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WO2012114325A1 - Polymorphes d'de maléate d'asénapine - Google Patents

Polymorphes d'de maléate d'asénapine Download PDF

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Publication number
WO2012114325A1
WO2012114325A1 PCT/IL2011/000464 IL2011000464W WO2012114325A1 WO 2012114325 A1 WO2012114325 A1 WO 2012114325A1 IL 2011000464 W IL2011000464 W IL 2011000464W WO 2012114325 A1 WO2012114325 A1 WO 2012114325A1
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Prior art keywords
asenapine maleate
amorphous
crystalline
maleate
asenapine
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PCT/IL2011/000464
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English (en)
Inventor
Ehud Marom
Shai Rubnov
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Mapi Pharma Ltd
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Mapi Pharma Ltd
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Publication of WO2012114325A1 publication Critical patent/WO2012114325A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a crystalline form and an amorphous form of asenapine maleate, pharmaceutical compositions comprising same, and use thereof as antidepressants.
  • 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.
  • 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.
  • US 7.741 .358 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 (2 ⁇ ) 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 ' .
  • 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 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.
  • 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).
  • 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.
  • XRD X-ray diffraction
  • the present invention provides an amorphous form of asenapine maieate characterized by a DSC profile substantially as shown in Figure 2 or 8.
  • 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.
  • XRD X-ray diffraction
  • 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.
  • 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 .
  • 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.
  • the Raman spectrum of the amorphous asenapine maieate of the present invention comprises characteristic peaks at about 245 ⁇ 4.
  • the amorphous asenapine maieate of the present invention has an average particle size of about 20-50 ⁇ . for example about 25 ⁇ . In one embodiment, the average particle size of the amorphous asenapine maleate of the present invention is about 25 ⁇ . with a D90 of about 60-70 ⁇ ⁇ .
  • the present invention provides a process for preparing amorphous asenapine maleate. the process comprising the steps of:
  • 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.
  • the present invention provides a process for preparing amorphous asenapine maleate. the process comprising the steps of:
  • step (b) cooling the melted asenapine maleate obtained in step (a), so as to provide amorphous asenapine maleate.
  • the cooling in step (b) is selected from fast cooling and slow cooling.
  • 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.
  • 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 .
  • the crystalline form of asenapine maleate 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.
  • 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.
  • 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.
  • the crystalline asenapine maleate (Form II) of the present invention is further characterized by an IR spectrum substantially as shown in Figure 20.
  • the crystalline asenapine maleate (Form II) of the present invention is further characterized by a Raman spectrum substantially as shown in Figure 21.
  • the crystalline asenapine maleate (Form 11 ) of the present invention has an average particle size of about ?( ) -70 ⁇ . for example about 50 ⁇ .
  • the average particle size of the crystalline asenapine maleate (Form II ) of the present invention is about 50 ⁇ . with a D90 of about 1 40- 150 ⁇ .
  • the present invention provides a process for preparing crystalline asenapine maleate (Form II). the process comprising the steps of:
  • cool ing of the solvent in step (b) is performed below room temperatures.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the pharmaceutical composition is in the form of a tablet.
  • the pharmaceutical composition is in the form of a sublingual tablet, an orally disintegrating tablet or an orally disintegrating wafer.
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • the subject is a mammal, such as a human.
  • 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.
  • DSC Differential Scanning Calorimetry
  • 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.
  • TGA Thermogravimetric analysis
  • 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.
  • PSD Particle Size Distribution
  • 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.
  • DSC Di fferential Scanning Calorimetry
  • Figure 9 illustrates a characteristic Thermogravi metric analysis (TGA) profile of an amorphous asenapine maleate. obtained by method II from methyl acetate.
  • TGA Thermogravi metric analysis
  • Figure 10 illustrates a characteristic Fourier Transform Infrared (FT1R) spectrum of an amorphous asenapine maleate. obtained by method II from methyl acetate.
  • FT1R Fourier Transform Infrared
  • Figure 1 1 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of an amorphous asenapine maleate. obtained by method II from methyl acetate.
  • FT-Raman Fourier Transform - Raman
  • 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 .
  • TGA Thcrmogravi metric analysis
  • Figure 17 illustrates a characteristic Thermogravimetric analysis (TGA) profile of crystalline asenapine maleate (Form 11 ). obtained by method III using acetone.
  • TGA Thermogravimetric analysis
  • 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.
  • NMR Nuclear Magnetic Resonance
  • Figure 20 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of crystalline asenapine maleate (Form I I ). obtained by method III from MEK.
  • FTIR Fourier Transform Infrared
  • Figure 21 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of crystalline asenapine maleate (Form II). obtained by method III from MEK.
  • FT-Raman Fourier Transform - Raman
  • 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.
  • DSC Differential Scanning Calorimetry
  • Figure 24 illustrates a characteristic Thermogravimetric analysis (TGA) profile of crystalline asenapine maleate (Form II). obtained by method I II (scale-up) using MEK.
  • TGA Thermogravimetric analysis
  • 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 ).
  • the present invention is directed to novel crystalline and amorphous forms of (3aRS.12bRS)-5-Chloro-2-methyl-2.3.3a. l 2b-tetrahydro-
  • 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 .
  • 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.
  • 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 )).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 20-50 ⁇ . In some embodiments, the average particle size is about 25 ⁇ . preferably w ith a D90 of about 60-70 ⁇ .
  • 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.
  • 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.
  • 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.
  • 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.
  • the asenapine maleate starting material is dissolved in a suitable solvent e.g.. at room temperatures or at temperatures below the solvent boiling point.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)).
  • TGA thermogravimetric analy sis
  • DSC differential scanning calorimctry
  • 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.
  • 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.
  • 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.
  • the crystalline asenapine maleate (Form 11) of the present invention may be further characterized by its average particle size of about 30-70 ⁇ . In some embodiments, the average particle size is about 50 ⁇ . preferably with a D90 of about 140-150 ⁇ .
  • the present invention further provides processes for the preparation of crystalline asenapine maleate (Form II).
  • the processes include crystallizations from saturated solutions.
  • 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.
  • API crystalline asenapine maleate
  • 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.
  • 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.
  • a suitable solvent e.g.. EK or acetone
  • 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.
  • 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.
  • ⁇ tablet may be made by compression or molding, optionally with one or more excipients as is known in the art.
  • 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 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.
  • the therapeutic benefit is inducing an antipsychotic effect thus treating disorders such as schizophrenia, bipolar disorder and psychosis.
  • 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.
  • Tube Voltage 40 kV. Tube Current: 40 mA
  • 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.
  • Deliquescent Sufficient water is absorbed to form a liquid.
  • Hygroscopic Increase in mass is less than 1 5 % and equal to or greater than
  • Non-hygroscopic Increase in mass is less than 0.2 %.
  • pH 6.8 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 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 0.01 N HC1. 0.05 % sodium lauryl sulfate. 0.2 %
  • Fasted state simulated intestinal fluid (FaSSIF): 29 mM NaH 2 P0 4 . 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 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 V 1 and 2 nd weeks were assessed.
  • 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.
  • 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 )
  • 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 .
  • 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 ⁇ and 24.95 ⁇ . respectively.
  • 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.
  • 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.
  • 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).
  • Figure 18 suggests that the molar ratio of MEK:Asenapine maleate is 0.28:1.
  • Figure 19 shows the ⁇ - 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 .
  • 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.
  • 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.
  • 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
  • the percentage of remaining of amorphous asenapine maleate at the various conditions 40 °C. 60 °C. 40 °C/75 % H.
  • 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.
  • 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 C C. 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.
  • 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.
  • 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 surface area of crystalline asenapine maleate ( Form II) was determined as 0.5 1 7 m 2 /g (total surface area 0.460 nr and weight 0.889 g).

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Abstract

Nouvelles formes cristallines ou amorphes de maléate d'asénapine compositions pharmaceutiques les renfermant, procédés de préparation et utilisation comme antipsychotique.
PCT/IL2011/000464 2011-02-23 2011-06-12 Polymorphes d'de maléate d'asénapine Ceased WO2012114325A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20121810A1 (it) * 2012-10-24 2014-04-25 Chemo Iberica Sa Poliformi di maleato di asenapina e processo per la loro preparazione
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene

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US20070027134A1 (en) * 2005-04-14 2007-02-01 Organon Ireland Ltd. Crystal form of asenapine maleate
US20080009619A1 (en) * 2006-07-05 2008-01-10 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
US20080090892A1 (en) * 2006-10-06 2008-04-17 N.V. Organon Amorphous asenapine and processes for preparing same

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Publication number Priority date Publication date Assignee Title
US20070027134A1 (en) * 2005-04-14 2007-02-01 Organon Ireland Ltd. Crystal form of asenapine maleate
US20080200671A1 (en) * 2005-04-14 2008-08-21 N.V. Organon Crystal form of asenapine maleate
US20080009619A1 (en) * 2006-07-05 2008-01-10 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
US20080090892A1 (en) * 2006-10-06 2008-04-17 N.V. Organon Amorphous asenapine and processes for preparing same

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20121810A1 (it) * 2012-10-24 2014-04-25 Chemo Iberica Sa Poliformi di maleato di asenapina e processo per la loro preparazione
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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