtOH:acetone = 1:1 (v/v), MeOH, MeOH:ACN = 1:1 (v/v), MeOH:l,4 dioxane = 1:1 (v/v), MeOH:EtOAc =1:1 (v/v), MeOH:EtOH = 1:1 (v/v), MeOH:MEK = 1 :1 (v/v), MeOH:MTBE = 1:1 (v/v) or MeOH:THF = 1 :1 (v/v) and filtered through 0.22 um filter into clean vessels. The solvents or mixture of solvents were then evaporated at 25 °C. The amorphous lurasidone HC1 obtained by this method was characterized by a broad X-ray diffraction peak between about 15 and about 35 [20°] characteristic of an amorphous powder (Figure 1, panels A-E; Figure 2, panels A-C; and Figure 3, panels A-B). Figure 4 illustrates a characteristic DSC profile of a sample prepared from MeOH:EtOAc =1:1 (v/v). The glass transition temperature of the amorphous lurasidone HC1 prepared by this method was found to be 42.84°C. Figure 5 illustrates a characteristic TGA profile with about 2.5% weight loss from 39°C to 154°C (residual solvents) and about 5.9% weight loss from 154°C to 268°C. Figure 6 illustrates a characteristic IR spectrum with peaks at about 738, 775, 963, 1040, 1143, 1181, 1263, 1288, 1315, 1369, 1424, 1493, 1686, 1761, 2448, 2879, 2930, and 3408 cm^"1. Figure 7 illustrates a characteristic FT-Raman spectrum with peaks at about 190, 436, 521, 655, 715, 836, 920, 1028, 1135, 1185, 1271, 1326, 1383, 1458, 1565, 1765, 2798, 2866, 2944, 3070, and 3484 cm⁴. The residual solvents (about 0.47% MeOH and 1.88% EtOAc) were calculated according to the NMR spectrum (Figure 8).

Example 3: Amorphous Lurasidone HC1 (Method II)

General method II was performed. Thus, Lurasidone HCL (Batch No. B 174-065 Al) was heated to melt under vacuum followed by its slow or fast cooling to afford amorphous lurasidone. The X-ray diffraction of the amorphous lurasidone HC1 obtained is shown in Figure 9, panels A and B. Figure 10 illustrates a characteristic DSC profile of the amorphous lurasidone HC1 prepared by fast cooling of the lurasidone HC1 melt with glass transition temperature of 61.31 °C. Figure 11 illustrates a characteristic TGA profile with a weight loss of about 1.97% between 40 and 150 °C and weight loss of about 1.6% between 158 and 240 °C. Figure 12 illustrates a characteristic IR spectrum with peaks at about 737, 772, 964, 1005, 1144, 1182, 1260, 1287, 1312, 1363, 1394, 1424, 1492, 1691, 1765, 2851, 2880, 2925, and 3436 cm^"1. Figure 13 illustrates a characteristic FT-Raman spectrum with peaks at about 1553, 1766, 1863, 1973, and 2085 cm^"1, and Figure 14 shows a characteristic NMR spectrum. The spectroscopic analyses suggest that the amorphous lurasidone HCl undergoes degradation during the melting process at high temperatures.

Example 4: Amorphous Lurasidone HCl (Method III)

General method III was performed. Thus, Lurasidone HCl (Batch No. B174-065A1) was milled by using planetary mono mill at 200 rpm for 200 min to afford amorphous lurasidone HCl. Figure 15 (panel A) shows a characteristic XRPD of the amorphous form obtained by this method. Figure 16 illustrates a characteristic DSC profile with glass transition temperature of 113.06 °C. Figure 17 illustrates a characteristic TGA profile with a weight loss of about 3.15% between 33 and 151 °C (residual solvent) and weight loss of 5.3% between 152 and 270 °C. Figure 18 illustrates a characteristic IR spectrum with peaks at about 739, 772, 956, 1136, 1 182, 1264, 1289, 1317, 1367, 1383, 1425, 1494, 1687, 1767, 2439, 2879, 2927, and 3417 cm^"1. Figure 19 illustrates a characteristic FT-Raman spectrum with peaks at about 197, 340, 457, 525, 642, 715, 764, 839, 916, 1025, 1075, 1188, 1286, 1326, 1380, 1461, 1562, 1765, 2867, 2947, and 3070 cm^"1, and Figure 20 shows a characteristic NMR spectrum. The NMR spectrum does not show any residual solvent. Without being bound by any theory or mechanism of action, it is contemplated that the loss of weight of 3.15% in the TGA profile is assigned to adsorbed water.

Example 5: Amorphous Lurasidone HCl (Method IV)

General method IV was performed. Thus, Lurasidone HCl (Batch No. B174-065A1) was dissolved in water with about 5 % MeOH. The water was then removed by freeze drying (lyophilization). Figure 21 (panel A) shows a characteristic XRPD of the amorphous form obtained by this method. Figure 22 illustrates a characteristic DSC profile with glass transition temperature of 112.28 °C. Figure 23 illustrates a characteristic TGA profile with a weight loss of about 3.6% between 33 and 151 °C (residual solvent) and weight loss of 5.4% between 152 and 271 °C. Figure 24 illustrates a characteristic IR spectrum with peaks at about 739, 768, 963, 1144, 1182, 1264, 1288, 1316, 1364, 1383, 1424, 1493, 1688, 1761, 2443, 2852, 2879, 2929, and 3424 cm^"1. Figure 25 illustrates a characteristic FT-Raman spectrum with peaks at about 211, 429, 518, 649, 715, 793, 916, 1028, 1135, 1185, 1274, 1326, 1386, 1455, 1565, 1765, 2868, 2884, 2944, 2980, 3072, and 3480 cm^"1, and Figure 26 shows a characteristic NMR spectrum. The NMR spectrum shows 0.36% residual MeOH.

Example 6: Amorphous Lurasidone HCl (Method V) General method V was performed. Thus, Lurasidone HC1 (Batch No. GVK-BIO-B174- 065A1) was dissolved in DCM, DCM:ACN=1:1 (v/v), DCM:MEK=1:1 (v/v), MeOH, MeOH:DCM=l:l (v/v), MeOH:acetone=l:l (v/v) or MeOH:EtOAc=l :l (v/v) to obtain saturated solutions at room temperatures. The solvents/mixture of solvents were then removed by rotary evaporator below 50 °C. Figures 27 (panels A-C) and 28 (panels A-D) show characteristic XRPD of the amorphous form obtained by this method. Figure 29 illustrates a characteristic DSC profile of a sample obtained from a MeOH solution. The glass transition temperature of the amorphous form obtained by this method is 110.36 °C. Figure 30 illustrates a characteristic TGA profile with a weight loss of about 4.5% between 37 and 150 °C (residual solvent) and weight loss of 5.9% between 150 and 260 °C. Figure 31 illustrates a characteristic IR spectrum with peaks at about 738, 776, 963, 1029, 1143, 1181, 1283, 1288, 1314, 1367, 1381, 1423, 1493, 1687, 1761, 2435, 2848, 2879, 2929, and 3417 cm^"1. Figure 32 illustrates a characteristic FT-Raman spectrum with peaks at about 204, 426, 525, 649, 715, 836, 920, 1025, 1132, 1181, 1268, 1326, 1383, 1458, 1565, 1768, 2887, 2944, 3072, and 3480 cm^"', and Figure 33 shows a characteristic NMR spectrum. The NMR spectrum shows 0.33 % residual MeOH.

Method V was scaled up. About 100 mg/ml solution of Lurasidone HC1 was prepared with MeOH at room temperature. Then the solvent was removed by rotary evaporator at 50 °C. The powder was dried in vacuum oven at 40 °C for 24 hrs. The dry powder was characterized by XRPD (Figure 34), DSC (Figure 35), TGA (Figure 36) and NMR (Figure 37). The results are consistent with Figures 28, 29, 30 and 33. As per the DSC (topem) results, the glass transition temperature of the amorphous form is 110.4 °C. The residual MeOH is less than 0.3 % based on NMR result.

Example 7: Hygroscopicity of Form I and amorphous Lurasidone HC1

The sorption/desorption profiles of Lurasidone HC1 (Form I and amorphous) were tested at 25 °C under 0-90 % relative humidity. The results are listed in Table 1 (Form I) and Table 2 (amorphous). As per the DVS results, Form I could be classified as slightly hygroscopic (0.90% weight gain from 0 to 90% RH), and the amorphous form could be classified as hygroscopic (13.13 % weight gain from 0 to 90 %RH) according to the following criterion:

(i) Deliquescent: sufficient water is absorbed to form a liquid.

(ii) Very hygroscopic: increase in mass is equal to or greater than 15 %.

(iii) Hygroscopic: increase in mass is less than 15 % and equal to or greater than 2 %.

(iv) Slightly hygroscopic: increase in mass is less than 2 % and equal to or greater than

0.2 %.

(v) Non-hygroscopic: increase in mass is less than 0.2 %.

Table 1 : DVS Isoterm Analysis (Form I)

Target

Sorption Besorptioii ¾¾t «sis

Cycle 1 0.0 00303

10.0 0.0721 01116 0.0394

2M 0.1369 0.1744 0.0374

mo 0.2043 0.3467 0.0424

0.2753 0.3100 0.0347

50.0 0.3458 0.3829 0.0371

60 0 0.4295 0.4SS5 OJQSOI

mo 03465 B.5SS3 OJ0 1S

mo ^■ami 0.7054 0.0131

^■ mo 0.9015 0.9015

Table 2: DVS Isotherm Analysis (Amorphous)

Target

% W!Fo Sorption DesoiTJti ji

0.0 0.00 QM

iao 1.24 3.45 2,20

mo 2.05 5.01 2,96

30J3 2.67 6.06 3.3»

40.Q 3.30 6.50 3.20

60.0 5.14 7.81 2,68

mo 730 ^■8.77 1.47

mo 9.70 10L« 0.75

90.0 LIB 13.13

Example 8: Aqueous solubility

Testing media used was: water, pH 1.2, 4.5, 6.8, 7.4 USP buffers, 0.01 N HCl, 0.1 N

HCl, SGF (simulated gastric fluid), FaSSIF (Fasted State Simulated Intestinal Fluid), and FeSSIF (Fed State Simulated Intestinal Fluid). Form I and Amorphous Lurasidone HC1 were added into different media with shaking for 24 hours at 25 °C. Then, the saturated solutions were filtered and the concentration of tes compound in filtrate was determined by HPLC. The final pH was tested. The results are listed in Table 3. As SHOWN, both Form I and amorphous Lurasidone HC1 showed better solubility in water, 0.01 N HC1, 0.1 N HC1 and showed poor solubility in PH 6.8 and PH 7.4 UPS buffer (<LOQ). Form I showed a little better solubility than amorphous form in most of the media except water and 0.0 IN HC1. The fact that amorphous Lurasidone HC1 has high solubility rate in water and acidic media suggests improved bioavailability of the amorphous form in comparison with the known crystalline form.

Table 3 - Aqueous Solubility

Example 9 - Intrinsic dissolution rate

About 100 mg lurasidone HCI (Form I and amorphous) was placed into the intrinsic dissolution apparatus (diameter: 0.795 cm) and the samples were compressed for 1 minute with 4 tons compression force to make the material compact. The intrinsic dissolution apparatus was slid into the dissolution test chuck, and tightened. The shaft in the spindle was adjusted to ensure the exposed surface of the compacted tablet is 3.8 cm from the bottom of the vessel when lowered. The temperature of chamber water was set at 37 °C, the shaft rotation as 100 rpm and the sampling time points as 2, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min. As with the results of aqueous solubility at 25 °C for 24 hrs, Form I and amorphous Lurasidone showed poor solubility in PH 6.8 USP buffer which are lower than LOQ (<2.51ug). Thus, pH 6.8 USP buffer was removed from intrinsic dissolution rate test, and water and 0.1 N HC1 was used as dissolution medium. 5 mL of solution was sampled at each time point. The samples were filtered with 0.45 um filter. The first 1 mL of filtrate was discarded. The concentrations of the filtrates was analyzed by HPLC.

The results are listed in Table 4 and in Figures 38 and Figure 39. As shown, thee amorphous form dissolved faster than Form I in 0.1 N HC1 while Form I dissolved faster than amorphous form in water. Some points within the first 10 min or 20 min whose concentration was lower than LOQ were not used for calculation. The results show that the amorphous form dissolved faster than the crystal form in 0.1N HC1. This is of significant pharmaceutical advantage, as lurasidone HC1 is typically formulated into an immediate release dosage form, in which the lurasidone is mainly absorbed in the acidic medium of the stomach.

Table 4: Intrinsic Dissolution Rate

While the present invention has been particularly described, persons skilled in the art will appreciate that many variations and modifications can be made. Therefore, the invention is not to be construed as restricted to the particularly described embodiments, and the scope and concept of the invention will be more readily understood by reference to the claims, which follow.

Claims

1. An amorphous form of lurasidone HCl.

2. The amorphous lurasidone HCl according to claim 1, characterized by an X-ray diffraction profile substantially as shown in any of Figures 1A, IB, 1C, ID, IE, 2A, 2B, 2C, 3A, 3B, 9A, 9B, 15A, 21A, 27A, 27B, 27C, 28A, 28B, 28C, 28D or 34.

3. The amorphous lurasidone HCl according to claim 1, characterized by a DSC profile substantially as shown in any of Figures 4, 10, 16, 22, 29 or 35.

4. The amorphous lurasidone HCl according to claim 1 having a glass transition temperature between about 40°C and about 11 °C.

5. The amorphous lurasidone HCl according to claim 4 having a glass transition temperature at about 43°C, about 61°C, about 110°C, about 112°C, or about 113°C.

6. The amorphous lurasidone HCl according to claim 1 characterized by a TGA profile substantially as shown in any of Figures 5, 11, 17, 23, 30 or 36.

7. The amorphous lurasidone HCl according to claim 1, characterized by an IR spectrum substantially as shown in any of Figures 6, 12, 18, 24 or 31.

8. The amorphous lurasidone HCl according to claim 7, wherein the IR spectrum comprises characteristic peaks at about 738±4, 776±4, 963±4, 1143±4, 1181±4, 1288±4, 1314±4, 1367±4, 1381±4, 1423±4, 1493±4, 1687±4, 1761±4, 2848±4, 2879±4, 2929±4, and 3417±4 cm^-1.

9. The amorphous lurasidone HCl according to claim 1, characterized by a Raman spectrum substantially as shown in any of Figures 7, 13, 19, 25, or 32.

10. The amorphous lurasidone HCl according to claim 9, wherein the Raman spectrum comprises characteristic peaks at about 429±4, 518±4, 649±4, 715±4, 916±4, 1028±4, 1135±4, 1185±4, 1274±4, 1326±4, 1386±4, 1455±4, 1565±4, 1765±4, 2884±4, 2944±4, 3072±4, and 3480±4 cm^"1.

11. The amorphous lurasidone HCl according to claim 1, characterized by a Nuclear Magnetic Resonance (NMR) spectrum substantially as shown in any of Figures 8, 14, 20, 26, 33 or 37.

12. A pharmaceutical composition comprising as an active ingredient the amorphous lurasidone HCl according to any one of claims 1 to 1 1 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12 in the form of a tablet.

14. The pharmaceutical composition according to claim 12 for use in treating schizophrenia or bipolar disorder.

15. A method of treating schizophrenia or bipolar disorder comprising administering to a subject in need thereof an effective amount of a composition comprising the amorphous lurasidone HCI according to any one of claims 1 to 11.

16. The method according to claim 15, wherein the subject is a human.

17. Use of the amorphous lurasidone HCI according to any one of claims 1 to 11 for the preparation of a medicament for treating schizophrenia or bipolar disorder.

18. An amorphous lurasidone HCI according to any one of claims 1 to 11 for use in the treatment of schizophrenia or bipolar disorder.

19. A process for preparing amorphous lurasidone HCI according to any one of claims 1 to 11, comprising the steps of:

(a) dissolving lurasidone in a solvent or a mixture of solvents selected from MeOH, DCM:MeOH, EtOH:acetone, MeOH:ACN, MeOH: 1,4 dioxane, MeOH:EtOAc,

MeOH:EtOH, MeOH:MEK, MeOH:MTBE and MeOH:THF; and

(b) evaporating the solvent or mixture of solvents so as to precipitate amorphous lurasidone HCI.

20. The process according to claim 19, wherein a mixture of solvents is used, wherein the solvents in the mixture of solvents are at a volume ratio of about 1 :1.

21. A process for preparing amorphous lurasidone HCI according to any one of claims 1 to 1 1, comprising the steps of:

(a) heating lurasidone HCI to melt under vacuum; and

(b) cooling the melted lurasidone obtained in step (a), so as to provide amorphous lurasidone HCI.

22. The process according to claim 21, wherein the cooling step (b) comprises fast cooling or slow cooling.

23. A process for preparing amorphous lurasidone HCI according to any one of claims 1 to 11, comprising the step of grinding crystalline lurasidone HCI with forces sufficient to induce the transformation of said crystalline lurasidone to amorphous lurasidone HCI.

24. A process for preparing amorphous lurasidone HCl according to any one of claims 1 to 11 comprising the steps of:

(b) removing the water by freeze drying so as to provide amorphous lurasidone HCl.

25. A process for preparing amorphous lurasidone HCl according to any one of claims 1 to 11 , comprising the steps of:

(a) dissolving lurasidone HCl in a solvent or mixture of solvents selected from DCM, DCM:ACN, DCM:MEK, MeOH, MeOH:DCM, MeOH:acetone and MeOH:EtOAc; and

26. The process according to claim 25, wherein a mixture of solvents is used, wherein the solvents in the mixture of solvents are at a volume ratio of about 1:1.