WO2012114325A1 - Polymorphs of asenapine maleate - Google Patents

Abstract

The present invention provides novel crystalline and amorphous forms of asenapine maleate, pharmaceutical compositions comprising same, methods for their preparation and use thereof as an antipsychotic.

Description

POLYMORPHS OF ASENAPINE MALEATE

FIELD OF THE INVENTION

The present invention relates to a crystalline form and an amorphous form of asenapine maleate, pharmaceutical compositions comprising same, and use thereof as antidepressants.

BACKGROUND OF THE INVENTION

Asenapine is a compound having a CNS-depressant activity (Boer et al, Drugs of the Future, 18(12), 1117-1 123, 1993) which may be used in the treatment of depression (WO 99/32108). Asenapine maleate (WO 95/23600) is marketed under the brand name SAPHRIS in the USA and is approved for the acute treatment of schizophrenia, and acute treatment of manic or mixed episodes associated with bipolar disorder in adults.

Asenapine maleate is chemically named (3aRS,12bRS)-5-Chloro-2-methyl- 2,3,3a,12b-tetrahydro- lHdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1 :1) and is represented by the following chemical structure:

The asenapine molecule is a trans-racemate where both enantiomers within this racemate contribute equally to the clinical effect of asenapine.

Asenapine and processes for its preparation are disclosed in US 4,145,434; EP

1710241 ; WO 2006/106136; Organic Process Research & Development 2008, 12, 196- 201 : WO 2007/046554: WO 2008/003460: WO 2008/08101 0: WO 2009/008405 : and WO 2009/087058.

A new crystalline or amorphous form of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing 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, compatibility, 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.

Funke et al. (Arzneim.-Forsch/Drug Res.. 40. 536-539. 1 990) discloses the phy sico-chemical properties and stability of asenapine maleate. In particular, the UV, 1R. NMR and mass spectra and the X-ray analysis, thermal properties, sol ubilities and partition coefficient were measured. Single X-ray analy sis showed a monoclinic symmetry (P2 ,/n space group) with a=l 7.762 (4), b= l 0.994 (2) and c= l 0.31 0 (3 ) A and β=1 01 .00° (2 ).

US 7.741 .358 (US 2008/0200671 ; WO 2006/ 1 061 35 ) discloses an orthorhombic crystalline form of asenapine maleate. which contains 1 0% or less of another crystalline form. The crystalline form is characterized by an X-ray pow der diffraction pattern obtained with Cu a radiation with peaks at values of 2-theta (2Θ) of 10.5°. 15.7°. 1 8.3°, 1 9.0°. 22.2°. 23.2°. and 27.5°. Additional X-ray powder diffraction peaks are at 20.3°. 20.8°. and 25.6°. The orthorhombic form was further characterized using Raman spectroscopy with peaks at 305 1 cirf ' . 3029 cm^{"' 1}. 301 1 cm^{" 1}. 2888 cm^{" 1}. 824 cm ' . and 71 7 cm^{- 1} : and additional peaks at 3072 cm^{" 1}. 2909 cm^{" 1}. 1245 cm^{" 1}. 747 cm^{" 1} , and 1 94 cm ' .

US 2008/0090892 discloses an amorphous form of asenapine and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof, w herein the compound is at least 50% amorphous based on total w eight of the compound. The amorphous asenapine malcate is characterized by one or more of the following: a C solid state nuclear magnetic resonance spectrum, wherein the spectrum includes chemical shifts in parts per million (ppm) of 1 69.9. 136.4. 129.5. and 42.6. the chemical shifts referenced to an external standard of solid adamantane at 29.5 ppm: an X-ray powder diffraction pattern obtained with Cu a radiation having a single broad peak between 2Θ values of about 15° and about 30°; and a glass transition onset temperature of about 38°C to about 53°C.

Synthon (Research Disclosure Database No. 523012. 2007) describes the recrystallization. precipitation, suspension and solid state experiments which were performed in order to investigate the polymorphism of asenapine maleate. The experiments yielded two crystalline forms, the monoclinic form (denoted as form H) and the orthorhombic form (denoted as form L).

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

SUMMARY OF THE INVENTION

The present invention provides a new crystalline form and a new amorphous form of asenapine maleate. pharmaceutical compositions comprising these forms, methods for their preparation and use thereof as antidepressants for treating mental disorders including schizophrenia, bipolar disorder and psychosis.

The present invention is based in part on the unexpected finding that the ne forms disclosed herein possess advantageous physicochemical properties which render their processing as medicaments beneficial. The new forms of the present invention have good bioavailability as well as adequate stabi lity characteristics enabling their incorporation into a variety of different formulations particularly suitable for pharmaceutical utility. For example, the crystalline asenapine maleate (Form II) of the present invention is less hygroscopic, has improved chemical stability at high humidity- conditions (75% RH). and shows enhanced aqueous solubility as compared to the known amorphous asenapine maleate of US 2008/0090892. Consequently, crystalline asenapine maieate (Form II ) may possess good bioavailability which would enable its easy formulation into a variety of sol id dosage forms (e.g. sub-lingual tablets).

According to one aspect, the present invention provides an amorphous form of asenapine maieate characterized by an X-ray diffraction (XRD ) profile substantially as shown in any of Figures 1 A. I B. 7A. 7B or 7C. Each possibility represents a separate embodiment of the invention. In another embodiment, the present invention provides an amorphous form of asenapine maieate characterized by a DSC profile substantially as shown in Figure 2 or 8. Each possibility represents a separate embodiment of the invention. In yet another embodiment, the amorphous form of asenapine maieate has a glass transition temperature between about 20°C and about 45°C. for example about 28°C. or about 38°C. Each possibility represents a separate embodiment of the invention. In some embodiments, the glass transition onset temperature of the amorphous asenapine maieate of the present invention is less than about 38°C. In one embodiment, the amorphous asenapine maieate of the present invention has a glass transition temperature of about 38°C. with a glass transition onset temperature of about 32.4°C. In another embodiment, the amorphous form of asenapine maieate is characterized by a TGA profile substantially as shown in Figure 3 or 9. 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 Figure 4 or 1 0. Each possibility represents a separate embodiment of the invention. In some embodiments, the IR spectrum of the amorphous form of asenapine maieate comprises characteristic peaks at about 55 1 ±4. 643±4. 741 ±4. 768±4. 862±4. 975±4. 1 088±4. 1 1 86±4. 1 243±4. 1347±4. 1 444±4. 1476±4. 1 574±4. and 1 699±4 cm^{" 1}. In certain embodiments, the amorphous form of asenapine maieate is characterized by a Raman spectrum substantially as show n in Figure 5 or 1 1 . Each possibility represents a separate embodiment of the invention. In particular embodiments, the Raman spectrum of the amorphous asenapine maieate of the present invention comprises characteristic peaks at about 245±4. 286±4. 3 1 7±4. 342±4. 709±4. 746±4. 837±4. 899±4. 1 040±4. 1 090±4. 1 1 59=4. 1 209±4. 1287±4. 1 366±4, 1460=4. 1 575±4. 1 603±4. 1 697±4. 2886±4. 2962±4. 3030=4. and 3062=4 cm^{" 1}. In further embodiments, the amorphous asenapine maieate of the present invention has an average particle size of about 20-50μηι. for example about 25μηι. In one embodiment, the average particle size of the amorphous asenapine maleate of the present invention is about 25μηι. with a D90 of about 60-70 μι^η.

In one embodiment, the present invention provides a process for preparing amorphous asenapine maleate. the process comprising the steps of:

(a) dissolving asenapine maleate in a solvent selected from methyl acetate, ethyl methanoate and 1.4-dioxane: and

(b) evaporating the solvent under vacuum so as to provide amorphous asenapine maleate.

In one embodiment, the evaporation in step (b) is performed at a temperature below the boiling point of the solvent (e.g. below 50°C). In another embodiment, step (b) is performed using rotary evaporator.

In another embodiment, the present invention provides a process for preparing amorphous asenapine maleate. the process comprising the steps of:

(a) heating asenapine maleate to melt under vacuum; and

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

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 process of preparing amorphous asenapine maleate further comprises the step of grinding the obtained precipitate so as to obtain amorphous asenapine maleate with an average particles size of about 25 microns and/or a D90 of about 62 microns.

According to another aspect, the present invention provides a crystalline form of asenapine maleate (Form II ) having an X-ray powder diffraction pattern with diffraction peaks at 2-theta values at about 1 9.8±0.1 and 25.1 ±0. 1 .

In one embodiment, the present invention provides a crystalline form of asenapine maleate ( Form II ) having an X-ray powder diffraction pattern with at least 3 di ffraction peaks selected from about 1 9.8±0.1 . 25. H0.1 . 1 3.2±0. 1 . 1 4.4⁺0. 1 . 21 .6=0.1 and 28.6±0. 1 degrees 2-theta.

3 In another embodiment, the present invention provides a crystalline form of asenapine maleate (Form II) having an X-ray powder diffraction pattern with diffraction peaks at 2-theta values at about 19.8=0.1.25.1=0.1. 13.2=0.1. 14.4±0.1.21.6=0.1 and 28.6±0.1.

In yet another embodiment, the present invention provides a crystalline form of asenapine maleate (Form II) having an X-ray powder diffraction pattern with diffraction peaks at 2-theta values at about 7.7±0.1. 8.9=0.1. 10.9=0.1. 13.2=0.1. 14.4=0.1. 18.0±0.1. 18.4=0.1. 19.8=0.1. 20.7±0.1. 21.1=0.1. 21.6=0.1. 25.1=0.1. 25.5=0.1. and 28.6=0.1.

In some embodiments, the crystalline form of asenapine maleate (Form II) is characterized by an X-ray diffraction (XRD) profile substantially as shown in any of Figures 12. 13 or 22. Each possibility represents a separate embodiment of the present invention.

In other embodiments, the crystalline form of asenapine maleate (Form II) is characterized by a DSC profile substantially as shown in any of Figures 14.15 or 23. In another embodiment, the crystalline form of asenapine maleate (Form II) is characterized by a TGA profile substantially as shown in any of Figures 16.17 or 24. In some embodiments, the crystalline asenapine maleate (Form II) of the present invention is further characterized by an IR spectrum substantially as shown in Figure 20. In certain embodiments, the IR spectrum of the crystalline form of asenapine maleate (Form II) comprises characteristic peaks at about 580=4.643±4.738=4.768=4.867±4. 938=4.976=4. 1092=4. 1187=4. I246±4. 1289=4. 1362±4. 1383=4. 1403=4. 1445±4. 1477±4. 1574=4. 1610=4. and 1699=4 cm^"1. In certain embodiments, the crystalline asenapine maleate (Form II) of the present invention is further characterized by a Raman spectrum substantially as shown in Figure 21. In particular embodiments, the Raman spectrum of the crystalline asenapine maleate (Form II) of the present invention comprises characteristic peaks at about 217=4, 245=4.292=4. 314=4, 339±4, 383=4. 399=4. 433=4. 480=4. 511=4, 558=4. 586=4. 640=4. 668=4. 705=4. 740=4. 771=4. 806=4. 846=4. 878=4. 896±4. 946=4. 975=4. 1006=4. 1037=4. 1093±4. 1124=4. 1153=4. 1209=4.1247=4.1287=4. 1353=4.1388=4.1463=4.1582=4.1613=4.1697=4. 2830=4. 2893=4. 2915=4. 2968=4. 3021=4. 3046±4. and 3068=4 cm^"1. In further embodiments, the crystalline asenapine maleate (Form 11 ) of the present invention has an average particle size of about ?(⁾-70μιη. for example about 50μηι. In one embodiment, the average particle size of the crystalline asenapine maleate (Form II ) of the present invention is about 50μιη. with a D90 of about 1 40- 150 μηι.

In one embodiment, the present invention provides a process for preparing crystalline asenapine maleate (Form II). the process comprising the steps of:

(a) dissolving asenapine maleate in a solvent selected from MEK and acetone at a temperature below the boiling point of the solvent: and

(b) cooling the solvent so as to precipitate crystalline asenapine maleate (Form II ).

In one embodiment, cool ing of the solvent in step (b) is performed below room temperatures.

In certain embodiments, the present invention provides a pharmaceutical composition comprising the crystalline (Form II) or the amorphous asenapine maleate 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. In another particular embodiment, the pharmaceutical composition is in the form of a sublingual tablet, an orally disintegrating tablet or an orally disintegrating wafer. Each possibility represents a separate embodiment of the present invention.

In one embodiment, the crystalline (Form II ) or the amorphous asenapine maleate of the present invention are useful for treating mental disorders selected from schizophrenia, bipolar disorder and psychosis.

In various embodiments, the present invention provides a pharmaceutical composition comprising the crystalline ( Form II ) or the amorphous asenapine maleate of the present invention as an active ingredient, and a pharmaceutically acceptable carrier for use in treating mental disorders selected from schizophrenia, bipolar disorder and psychosis.

In some embodiments, the present invention provides a method of treating mental disorders selected from schizophrenia, bipolar disorder and psychosis comprising administering to a subject in need thereof an effective amount of the crystalline ( Form I I ) or the amorphous asenapine maleate of the present invention, or a pharmaceutical composition comprising the crystalline ( Form II ) or the amorphous asenapine maleate of the present invention.

In additional embodiments, the present invention provides the use of the crystalline (Form I I ) or the amorphous asenapine maleate of the present invention for treating mental disorders selected from schizophrenia, bipolar disorder and psychosis.

In other 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 onh . 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 asenapine maleate. obtained by method I with slo (panel A ), or fast (panel B) cooling of the melt. Also shown for comparison is the X-ray diffraction pattern of crystalline asenapine maleate Form I (Asenapine API. panel C ).

Figure 2 illustrates a characteristic Differential Scanning Calorimetry (DSC ) profile of an amorphous form of asenapine maleate. obtained by method I with slow cooling of the melt.

Figure 3 illustrates a characteristic Thermogravimetric analysis (TGA ) profile of an amorphous form of asenapine maleate. obtained by method 1 with slow cooling of the melt.

Figure 4 il lustrates a characteristic Fourier Transform Infrared ( FTIR ) spectrum of an amorphous form of asenapine maleate obtained by method I with slow cooling of the melt. Figure 5 illustrates a characteristic Fourier Transform - Raman ( FT-Raman) spectrum of an amorphous form of asenapine maleate obtained by method I with slow cooling of the melt.

Figure 6 illustrates a characteristic Particle Size Distribution ( PSD) curve of an amorphous form of asenapine maleate obtained by method I with slow cool ing of the melt followed by milling using planetary mono mill.

Figure 7 illustrates a characteristic X-ray diffraction pattern of an amorphous asenapine maleate obtained by method II from 1 .4 dioxane (panel A), ethyl methanoate (panel B ) or methyl acetate (panel C ). Also shown for comparison is the X-ray diffraction pattern of crystalline asenapine maleate Form I (Asenapine API. panel D).

Figure 8 illustrates a characteristic Di fferential Scanning Calorimetry (DSC) profile of an amorphous asenapine maleate. obtained by method II from methyl acetate.

Figure 9 illustrates a characteristic Thermogravi metric analysis (TGA) profile of an amorphous asenapine maleate. obtained by method II from methyl acetate.

Figure 10 illustrates a characteristic Fourier Transform Infrared ( FT1R) spectrum of an amorphous asenapine maleate. obtained by method II from methyl acetate.

Figure 1 1 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of an amorphous asenapine maleate. obtained by method II from methyl acetate.

Figure 12 illustrates a characteristic X-ray diffraction pattern of crystalline asenapine maleate (Form II). obtained by method III using ME . The diffraction pattern was obtained using a 10 deg 29/min scan.

Figure 13 illustrates a characteristic X-ray diffraction pattern of crystalline asenapine maleate (Form II ). obtained by method I I I using MEK. The diffraction pattern was obtained using a 2 deg 29/min scan.

Figure 14 i llustrates a characteristic Di fferentia! Scanning Calorimetn (DSC ) profile of crystal line asenapine maleate ( Form I I ). obtained by method III using MEK. Figure 15 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of crystall ine asenapine maleate (Form 11 ). obtained by method 111 using acetone.

Figure 16 illustrates a characteristic Thcrmogravi metric analysis (TGA ) profile of crystalline asenapine maleate (Form I I ). obtained by method III using ME .

Figure 17 illustrates a characteristic Thermogravimetric analysis (TGA) profile of crystalline asenapine maleate (Form 11 ). obtained by method III using acetone.

Figure 18 illustrates a Nuclear Magnetic Resonance (NMR) spectrum of crystalline asenapine maleate (Form I I ). obtained by method III from MEK.

Figure 19 illustrates a characteristic Nuclear Magnetic Resonance (NMR) spectrum of crystalline asenapine maleate (Form II). obtained by method II I from acetone.

Figure 20 illustrates a characteristic Fourier Transform Infrared ( FTIR) spectrum of crystalline asenapine maleate (Form I I ). obtained by method III from MEK.

Figure 21 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of crystalline asenapine maleate (Form II). obtained by method III from MEK.

Figure 22 i llustrates a characteristic X-ray diffraction pattern of crystalline asenapine maleate (Form II). obtained by method III ( scale-up) using M EK.

Figure 23 illustrates a characteristic Differential Scanning Calorimetry ( DSC) profile of cry stalline asenapine maleate (Form I I ). obtained by method III (scale-up) using MEK.

Figure 24 illustrates a characteristic Thermogravimetric analysis (TGA) profile of crystalline asenapine maleate (Form II). obtained by method I II (scale-up) using MEK.

Figure 25 i l lustrates a characteristic Particle Si/e Distribution (PSD ) curve of crystalline asenapine maleate ( Form I I ). obtained by method I I I (scale-up ) using MEK. Figure 26 illustrates a characteristic dynamic vapor sorption (DVS ) isotherm plot of crystalline asenapine maleate ( Form I I ). obtained by method I II (scale-up ) using ME .

Figure 27 illustrates a characteristic dynamic vapor sorption (DVS ) isotherm plot of amorphous asenapine maleate (US 2008/0090892 ).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel crystalline and amorphous forms of (3aRS.12bRS)-5-Chloro-2-methyl-2.3.3a. l 2b-tetrahydro-

1 Hdibenzo[2.3 :6.7]oxepino[4.5-c]pyrrole (2Z)-2-butenedioate ( 1 : 1 ) (Asenapine maleate).

The present invention is further directed to pharmaceutical compositions comprising the crystalline or the amorphous form of the present invention and a pharmaceutically acceptable carrier and their use in treating mental disorders including schizophrenia, bipolar disorder and psychosis.

The present invention is further directed to methods of preparing the novel crystalline and amorphous forms of the present invention.

Polymorphs are tw o or more solid state phases of the same chemical compound that possess different arrangement and/or conformation of the molecules. Polyamorphism is the ability of a substance to exist in several different amorphous forms. Different forms of amorphous pharmaceuticals w ith readily discernible physical and chemical characteristics and some marked differences in their pharmaceutical performance have been reported. Even though amorphous materials do not exhibit long-range periodic atomic ordering, different amorphous phases of the same chemical substance can exhibit significant structural di fferences in their short-range atomic arrangement. These differences may lead to different physical and chemical properties such as density, stability, proeessability. dissolution and even bioavailability. Polyamorphism in pharmaceuticals is reviewed in Hancock et al . (Journal of Pharmacy and Pharmacology 2002. 54: 1 1 5 1 -1 1 52). the content of which is hereby incorporated by reference. The identi ication and characterization of various morphic or amorphic forms of a pharmaceutically active compound is 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 forms of asenapine maleate disclosed herein possess improved physicochemical properties including low er hygroscopicity. improved chemical stability at high humidity conditions (75% RH ). and improved aqueous solubil ity.

In one embodiment, the present i m ention provides an amorphous form of asenapine maleate w hich is characterized b) an X-ray diffraction pattern having a single broad peak expressed bet een about 1 5 and about 30 degrees two theta [29° j as is show n in any of Figures 1 A. I B. 7A. 7B or 7C. Hach 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, but not limited to. infrared spectroscopy. Raman spectrometry, and thermal analysis (e.g. thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC )).

In one embodiment, the amorphous form of asenapine maleate of the present invention is characterized by a DSC profile substantially as shown in an}' of Figures 2 or 8. Each possibility represents a separate embodiment of the present invention. In another embodiment, the amorphous form of asenapine maleate of the present invention is further characterized by a TGA profile substantially as shown in any of Figures 3 or 9. Each possibility represents a separate embodiment of the present invention. In other embodiments, the amorphous form has a glass transition temperature betw een about 20°C and about 45°C. with a glass transition onset temperature of less than about 38°C. In some embodiments, the glass transition temperature of amorphous asenapine maleate is about 28°C. In other embodiments, the glass transition temperature of amorphous asenapine maleate is about 38°C. In yet other embodiments, the glass transition temperature of amorphous asenapine maleate is about 38°C. w ith a glass transition onset temperature of about 32.4°C. In another embodiment, the amorphous asenapine maleate of the present invention is characterized by an infrared spectrum substantially as show n in any of Figures 4 or 1 0 w ith characteristic peaks at the follow ing \\ a\ enumbers: about 5 1 . about 643. about 74 1 . about 768. about 862. about 975. about 1 088. about 1 1 86. about 1 243. about 1 347. about 1 444. about 1476. about 1 574. and about 1 699 cm^" . In other embodiments, the amorphous form of asenapine maleate of the present invention is characterized by a Raman spectrum substantialK as show n in any of Figures 5 or 1 1 w ith characteristic peaks at the following wavenumbers: about 245. about 286. about 3 1 7. about 342. about 709. about 746. about 837. about 899. about 1 040. about 1090. about 1 1 59. about 1 209. about 1 287. about 1 366. about 1460. about 1 575. about 1 603. about 1697. about 2886. about 2962. about 3030. and about 3062 cm^"' . Each possibility represents a separate embodiment of the present invention. The amorphous form of asenapine maleate of the present invention may be further characterized by an average particle size of about 20-50μητ. In some embodiments, the average particle size is about 25μηι. preferably w ith a D90 of about 60-70 μηι.

In other embodiments, the present invention further provides processes for the preparation of amorphous asenapine maleate. The processes include thermal precipitations by fast or slow^r cooling and precipitations from saturated solutions. In one embodiment, these processes involve the use of asenapine. such as crystalline asenapine maleate as the starting material or any other asenapine maleate prepared by any methods known in the art. Alternatively, asenapine free base made in accordance with any method known in the art. including, for example, the methods described in US 4.1 45.434: EP 1 710241 : WO 2006/ 1 06136: Organic Process Research & Development 2008. 12. 1 96-201 ; WO 2007/046554: WO 2008/003460: WO 2008/08101 0: WO 2009/008405: and WO 2009/087058. the contents of all of the aforementioned references are hereby incorporated by reference in their entirety, and converted to its maleate salt by conventional methods can be used as the starting material in the processes of the present invention. According to one embodiment, the asenapine maleate starting material is heated until fully melted, preferably under vacuum follow ed by controlled precipitation by slow/fast cooling. The obtained product may optionally be ground using e.g. mortar and pestle to obtain amorphous asenapine maleate particles with an average particles size of about 25 microns. According to another embodiment, the asenapine maleate starting material is dissolved in a suitable solvent e.g.. at room temperatures or at temperatures below the solvent boiling point. The solvent is then removed by fast evaporation, preferably under vacuum. Suitable solvents include, but are not limited to. methyl acetate, ethy l methanoate and 1 .4-dioxane. Each possibilit represents a separate embodiment of the invention. Several non-limiting processes used to prepare amorphous asenapine maleate are provided herein.

Methods for "precipitation from solution" include, but are not limited to. evaporation of a solvent, a slow cooling method, a fast cooling method, and so forth. The solution can be a saturated solution or a 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.

Further encompassed by the present imention is a process for preparing amorphous asenapine maleate comprising heating crystalline asenapine maleate to a melt followed by fast or slow cooling of the melt to obtain amorphous asenapine maleate.

Further provided herein is a crystalline asenapine maleate (Form II) which is characterized by a unique X-ray diffraction pattern. Characteristic X-ray diffraction patterns can be seen in any of Figures 12. 13 or 22. The X-ray diffraction pattern comprises characteristic peaks expressed in degrees 2-theta at about 19.8±0.1 and 25.1±0.1. In some embodiments, the X-ray diffraction pattern has additional characteristic peaks expressed in degrees 2- thcta at about 13.2±0.1.14.4=0.1.21.6±0.1 and 28.6±0.1. In further embodiments, the X-ray diffraction pattern of crystalline asenapine maleate (Form II) has characteristic peaks expressed in degrees 2- theta at about 7.7=0.1. 8.9±0.1. 10.9=0.1. 13.2=0.1. 14.4=0.1. 18.0=0.1. 18.4=0.1. 19.8±0.1. 20.7=0.1.21.1=0.1.21.6=0.1.25.1=0.1.25.5=0.1. and 28.6=0.1.

The crystalline asenapine maleate (Form II) of the present imention can be further characterized by its melting point and by using various techniques including, but not limited to. infrared absorption. Raman spectrometry, and thermal analysis (e.g. thermogravimetric analy sis (TGA) and differential scanning calorimctry (DSC)).

In certain embodiments, the crystalline asenapine maleate (Form II) of the present imention is characterized by a DSC profile substantially as shown in any of Figures 14. 15 or 23 with peaks at about 70-83°C and about 136-137°C. The crystalline asenapine (Form II) may be further characterized by a TGA profile substantially as shown in any of Figures 16.17 or 24. In other embodiments, the crystalline asenapine maleate (Form II) is characterized by an infrared spectrum substantially as shown in Figure 20 with characteristic peaks at the following wavenumbers: about 580. about 643. about 738. about 768. about 867. about 938. about 976. about 1092. about 1187. about 1246. about 1289. about 1362. about 1383. about 1403. about 1445. about 1477. about 1574. about 1610. and about 1699 cm^"1. In other embodiments, the crystalline asenapine maleate (Form II) is characterized by a Raman spectrum substantially as shown in Figure 21 with characteristic peaks at the following wavenumbers: about 217. about 245. about 292. about 314. about 339. about 383. about 399. about 433. about 480. about 511. about 558. about 586. about 640. about 668. about 705. about 740. about 771, about 806. about 846. about 878. about 896. about 946. about 975. about 1006. about 1037. about 1093. about 1124. about 1153. about 1209. about 1247. about 1287. about 1353. about 1388. about 1463. about 1582. about 1613. about 1697. about 2830. about 2893. about 2915, about 2968. about 3021, about 3046. and about 3068 cm^"1. Each possibility represents a separate embodiment of the present invention. The crystalline asenapine maleate (Form 11) of the present invention may be further characterized by its average particle size of about 30-70 μιη. In some embodiments, the average particle size is about 50 μηι. preferably with a D90 of about 140-150 μηι.

The present invention further provides processes for the preparation of crystalline asenapine maleate (Form II). The processes include crystallizations from saturated solutions. In one embodiment, these processes involve the use of asenapine. such as crystalline asenapine maleate (Form I, designated herein "API") as the starting material or any other asenapine maleate prepared by any methods known in the art. Alternatively, asenapine free base made in accordance with an}^' method known in the art, including, for example, the methods described in US 4.145.434: EP 1710241: WO 2006/106136: Organic Process Research & Development 2008. 12. 196-201: WO 2007/046554: WO 2008/003460: WO 2008/081010: WO 2009/008405: and WO 2009/087058, the contents of all of the aforementioned references are hereby incorporated by reference in their entirety, and converted to its maleate salt by conventional methods can be used as the starting material in the processes of the present invention. In one embodiment, the asenapine maleate starting material is dissolved in a suitable solvent e.g.. EK or acetone at room temperatures or at temperatures below the boiling point of the solvent. The solutions are then cooled dow n below room temperatures (e.g. -20°C ) to afford the precipitation of crystalline asenapinc maleate (Form I I ).

The novel forms of the present invention are useful for the treatment of mental disorders including, but not limited to. schizophrenia, bipolar disorder and psychosis. The present invention thus provides pharmaceutical compositions comprising the novel forms disclosed herein and a pharmaceutically acceptable carrier. The pharmaceuticals 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 asenapine maleate forms of the present invention are 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 know n 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, cry stalline cellulose, a-starch. polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substitutional hydroxypropyl cellulose. Suitable disintegrants include e.g. crosslinked povidone (any crosslinked l -ethenyl-2- pyrrolidinone homopolymer including polyvinylpyrrolidone ( PVPP) and l -vinyl-2- pyrrolidinone homopolymer). crossl inked carmellosc sodium, carmellose calcium. carboxymethvl starch sodium, low -substituted hydroxypropvl cellulose, cornstarch and the like. Suitable w ater-soluble polymers include e.g. cell ulose derivatives such as hydroxypropvl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, methyl cellulose and carboxymethvl cellulose sodium, sodium polyacrylate. polyvinyl alcohol, sodi um alginate, guar gum and the like.

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 asenapine malcate forms of the present invention are particularly suitable for oral administration in the form of tablets including sublingual tablet, capsules, pills, dragees. powders, granules, orally disintegrating wafers, orally disintegrating tablets, and the like. Λ 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 w ith coatings and shells, such as enteric coatings and other coatings w ell 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 mental disorders including, but not limited to. schizophrenia, bipolar disorder and psychosis comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising any one of the asenapine maleate forms disclosed herein, for example the amorphous asenapine maleate or the crystalline asenapine maleate ( Form II ) described 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, bipolar disorder and psychosis. In additional embodiments, the asenapine maleate forms of the present invention are used for the preparation of an antipsychotic medicament.

The present invention further provides the administration of the asenapine maleate forms 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 skil led artisan.

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

EXAMPLES

Example 1 : General Preparation Methods of Asenapine Maleate Forms 1. Reagents

Acetone. AR. Sinopharm Chemical Reagent Co.. Ltd. Lot No. T20081202

MEK. AR. Sinopharm Chemical Reagent Co.. Ltd. Lot No. T200703 1 5 or 1 20090724

Acetonitrile. HPLC grade. Merck. Lot No. 1JOIF60540

TFA. HPLC grade. Merck. Lot No. S6002262 009

Ι Ί. AR. Sinopharm Chemical Reagent Co. Ltd. Lot No. 1 001 1 01 8:

KI LPO₄. AR. Sigma. Lot No. 0001 94691 : NaOH. AR. Shanghai LingFeng Chemical Reagent Co. Ltd. Lot No. 081 1 1 8: NaCL AR. Shanghai LingFeng Chemical Reagent Co. Ltd. Lot No. 0901 1 3 :

2. Instruments

Sartorius CP 225D Balance

ELGA Water Purification Equipment

TA Q2000 DSC

Mettler Toledo DSC 1

TA Q5000IR TGA

Rigaku D/MAX 2200 X-ray powder diffractometer

Thermo Nicolet 380 FT-IR

NMR Varian 400

Nikon LV 1 00 Polarized Light Microscopy

Eyela FDLJ- 1 1 00 freeze dryer

Jobin Yvon LabRam- 1 B FT-Raman

Sympatec I IELOS PSD

Agilent 1 200 series HPLC

Mettler-Tolcdo MX5 Balance

SOTAX Dissolution Testing System

DVS Advantage 1

Shanghai ShanYue Scientific Instrument Co.. Ltd. YP-2 Hydraulic Press Horiba SA-9601 MP Single Station Multipoint Surface Area Analyzer 3. XRPD, DSC, TGA, Polarized light microscope, FT-IR, FT-Raman, PSD and HPLC methods

3.1 XRPD method

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

- X-ray Generator: Cu. ka. (7 = 1 .54056 A)

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

- DivSlit: 1 dee

- DivH.L.Slit: 1 0 mm

- SctSlit: 1 deg

- RecSlit: 0.1 5 mm

- Monochromator: Fixed Monochromator

- Scanning Scope: 2-40 deg

- Scanning Step: 1 0 deg/min or 2 deg/min

3.2 DSC and TGA methods

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

- Heat from 30 °C to 1 60 °C or 300 °C at 10 °C /min

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

- Heat from 0 °C to 200 °C at 2 °C /min

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

- Heat from 30 °C to 300 °C or 350 °C at 1 0 °C /min

3.3 Polarized light microscope

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

- Nikon LV 100POL equipped with 5 megapixel CCD

- Ocular lens: 1 0 X

- Objective 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

- Pow er: 1 mW

- Resolution: 1 cm^{" 1}

- Time for integration: 50 s

3.5 PSD method

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

- time base: 1 0.00 ms

- valid: 2 %<=c.opt<=30 %

- disp.meth.: 1 .5 bar pressure

3.6 HPLC method

Details of chromatographic conditions used in the tests are mentioned below (The typical retention time of asenapine maleate main peak is 17. 1 min

Tabic 1.

Detector wavelength 220 nm

4. General Preparation Methods

4.1 Method I : Thermal heating/cooling

Asenapine maleate (as described in Arzneim.-Forsch/Drug Res.. 40. 536-539. 1 990: Batch No. 201 01 001 : also designated asenapine maleate API) was heated to melt under vacuum. The asenapine maleate melt w as then rapidly or slowly cooled. Amorphous asenapine maleate was identi fied by this method, as set forth in the Examples below.

4.2 Method II : Fast precipitation from saturated solutions

Saturated solutions of asenapine maleate (API: Batch No. 20101001 ) in different solvents were prepared at room temperatures. The solvents were then removed by rotary evaporator below 50 °C. Amorphous asenapine maleate w as identified by this method, as set forth in the Examples below .

4.3 Method I II: Solvent-thermal heating/cooling

Saturated sol utions of asenapine maleate (API; Batch No. 201 01 001 ) in di fferent solvents w ere prepared at 50 °C. and then cooled down to -20 °C. Crystalline asenapine maleate ( Form I I ) was identified by this method, as set forth in the Examples below.

5. Methods of Assessment of Physical and Chemical Properties

5.1 H groscopicity

Details of hygroscopicity measurements are mentioned below:

The crystalline asenapine maleate (form II ) was tested for its sorption/desorption profiles at 25 °C under 0-90 % relative humidity (RH ) and compared to amorphous asenapine maleate of US 2008 0090892. The following criteria were used for the classification:

Deliquescent: Sufficient water is absorbed to form a liquid.

Very hygroscopic: Increase in mass is equal to or greater than 1 5 %.

Hygroscopic: Increase in mass is less than 1 5 % and equal to or greater than

2 %.

Slightly hygroscopic: Increase in mass is less than 2 % and equal to or greater than 0.2 %.

Non-hygroscopic: Increase in mass is less than 0.2 %.

5.2 Aqueous solubility

Details of solubility measurements are mentioned below:

Testing media: water. pH 1 .2. 4.5. 6.8. 7.4 USP buffers. 0.01 N HC1. 0.1 N HC1. SGF. FaSSIF, and FeSSIF. pH 1 .2 (U SP ): 50 mL of 0.2 M potassium chloride solution was placed in a 200 mL volumetric ilask followed by the addition of 85.0mL of 0.2M hydrochloric acid solution and water. pH 4.5 ( U SP ): 50 mL of 0.2 M potassium biphthalate solution was placed in a 200 mL volumetric ilask followed by the addition of 8.8 mL of 0.2 M sodium hydroxide solution and water. pH 6.8 ( USP ): 50 niL of 0.2 M monobasic potassium phosphate solution was placed in a 200 niL volumetric flask fol low ed by the addition of 22.4 ml of 0.2 M sodium hydroxide solution and w ater. pH 7.4 (USP): 50 mL of 0.2 M monobasic potassium phosphate sol ution was placed in a 200 mL volumetric flask followed by the addition of 39. 1 mL of 0.2 M sodium hydroxide solution and w ater.

Simulated gastric fluid ( SGF): 0.01 N HC1. 0.05 % sodium lauryl sulfate. 0.2 %

NaCl .

Fasted state simulated intestinal fluid (FaSSIF): 29 mM NaH₂P0₄. 3 mM Na taurocholate. 0.75 mM lecithin. 1 03 mM NaCl. NaOH to pl l 6.5.

Fed state simulated intestinal fluid (FeSSIF): 144 mM acetic acid. 1 5 mM Na taurocholate. 3.75 mM lecithin. 204 mM NaCl. NaOH to pH 5.0.

Testing procedure: Certain amount of a sample was added to the different media and kept shaken for 24 hours at 25 °C. Then, the saturated solution was filtered and the concentration of the testing compound in fi ltrate was determined using HPLC. The final pH was then measured.

5.3 Intrinsic dissolution rate

Details of the intrinsic dissol ution rate measurements are mentioned below:

About 1 50 mg sample were weighed into the intrinsic dissolution apparatus (diameter: 0.795 cm ) and compressed for 1 minute with 4 tons compression force. The sample w as made compact. The intrinsic dissolution apparatus was slid into the dissolution test chuck, and tightened. The shaft in the spindle was adj usted to ensure that the exposed surface of the compacted tablet was 3.8 cm from the bottom of the vessel w hen low ered. The temperature of the chamber water w as set at 37 °C. the shaft rotation at 1 00 rpm and the sampling time points at 1 . 2, 3. 4. 5. 1 0. 1 5, 20 and 30 min. Water. 0. 1 N I lCl or pH 6.8 USP buffer w ere used as dissolution media. At each time point. 5 m L of solution w as sampled. The samples w ere filtered with a 0.22 μιη fi lter and the first 1 mL w as discarded. The concentrations of the filtrates w ere analyzed using HPLC. 5.4 Chemical stability

Details of the chemical stability measurements are mentioned below:

Testing conditions: 40 °C. 60 °C. 40 ^CC/RJ 1 75 %. 60 °C/RH 75 %. light.

Testing procedure: About 1 0 mg of sample was placed in a glass vial and stored at different testing conditions for 1 and 2 weeks separately. An additional sample was stored at - 20 °C as control. The physical appearance, assay and total related substances at end of the V¹ and 2^nd weeks were assessed.

5.5 Physical stability'

Details of physical stability measurements are mentioned below⁷:

Testing conditions: 40 °C. 60 °C. 40 °C/RH 75 %, 60 °C/RH 75 %. light.

Testing procedure: About 50 mg of sample were weighed in a glass vial and stored at different conditions for 1 week and 2 weeks separately. An additional sample w as stored at -20 °C as control . XRPD and DSC were measured at the end of the first and second week.

5.6 BulkTapped density

Details of bulk/tapped density measurements are mentioned below:

Bulk density testing: Λ quantity of a sample sufficient to complete the test was passed through a 1 .0 mm (No.1 8 ) screen to break up agglomerates that may have formed during storage. Then, a quantity of sample was weighed ( M) and placed into 1 0 niL graduated cylinder. The powder was leveled without compacting, and the unsettled apparent volume was read (Vo). The bulk density was calculated in g per niL. according to the formula:

Bulk Density=M/Vo

^'l apped density testing: A quantity of a sample sufficient to complete the test was passed through a 1 .0 mm (No. 1 8) screen to break up agglomerates that max have formed during storage. Then, a quantity of the sample was weighed ( M ) and placed into 1 0 mL graduated cylinder. The powder was leveled without compacting. The cylinder w as tapped 500 times initial ly and the tapped \ olume. Va. w as measured to the nearest graduated unit. The tapping was repeated for additional 750 times and the tapped volume. Vb. w as measured to the nearest graduated unit. It^" the difference between the two volumes was less than 2%. Vb was the final tapped v ol ume. V f. The tapped density was calculated, in g per mL. according to the formula:

Tapped Densitv=M/Vf

5.7 Surface area

Details of surface area measurement are mentioned below:

About I g of sample was weighed into the sample cell and de-gassed at 30 °C for 2 hrs to remove the gases that were already absorbed on its surfaces. Then the sample cell w as fixed on a test station and the surface area as determined.

Example 2: Amorphous Asenapine Maleate (Method 1 )

General method I was performed. Thus, asenapine maleate (API; Batch No. 201 01 001 ) was heated to melt under vacuum followed by its slow or fast cooling to afford amorphous asenapine maleate. The amorphous asenapine maleate obtained by this method was characterized by a broad X-ray diffraction peak between about 15 and about 30 [2Θ⁰] characteristic of an amorphous powder (Figure 1 . panels A-B ). Figure 2 illustrates a characteristic DSC profile of a sample prepared by slow cooling of the melt. The DSC profile shows a glass transition temperature of 38.28 °C with an onset of 32.40 °C. Figure 3 illustrates a characteristic TGA profile w ith about 0.48% weight loss from about 30°C to about 100°C and about 96.07% weight loss from about 1 00°C to about 300"C. Figure 4 illustrates a characteristic IR spectrum w ith peaks at about 55 1 . 643, 741 . 768. 862. 975, 1 088. 1 1 86. 1243, 1347. 1444. 1476. 1 574. and 1 699 cm^{" 1}. Figure 5 illustrates a characteristic FT-Raman spectrum with peaks at about 245. 286. 3 1 7. 342. 709. 746. 837. 899. 1 040. 1 090. 1 1 59. 1209. 1287. 1366. 1460. 1 575. 1 603. 1 697. 2886. 2962. 3030. and 3062 cm^{" 1}.

When scaling up the preparation of the amorphous asenapine maleate form of the present invention the asenapine maleate melt was cooled down (slowly/rapidly ) and the sample was milled by planetary mono mill for 90 min. During the milling process, three samples w ere pulled out after 10. 30 and 90 min and characterized by PSD. The results are shown in Figure 6. No reduction in particle size was measured after 30 min. The D 0 and average particle size are 61.90 μιη and 24.95 μιη. respectively.

Example 3: Amorphous Asenapine Maleate (Method II)

General method II was performed. Thus, asenapine maleate (API: Batch No. 20101001 ) was dissolved in methyl acetate, ethyl mcthanoate. or 1.4-dioxane to obtain saturated solutions at room temperatures. The solvents were then removed by rotary evaporator below 50 °C. Figure 7 (panels A-C) show characteristic X PD of the amorphous form obtained by this method. Figure 8 illustrates a characteristic DSC profile of a sample obtained from a methyl acetate solution. The glass transition temperature of the amorphous form obtained by this method is 28.32 °C. Figure 9 illustrates a characteristic TGA profile with a weight loss of about 1.43% between about 31 and about 130 °C and weight loss of about 92.75% between about 130 and about 301 °C. Figure 10 illustrates a characteristic IR spectrum with peaks at about 547. 645.741.767.861.972. 1088. 1186. 1244. 1347. 1443. 1476. 1575. 1614. and 1699 cm^"'. Figure 11 illustrates a characteristic FT-Raman spectrum with peaks at about 220. 245.289.314.339.402.477.508.561.605.637.671.709.746.771.843.874.896. 943.996. 1040. 1093. 1131. 1156. 1209. 1244. 1287. 1356. 1378. 1466. 1578. 1603. 1672.2890.2962.3021. and 3065 cm^"'. The IR and Raman spectra of the amorphous asenapine maleate obtained by this method are substantially similar to the spectra obtained by using Method 1 (Example 2) and could be used as alternatives for the identification of the amorphous form of the present invention. The amorphous form obtained by this method is relatively unstable as evident from its relatively low glass transition temperature.

Example 4: Crystalline Asenapine Maleate (Form II) (Method III)

General method III was performed. Thus, asenapine maleate (API; Batch No.

20101001) was dissolved in MEK or acetone al 50 °C to obtain saturated solutions. The solutions were then cooled down to -20°C to precipitate out crystals of asenapine maleate (Form II). The asenapine maleate (Form II) was characterized by X-ray diffraction in 10 deg/min and 2 deg/min (Figures 12 and 13. respectively). The characteristic X-ray diffraction peaks are listed in Table 2. Figures 14 and 15 illustrate characteristic DSC profiles of asenapine maleate (Form II) prepared from MEK and acetone, respectively. Figure 16 illustrates a characteristic TGA profile of the asenapine maleate (Form II) prepared from MEK with a weight loss of about 3.636% between 32 and 114 °C and weight loss of 93.66% between 114 and 303 °C. Figure 17 illustrates a characteristic TGA profile of the asenapine maleate (Form II) prepared from acetone with a weight loss of about 1.178% between 31 and 106 °C and w eight loss of 95.02% between 106 and 294 °C. The differences in TGA profiles between the preparation from MEK and the preparation from acetone are attributed to different amounts of residual solvents (3.64% and 1.18%. respectively). The Ή-NMR spectrum (Figure 18) suggests that the molar ratio of MEK:Asenapine maleate is 0.28:1. Figure 19 shows the Ή- NMR spectrum of asenapine maleate (Form II) obtained from acetone for comparison. From II was dcsolvated to asenapine maleate (API) by heating at 95°C for 5 minutes. Without being bound by any theory or mechanism of action, the asenapine maleate (Form II) of the present invention is an isomorphous solvate form. Figure 20 illustrates a characteristic IR spectrum of the crystalline asenapine maleate (Form II) with peaks at about 580.643.738.768.867.938.976.1092.1187.1246.1289.1362.1383.1403. 1445.1477.1574.1610. and 1699 cm^"1. Figure 21 illustrates a characteristic FT-Raman spectrum with peaks at about 217.245.292.314.339.383.399.433.480.511.558. 586.640.668.705.740.771.806.846.878.896.946.975. 1006. 1037. 1093. 1124. 1153.1209. 1247, 1287.1353. 1388. 1463, 1582, 1613. 1697.2830.2893.2915.2968. 3021.3046. and 3068 cm^"1.

Table 2.

When scaling up the preparation of asenapine maleate (Form II). saturated solutions of asenapine maleate ( API; Batch No.20101001)) in MEK was prepared at 50 °C. and then cooled down to -20 °C for 2 weeks to precipitate asenapine maleate (Form II). The precipitates were gently crushed into powder by hand and then characterized by X-ray powder diffraction (Figure 22), DSC (Figure 23). and TGA (Figure 24). The precipitates were further characterized by PSD (Figure 25) to have D90 of about 146.19 μιη and average particle size of about 49.91 LUTL When milling the precipitate of asenapine maleate (Form II) using planetary mono mill at 200 rpin for 5 min. the form started to convert to an amorphous ibrm as characterized by XRPD. Example 5: Characterization of Cr^ystalline Asenapinc Maleate (Form II)

Crystalline ascnapine maleate (Form II) prepared according to method III (scale up) was characterized for assessing its physical and chemical properties. The DVS isotherm plot of crystalline asenapine maleate (Form II) is shown in Figure 26. The DVS isotherm plot of amorphous asenapine maleate (US 2008/0090892) is shown in Figure 27 for comparison. The results are summarized in Table 3.

Table 3.

The crystalline asenapine maleate (Form II) of the present invention is classified as being slightly hygroscopic (0.65 % weight gain from 0 to 90 %RH) whereas the amorphous asenapine maleate of US 2008 0090892 is classified as hygroscopic ( 1 1 .64 % weight gain from 0 to 90 %RH. Thus, the crystalline asenapine maleate (Form II ) of the present invention may possess longer term stability in humid environments and is thus more advantageous for use in the pharmaceutical industry in comparison to the amorphous asenapine maleate of US 2008/0090892.

The chemical stability of the crystalline asenapine maleate (Form II) of the present invention was examined in various conditions and compared to the chemical stability of amorphous asenapine maleate (US 2008/0090892). The percentage of remaining of Form II at the various conditions (40 °C. 60 °C. 40 °C/75 %RH. 60 °C/75 %RH and light) was above 97.2 % at end of the 1 ^st week and above 95.5 % at end of the 2^nd week. The percentage of remaining of amorphous asenapine maleate at the various conditions (40 °C. 60 °C. 40 °C/75 % H. 60 °C 75 %RH and light) was above 96.8 % at end of the 1 ^st week and 93.6 % at end of the 2^nd week. At high humidity- conditions (75 %RH). however, the amorphous form absorbed a significant amount of moisture and became gel like semi-solid. Thus, the crystalline asenapine maleate (Form II) of the present invention has improved chemical stabi lity at high humidity conditions. The results are summarized in Table 4.

Table 4.

X-ray powder diffraction and differential scanning calorimetry of crystalline asenapine maleate ( Form II) were performed after storing the samples in a glass vial under different conditions ( 40 °C. 60 °C. 40 °C75 % RH. 60 °C/75 % RH). Form II remained stable under light with no significant change in its XRPD pattern. The DSC thermogram show ed some exotherm before melting, which ma}^' suggest the beginning of phase conversion. Form Π completely converted to asenapine maleate Form I (API ) at 60 °C. and 60 °C '75 % RH at end of the ¹ week and 2^nd weeks. At 40 ^CC. Form II partially converted to asenapine maleate Form I (API ) at the end of the \ ^[ week and completely converted to asenapine maleate Form I (API) at the end of the 2^nd week. At 40 °C/75 % RH. Form II partially converted to asenapine maleate Form I ( API ). Amorphous asenapine maleate (US 2008/0090892) was found to be unstable at 60 ^CC. 40 °C/75 % RFI. 60 °C/75 % RH and converted to asenapine maleate Form I (API ) having poor crystallinity. This amorphous form was found to be relatively stable at 40 °C and under light based on its XRPD. However, the DSC isotherms of the amorphous form showed a change in the glass transition temperature from 50 °C to about 1 5 °C at end of the 1 ^st week and 2^nd weeks. Decrease in glass transition temperature of this amorphous form was also observed for the control sample which w as stored at -20 °C at the end of the 2^nd week. Without being bound by any theory or mechanism of action, the decrease in glass transition temperature might be attributed to a tendency to convert into a stable crystalline form.

The crystalline asenapine maleate (Form II) of the present invention shows good solubility, particularly in acidic conditions. Form II has an improved aqueous solubi lity w hen compared to the amorphous form of US 2008/0090892. The results are summarized in Tabic 5.

Table 5.

The intrinsic dissolution rate (mg/cm7min) of asenapine maleate (Form II) was determined as 1 .46. 6.55 and 0.95 in water. 0. 1 N HC1 and pH6.8 USP buffer, respectively. The fast (w ithin 1 0 minutes ) dissolution of asenapine maleate (Form I I ) at pH 6.8 USP buffer which simulate the oral cavity conditions indicates a possible advantage of formulating asenapine maleate (Form I I ) as a sub-lingual dosage form.

The bulk and tapped

of asenapine maleate (Form I I ) were measured and the results are summarized in Table 6. Table 6.

The surface area of crystalline asenapine maleate ( Form II) was determined as 0.5 1 7 m²/g (total surface area 0.460 nr and weight 0.889 g).

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, w hich follow .

Claims

1. A crystalline form of asenapine maleate (Form II) having an X-ray powder diffraction pattern with diffraction peaks at 2-theta values at about 19.8±0.1 and 25.1 ±0.1.

2. The crystalline asenapine maleate (Form II) according to claim 1 having an X- ray powder diffraction pattern with at least 3 diffraction peaks selected from about 19.8=0.1.25.1=0.1. 13.2=0.1. 14.4=0.1.21.6±0.1. and 28.6=0.1 degrees 2-theta.

3. The crystalline asenapine maleate (Form II) according to claim 1 having an X- ray powder diffraction pattern with diffraction peaks at 2-theta values at about 19.8=0.1.25.H0.1.13.2±0.1.14.4=0.1.21.6±0.1. and 28.6=0.1.

4. The crystalline asenapine maleate (Form II) according to claim I having an X- ray powder diffraction pattern with diffraction peaks at 2-theta values at about 7.7=0.1.8.9=0.1. 10.9=0.1. 13.2=0.1. 14.4±0.1. 18.0±0.1. 18.4=0.1. 19.8=0.1. 20.7=0.1.21.1=0.1.21.6=0.1.25.1±0.1.25.5=0.1. and 28.6=0.1.

5. The crystalline asenapine maleate (Form II) according to claim 1 characterized by an X-ray diffraction (XRD) profile substantially as shown in any of Figures 12.1301-22.

6. The crystalline asenapine maleate (Form II) according to claim 1. further characterized by a DSC profile substantially as shown in any of Figure 14. 15 or 23.

7. The crystalline asenapine maleate (Form II) according to claim 1. further characterized by a TGA profile substantially as shown in any of Figures 16.17 or 24.

8. The crystalline asenapine maleate (Form II) according to claim 1. further characterized by an TR spectrum substantially as shown in Figure 20.

9. The crystalline asenapine maleate (Form ΙΓ) according to claim 8. wherein the IR spectrum comprises characteristic peaks at about 580=4. 643=4. 738=4. 768=4. 867±4. 938=4. 976=4. 1092=4. 1187=4. 1246±4. 1289=4. 1362±4. 13 3±4. 1403=4.1445±4.1477=4. 1574=4. 1610=4. and 1699=4 cm^"1.

10. The crystalline asenapine maleate (Form II) according to claim 1. further characterized by a Raman spectrum substantially as shown in Figure 21.

11. The crystalline asenapine maleate (Form II) according to claim 10. wherein the Raman spectrum comprises characteristic peaks at about 217±4. 245=4. 292=4. 314=4. 339=4. 383±4. 399=4.433=4. 480=4. 511=4. 558=4. 586=4. 640±4. 668=4. 705±4. 740+4. 771=4. 806±4. 846=4. 878=4. 896±4. 946±4. 975±4. 1006±4. 1037=4.1093±4. 1124±4. 1153=4. 1209=4.1247=4. 1287=4. 1353=4. 1388=4. 1463=4. 1582=4. 1613=4. 1697=4. 2830=4. 2893=4. 2915=4.2968=4.3021=4, 3046=4. and 3068±4 cm^"1.

12. The crystalline asenapine maleate (Form II) according to any of claims 1 to 11. having an average particle size of about 30-70μηι.

13. The crystalline asenapine maleate (Form II) according to claim 12. having an average particle size of about 50μιη.

14. The crystalline asenapine maleate (Form II) according to claim 12. having an average particle size of about 50μιη. with a D90 of about 140-150 μιη.

15. An amorphous form of asenapine maleate characterized by a DSC profile substantially as shown in any of Figures 2 or 8.

16. The amorphous asenapine maleate according to claim 15, having a glass transition temperature between about 20°C and about 45°C. with a glass transition onset temperature ofless than about 38°C.

17. The amorphous asenapine maleate according to claim 16, having a glass transition temperature at about 28°C or about 38°C.

18. The amorphous asenapine maleate according to claim 17. having a glass transition temperature of about 38°C. with a glass transition onset temperature of about 32.4^l,C.

19. The amorphous asenapine maleate according to claim 15. further characterized by a TGA profile substantially as shown in an}' of Figures 3 or 9.

20. The amorphous asenapine maleate according to claim 15. further characterized by an IR spectrum substantially as shown in any of Figures 4 or 10.

21 . The amorphous asenapine maleate according to claim 20. wherein the IR spectrum comprises characteristic peaks at about 55 1 -4. 643=4. 741 ±4. 768±4. 862=4. 975=4. 1 088=4. 1 1 86=4. 1243=4. 1 347=4. 1444=4. 1476=4. 1 574=4. and 1 699=4 cm^{" 1}.

22. The amorphous asenapine maleate according to claim 1 5. further characterized by a Raman spectrum substantially as show n in any of Figures 5 or 1 1 .

23. The amorphous asenapine maleate according to claim 22. wherein the Raman spectrum comprises characteristic peaks at about 245=4. 286±4. 31 7±4. 342=4. 709=4. 746±4. 837=4. 899±4. 1040±4. 1 090±4. 1 159±4. 1209=4. 1 287±4. 1366=4. 1 460±4. 1575=4. 1 603=4. 1 697±4. 2886±4. 2962=4. 3030=4. and 3062=4 cm^{" 1}.

24. The amorphous asenapine maleate according to any of claims 15 to 23. having an average particle size of about 20-50μηι.

25. The amorphous asenapine maleate according to claim 24. having an av erage particle size of about 25μηι.

26. The amorphous asenapine maleate according to claim 24. having an average particle size of about 25μηι. with a D90 of about 60-70 μιη.

27. A pharmaceutical composition comprising as an activ e ingredient the crystalline asenapine maleate (Form II) according to any one of claims 1 to 14 or the amorphous asenapine maleate according to any one of claims 1 5 to 26. and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition according to claim 27 in the form of a tablet.

29. The pharmaceutical composition according to claim 27 in the form of a sublingual tablet, on orally disintegrating tablet or an orally disintegrating w afer.

30. The pharmaceutical composition according to claim 27 for use in treating of mental disorders selected from schizophrenia, bipolar disorder and psychosis.

3 1 . A method of treating a mental disorder selected from schizophrenia, bipolar disorder and psychosis comprising administering to a subject in need thereof an effective amount of a composition comprising the crystalline asenapine maleate ( Form II ) according to any one of claims 1 to 14 or the amorphous asenapine maleate according to any one of claims 1 5 to 26.

2. A crystalline asenapine maleate ( Form II ) according to am one of claims 1 to 14 or the amorphous asenapine maleate according to any one of claims 1 5 to 26. for use in treating of mental disorders selected from schizophrenia, bipolar disorder and psychosis.

3. A process for preparing the crystalline asenapine maleate (Form II ) according to any one of claims 1 to 14. the process comprising the steps of:

(a) dissolving asenapine maleate in a solvent selected from MKK and acetone at a temperature below the boiling point of the solvent: and

(b) cooling the solvent so as to precipitate crystalline asenapine maleate (Form II).

4. The process according to claim 33 wherein step (b) comprises cooling the solvent to below room temperature.

5. A process for preparing amorphous asenapine maleate according to any one of claims 1 to 26. the process comprising the steps of:

(a) dissolving asenapine maleate in a solvent selected from methyl acetate, ethyl methanoate and 1 .4-dioxane: and

(b) evaporating the solvent under vacuum so as to provide amorphous asenapine maleate.

6. The process according to claim 35. wherein the evaporation in step (b) is performed at a temperature below the boiling point of the solvent.

7. The process according to claim 35. wherein step (b) is performed using rotary evaporator.

8. A process for preparing amorphous asenapine maleate according to am one of claims 1 5 to 26. the process comprising the steps of:

(a) heating asenapine maleate to melt under vacuum: and ( b) cooling the melted asenapine maleate obtained in step (a ), so as to ^•ovide amorphous asenapine maleate.

The process according to claim 38. w herein the cooling in step (b) is selected from fast cooling and slow cooling.

The process according to claim 38. further comprising the step of grinding the obtained precipitate so as to obtain amorphous asenapine maleate with an average particles size of about 25 microns and a D90 of about 62 microns.