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WO2012063246A1 - Forme amorphe du chlorhydrate de lurasidone - Google Patents

Forme amorphe du chlorhydrate de lurasidone Download PDF

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Publication number
WO2012063246A1
WO2012063246A1 PCT/IL2011/050009 IL2011050009W WO2012063246A1 WO 2012063246 A1 WO2012063246 A1 WO 2012063246A1 IL 2011050009 W IL2011050009 W IL 2011050009W WO 2012063246 A1 WO2012063246 A1 WO 2012063246A1
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WIPO (PCT)
Prior art keywords
lurasidone
amorphous
meoh
hcl
lurasidone hcl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/IL2011/050009
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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 WO2012063246A1 publication Critical patent/WO2012063246A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and filtration properties. Variations in any one of these properties may affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for pharmaceutical and medical use.
  • the present invention provides a new amorphous form of lurasidone HCl, pharmaceutical compositions comprising this form, methods for its preparation and use thereof in treating schizophrenia and bipolar disorder.
  • the present invention is based in part on the unexpected finding that the new amorphous form disclosed herein possesses advantageous physicochemical properties which render its processing and use as a medicament beneficial.
  • the new amorphous form has a higher maximal solubility value in water and acidic media, indicating improved bioavailability as compared with the known crystalline form.
  • the amorphous form dissolves more rapidly than the crystalline form in 0.1N HCl, which is of significant pharmaceutical advantage, as lurasidone HCl is typically formulated into an immediate release dosage form, in which the lurasidone active ingredient is mainly absorbed in the acidic medium of the stomach.
  • the new form of the present invention thus has good solubility, bioavailability as well as adequate stability characteristics enabling its incorporation into a variety of different formulations particularly suitable for pharmaceutical utility.
  • the present invention provides an amorphous form of lurasidone HCl.
  • the present invention provides an amorphous form of lurasidone HCl characterized by an X-ray diffraction (XRD) profile substantially as shown in any of Figures 1A, IB, 1C, ID, IE, 2A, 2B, 2C, 3A, 3B, 9A, 9B, 15A, 21A, 27A, 27B, 27C, 28A, 28B, 28C, 28D or 34.
  • XRD X-ray diffraction
  • the present invention provides an amorphous form of lurasidone HCl characterized by a DSC profile substantially as shown in any of Figures 4, 10, 16, 22, 29 or 35.
  • amorphous form of lurasidone HCl has a glass transition temperature between about 40°C and about 115°C, for example about 43°C, about 61°C, about 110°C, about 112°C, or about 113°C.
  • the amorphous form of lurasidone is characterized by a TGA profile substantially as shown in any of Figures 5, 11, 17, 23, 30 or 36.
  • the amorphous form is characterized by an IR spectrum substantially as shown in any of Figures 6, 12, 18, 24 or 31.
  • the IR spectrum of the amorphous form of lurasidone HCl comprises characteristic peaks at about 738 ⁇ 4, 776 ⁇ 4, 963 ⁇ 4, 1143 ⁇ 4, 1181 ⁇ 4, 1288 ⁇ 4, 1314 ⁇ 4, 1367 ⁇ 4, 1381 ⁇ 4, 1423 ⁇ 4, 1493 ⁇ 4, 1687 ⁇ 4, 1761 ⁇ 4, 2848 ⁇ 4, 2879 ⁇ 4, 2929 ⁇ 4, and 3417 ⁇ 4 cm "1 .
  • the amorphous form of lurasidone HCl is characterized by a Raman spectrum substantially as shown in any of Figures 7, 13, 19, 25, or 32. Each possibility represents a separate embodiment of the invention.
  • the Raman spectrum of the amorphous lurasidone HCl comprises characteristic peaks at about 429 ⁇ 4, 518 ⁇ 4, 649 ⁇ 4, 715 ⁇ 4, 916 ⁇ 4, 1028 ⁇ 4, 1135 ⁇ 4, 1185 ⁇ 4, 1274 ⁇ 4, 1326 ⁇ 4, 1386 ⁇ 4, 1455 ⁇ 4, 1565 ⁇ 4, 1765 ⁇ 4, 2884 ⁇ 4, 2944 ⁇ 4, 3072 ⁇ 4, and 3480 ⁇ 4 on ⁇
  • the amorphous form of lurasidone HCl is characterized by an 1H- NMR spectrum substantially as shown in any of Figures 8, 14, 20, 26, 33 or 37. Each possibility represents a separate embodiment of the invention.
  • the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:
  • MeOH:EtOAc MeOH:EtOH, MeOH:MEK, MeOH:MTBE and MeOH:THF;
  • the solvents in the mixture of solvents are at a volume ratio of about 1:1.
  • the evaporation in step (b) is performed at a room temperature or at a temperature below the boiling point of the solvent or mixture of solvents.
  • the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:
  • step (b) cooling the melted lurasidone obtained in step (a), so as to provide amorphous lurasidone HCl.
  • the cooling in step (b) is selected from fast cooling and slow cooling.
  • fast cooling and slow cooling are selected from fast cooling and slow cooling.
  • the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the step of grinding crystalline lurasidone HCl with forces sufficient to induce the transformation of crystalline lurasidone HCl to amorphous lurasidone HCl.
  • the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:
  • the present invention provides a process for preparing amorphous lurasidone HCl, the process comprising the steps of:
  • step (b) is performed using rotary evaporator.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the amorphous lurasidone HCl of the present invention as an active ingredient, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is in the form of a tablet, suitable for any mode of administration, such as immediate release, slow release, extended release, sustained release, delayed release, controlled release of various orders, and the like. Each possibility represents a separate embodiment of the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the amorphous lurasidone HC1 of the present invention as an active ingredient, and a pharmaceutically acceptable carrier for use in treating schizophrenia or bipolar disorder.
  • the present invention provides a method of treating schizophrenia or bipolar disorder comprising administering to a subject in need thereof an effective amount of the amorphous lurasidone HC1 of the present invention, or a pharmaceutical composition comprising the amorphous lurasidone HC1 of the present invention.
  • the present invention provides the use of the amorphous lurasidone HC1 of the present invention for the preparation of a medicament for treating schizophrenia or bipolar disorder.
  • the subject is a mammal, such as a human.
  • DSC Differential Scanning Calorimetry
  • FTIR Fourier Transform Infrared
  • FT-Raman Fourier Transform - Raman
  • Figure 9 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone
  • Figure 10 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of amorphous lurasidone HCl, obtained by method II with fast cooling.
  • DSC Differential Scanning Calorimetry
  • FIG 11 illustrates a characteristic Thermogravimetric analysis (TGA) profile of amorphous lurasidone HCl, obtained by method II with fast cooling.
  • TGA Thermogravimetric analysis
  • Figure 12 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method II with fast cooling.
  • FTIR Fourier Transform Infrared
  • Figure 13 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method II with fast cooling.
  • FT-Raman Fourier Transform - Raman
  • Figure 14 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method II with fast cooling.
  • NMR Nuclear Magnetic Resonance
  • Figure 15 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min; panel A). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl Form I (Lurasidone API, panel E) and lurasidone HCl Form I after milling at 200 rpm for 10, 20 and 30 min (panels D, C and B).
  • Figure 16 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).
  • DSC Differential Scanning Calorimetry
  • Figure 17 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).
  • TGA Thermogravimetric analysis
  • Figure 18 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).
  • FTIR Fourier Transform Infrared
  • Figure 19 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).
  • FT-Raman Fourier Transform - Raman
  • Figure 20 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method III (milling at 200 rpm for 200 min).
  • NMR Nuclear Magnetic Resonance
  • Figure 21 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by method IV (panel A). Also shown for comparison is the X-ray diffraction pattern of crystalline lurasidone HCl Form I (Lurasidone API, panel B).
  • Figure 22 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by method IV.
  • DSC Differential Scanning Calorimetry
  • FIG. 23 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by method IV.
  • TGA Thermogravimetric analysis
  • Figure 24 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method IV
  • Figure 25 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method IV.
  • FT-Raman Fourier Transform - Raman
  • Figure 26 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method IV.
  • Figure 28 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone
  • Figure 29 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by method V using MeOH.
  • DSC Differential Scanning Calorimetry
  • Figure 30 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by method V using MeOH.
  • TGA Thermogravimetric analysis
  • Figure 31 illustrates a characteristic Fourier Transform Infrared (FTIR) spectrum of amorphous lurasidone HCl, obtained by method V using MeOH.
  • FTIR Fourier Transform Infrared
  • Figure 32 illustrates a characteristic Fourier Transform - Raman (FT-Raman) spectrum of amorphous lurasidone HCl, obtained by method V using MeOH.
  • FT-Raman Fourier Transform - Raman
  • Figure 33 illustrates characteristic Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by method V using MeOH.
  • Figure 34 illustrates a characteristic X-ray diffraction pattern of amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.
  • Figure 35 illustrates a characteristic Differential Scanning Calorimetry (DSC) profile of an amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.
  • DSC Differential Scanning Calorimetry
  • Figure 36 illustrates a characteristic Thermogravimetric analysis (TGA) profile of an amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.
  • TGA Thermogravimetric analysis
  • Figure 37 illustrates characteristic 1H-Nuclear Magnetic Resonance (NMR) spectrum of amorphous lurasidone HCl, obtained by scaled-up method V using MeOH.
  • Figure 38 shows intrinsic dissolution curves of Form I and amorphous lurasidone HCl in water.
  • Figure 39 shows intrinsic dissolution curves of Form I and amorphous lurasidone HCl in 0. IN HCl.
  • the present invention is directed to novel amorphous form of 3aR,45 , ,7R,7aS)-2- [(( ⁇ R,2R)-2- ⁇ [4-( 1 ,2-benzisothiazol-3-yl)-piperazin- 1 -yljmethyl ⁇ cyclohexyl)methyl] hexahydro-lH-4,7-methanisoindol-l,3-dione hydrochloride.
  • the present invention is further directed to pharmaceutical compositions comprising the amorphous form of the present invention and a pharmaceutically acceptable carrier and its use in treating schizophrenia or bipolar disorder.
  • the present invention is further directed to methods of preparing the novel amorphous form of the present invention.
  • Polymorphs are two or more solid state phases of the same chemical compound that possess different arrangement and/or conformation of the molecules. Different polymorphs of an active pharmaceutical compound can exhibit different physical and chemical properties such as color, stability, processability, dissolution and even bioavailability.
  • a compound used as an active ingredient of a medicament is its solubility in aqueous media, e.g. gastric and intestinal fluids. This may bear consequences on the absorption ability of the compound and hence on its bioavailability.
  • the identification and characterization of various morphic or amorphic forms of a pharmaceutically active compound is therefore of great significance in obtaining medicaments with desired properties including a specific dissolution rate, milling property, bulk density, thermal stability or shelf-life.
  • the novel form of lurasidone HCl disclosed herein possess improved physicochemical properties. For example, the new amorphous form has a higher maximal solubility value in water and acidic media, indicating improved bioavailability as compared with the known crystalline form.
  • the amorphous form dissolves more rapidly than the crystalline form in 0.1N HCl, which is of significant pharmaceutical advantage, as lurasidone HCl is typically formulated into an immediate release dosage form, in which the Lurasidone active ingredient is mainly absorbed in the acidic medium of the stomach.
  • the present invention provides an amorphous form of lurasidone HCl which is characterized by an X-ray diffraction pattern having a single broad peak expressed between about 15 and about 35 degrees two theta [2 ⁇ °] as is shown in any of Figures 1A, IB, 1C, ID, IE, 2A, 2B, 2C, 3A, 3B, 9A, 9B, 15A, 21A, 27A, 27B, 27C, 28A, 28B, 28C, 28D or 34.
  • Each possibility represents a separate embodiment of the present invention.
  • the amorphous form is further characterized by its glass transition temperature and by using various techniques including infrared spectroscopy, Raman spectrometry, and thermal analysis (e.g. thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the amorphous form of lurasidone HCl of the present invention is characterized by a DSC profile substantially as shown in any of Figures 4, 10, 16, 22, 29 or 35. Each possibility represents a separate embodiment of the present invention.
  • the amorphous form of lurasidone HCl of the present invention is further characterized by a TGA profile substantially as shown in any of Figures 5, 11, 17, 23, 30 or 36. Each possibility represents a separate embodiment of the present invention.
  • the amorphous form has a glass transition temperature between about 40°C and about 115°C. In some embodiments, the glass transition temperature of amorphous lurasidone HCl is about 43°C.
  • the glass transition temperature of amorphous lurasidone HCl is about 61°C. In yet other embodiments, the glass transition temperature of amorphous lurasidone HCl is about 110°C. In particular embodiments, the glass transition temperature of amorphous lurasidone HCl is about 112°C. In further embodiments, the glass transition temperature of amorphous lurasidone HCl is about 113°C.
  • the amorphous lurasidone HCl is characterized by an infrared spectrum substantially as shown in any of Figures 6, 12, 18, 24 or 31 with characteristic peaks at the following wavenumbers: about 738, about 776, about 963, about 1 143, about 1181, about 1288, about 1314, about 1367, about 1381, about 1423, about 1493, about 1687, about 1761, about 2848, about 2879, about 2929, and about 3417 cm "1 .
  • the amorphous form of lurasidone HCl is characterized by a Raman spectrum substantially as shown in any of Figures 7, 13, 19, 25 or 32 with characteristic peaks at the following wavenumbers: about 429, about 518, about 649, about 715, about 916, about 1028, about 1135, about 1185, about 1274, about 1326, about 1386, about 1455, about 1565, about 1765, about 2884, about 2944, about 3072, and about 3480 cm "1 .
  • the amorphous form of lurasidone HCl is characterized by an IH-NMR spectrum substantially as shown in any of Figures 8, 14, 20, 26, 33 or 37. Each possibility represents a separate embodiment of the invention.
  • the present invention further provides processes for the preparation of amorphous lurasidone HCl.
  • the processes include thermal precipitations by fast or slow cooling, precipitations from saturated solutions, precipitations under high pressure, and precipitations using freeze-drying. Any type of lurasidone can be used as the starting material in the methods Of the present invention.
  • these processes involve the use of lurasidone, such as crystalline lurasidone HCl (Form I, designated herein "API") as the starting material or any other lurasidone prepared by any methods known in the art, including, for example, the methods described in JP2004224764 (SUMITOMO PHARMA, 2004); WO 2005/009999 (US 7,605,260); JP-A-5-17440 (US 5,532,372 and US 5,780,632) or any other synthetic method.
  • the lurasidone HCl starting material is heated until fully melted, preferably under vacuum followed by controlled precipitation by slow/fast cooling.
  • the lurasidone HC1 starting material is dissolved in water comprising about 5% MeOH. The water is then removed using freeze drying (lyophilization).
  • the lurasidone HC1 starting material is dissolved in a suitable solvent or a mixture of solvents, e.g., at room temperatures or at temperatures below the solvent boiling point. The solvent is then removed by slow or fast evaporation.
  • Suitable solvents include, but are not limited to, acetone, methanol (MeOH), ethanol (EtOH), methylene chloride ((3 ⁇ 4(3 ⁇ 4), dichloromethane (DCM), acetonitrile (ACN), tetrahydrofuran (THF), ethyl acetate (EtOAc), methyl ethyl ketone (MEK), methyl t- butyl ether (MTBE), 1,4 dioxane and mixtures thereof including, but not limited to, DCM:MeOH (1:1), EtOH:acetone (1:1), MeOH:ACN (1:1), MeOH:l,4 dioxane (1 :1), MeOH:EtOAc (1:1), MeOH:EtOH (1 :1), MeOH:MEK (1:1), MeOH:MTBE (1:1), MeOH:THF (1 :1), DCM:ACN (1 :1), DCM:MEK (1:1), MeOH:D
  • Methods for "precipitation from solution” include, but are not limited to, evaporation of a solvent or solvent mixture, a concentration method, a slow cooling method, a fast cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, a fusing agent method, and so forth.
  • the solution can be a saturated solution or supersaturated solution, optionally heated to temperatures below the solvent boiling point.
  • the recovery of the forms can be done for example, by filtering the suspension and drying. Alternatively, the solvents may be removed by rotary evaporation at desired temperatures.
  • Techniques for precipitation from a solvent or solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, or freeze drying the solvent mixture.
  • amorphous lurasidone HC1 comprising heating crystalline lurasidone HC1 to a melt followed by fast or slow cooling of the melt to obtain amorphous lurasidone HC1.
  • the novel amorphous form of the present invention is useful as an antipsychotic pharmaceutical for treating schizophrenia or bipolar disorder.
  • the present invention thus provides pharmaceutical compositions comprising the novel amorphous form disclosed herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical amorphous form can be safely administered orally or non-orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual.
  • the lurasidone HC1 amorphous form of the present invention is administered orally.
  • the pharmaceutical compositions can be formulated as tablets (including e.g. film-coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, and sustained-release preparations as is well known in the art.
  • Pharmacologically acceptable carriers that may be used in the context of the present invention include various organic or inorganic carriers including, but not limited to, excipients, lubricants, binders, disintegrants, water-soluble polymers and basic inorganic salts.
  • the pharmaceutical compositions of the present invention may further include additives such as, but not limited to, preservatives, antioxidants, coloring agents, sweetening agents, souring agents, bubbling agents and flavorings.
  • Suitable excipients include e.g. lactose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride and titanium oxide.
  • Suitable lubricants include e.g. magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc and stearic acid.
  • Suitable binders include e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, crystalline cellulose, a- starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low-substitutional hydroxypropyl cellulose.
  • Suitable disintegrants include e.g.
  • crosslinked povidone any crosslinked 1 -ethenyl-2-pyrrolidinone homopolymer including polyvinylpyrrolidone (PVPP) and l-vinyl-2-pyrrolidinone homopolymer
  • PVPP polyvinylpyrrolidone
  • l-vinyl-2-pyrrolidinone homopolymer crosslinked carmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cornstarch and the like.
  • Suitable water-soluble polymers include e.g. cellulose derivatives such as hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like.
  • Suitable basic inorganic salts include e.g. basic inorganic salts of sodium, potassium, magnesium and/or calcium. Particular embodiments include the basic inorganic salts of magnesium and/or calcium.
  • Basic inorganic salts of sodium include, for example, sodium carbonate, sodium hydrogen carbonate, disodiumhydrogenphosphate, etc.
  • Basic inorganic salts of potassium include, for example, potassium carbonate, potassium hydrogen carbonate, etc.
  • Basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite, aluminahydroxidemagnesium and the like.
  • Basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium hydroxide, etc.
  • Suitable preservatives include e.g. sodium benzoate, benzoic acid, and sorbic acid.
  • Suitable antioxidants include e.g. sulfites, ascorbic acid and a-tocopherol.
  • Suitable coloring agents include e.g. food colors such as Food Color Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2 and the like.
  • Suitable sweetening agents include e.g. dipotassium glycyrrhetinate, aspartame, stevia and thaumatin.
  • Suitable souring agents include e.g. citric acid (citric anhydride), tartaric acid and malic acid.
  • Suitable bubbling agents include e.g. sodium bicarbonate.
  • Suitable flavorings include synthetic substances or naturally occurring substances, including e.g. lemon, lime, orange, menthol and strawberry.
  • the lurasidone HCl amorphous form of the present invention is particularly suitable for oral administration in the form of tablets, capsules, pills, dragees, powders, granules and the like.
  • a tablet may be made by compression or molding, optionally with one or more excipients as is known in the art.
  • molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets and other solid dosage forms of the pharmaceutical compositions described herein may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices and the like.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • the present invention provides a method of treating schizophrenia or bipolar disorder comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising the amorphous lurasidone HCl disclosed herein.
  • a therapeutically effective amount 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 and bipolar disorder.
  • the lurasidone HCl amorphous form of the present invention are used for the preparation of an antipsychotic medicament.
  • the present invention further provides the administration of the lurasidone HC1 amorphous form of the present invention in combination therapy with one or more other active ingredients.
  • the combination therapy may include the two or more active ingredients within a single pharmaceutical composition as well as the two or more active ingredients in two separate pharmaceutical compositions administered to the same subject simultaneously or at a time interval determined by a skilled artisan.
  • Tube Voltage 40 kV
  • Tube Current 40 mA.
  • Lurasidone HCl (Batch No. B174-065A1) was heated to melt under vacuum. The lurasidone melt was then rapidly or slowly cooled. Amorphous lurasidone HCl was identified by this method, as set forth in the Examples below.
  • Lurasidone HCl (Batch No. B 174-06 A 1) was milled by using planetary mono mill at 200 rpm for 200 min. Amorphous lurasidone HCl was identified by this method, as set forth in the Examples below.
  • Lurasidone HCl (Batch No. B174-065A1) was dissolved in water with 5 % MeOH. The water was then removed by freeze drying. Amorphous lurasidone HCl was identified by this method, as set forth in the Examples below. 4.5 Method V: Fast precipitation from saturated solutions
  • the amorphous lurasidone HC1 obtained by this method was characterized by a broad X-ray diffraction peak between about 15 and about 35 [20°] characteristic of an amorphous powder ( Figure 1, panels A-E; Figure 2, panels A-C; and Figure 3, panels A-B).
  • the glass transition temperature of the amorphous lurasidone HC1 prepared by this method was found to be 42.84°C.
  • Figure 5 illustrates a characteristic TGA profile with about 2.5% weight loss from 39°C to 154°C (residual solvents) and about 5.9% weight loss from 154°C to 268°C.
  • Figure 6 illustrates a characteristic IR spectrum with peaks at about 738, 775, 963, 1040, 1143, 1181, 1263, 1288, 1315, 1369, 1424, 1493, 1686, 1761, 2448, 2879, 2930, and 3408 cm “1 .
  • Figure 7 illustrates a characteristic FT-Raman spectrum with peaks at about 190, 436, 521, 655, 715, 836, 920, 1028, 1135, 1185, 1271, 1326, 1383, 1458, 1565, 1765, 2798, 2866, 2944, 3070, and 3484 cm 4 .
  • the residual solvents (about 0.47% MeOH and 1.88% EtOAc) were calculated according to the NMR spectrum ( Figure 8).
  • Figure 12 illustrates a characteristic IR spectrum with peaks at about 737, 772, 964, 1005, 1144, 1182, 1260, 1287, 1312, 1363, 1394, 1424, 1492, 1691, 1765, 2851, 2880, 2925, and 3436 cm “1 .
  • Figure 13 illustrates a characteristic FT-Raman spectrum with peaks at about 1553, 1766, 1863, 1973, and 2085 cm "1
  • Figure 14 shows a characteristic NMR spectrum. The spectroscopic analyses suggest that the amorphous lurasidone HCl undergoes degradation during the melting process at high temperatures.
  • Lurasidone HCl (Batch No. B174-065A1) was milled by using planetary mono mill at 200 rpm for 200 min to afford amorphous lurasidone HCl.
  • Figure 15 panel A) shows a characteristic XRPD of the amorphous form obtained by this method.
  • Figure 16 illustrates a characteristic DSC profile with glass transition temperature of 113.06 °C.
  • Figure 17 illustrates a characteristic TGA profile with a weight loss of about 3.15% between 33 and 151 °C (residual solvent) and weight loss of 5.3% between 152 and 270 °C.
  • Figure 18 illustrates a characteristic IR spectrum with peaks at about 739, 772, 956, 1136, 1 182, 1264, 1289, 1317, 1367, 1383, 1425, 1494, 1687, 1767, 2439, 2879, 2927, and 3417 cm "1 .
  • Figure 19 illustrates a characteristic FT-Raman spectrum with peaks at about 197, 340, 457, 525, 642, 715, 764, 839, 916, 1025, 1075, 1188, 1286, 1326, 1380, 1461, 1562, 1765, 2867, 2947, and 3070 cm "1
  • Figure 20 shows a characteristic NMR spectrum.
  • the NMR spectrum does not show any residual solvent. Without being bound by any theory or mechanism of action, it is contemplated that the loss of weight of 3.15% in the TGA profile is assigned to adsorbed water.
  • Figure 24 illustrates a characteristic IR spectrum with peaks at about 739, 768, 963, 1144, 1182, 1264, 1288, 1316, 1364, 1383, 1424, 1493, 1688, 1761, 2443, 2852, 2879, 2929, and 3424 cm “1 .
  • Figure 25 illustrates a characteristic FT-Raman spectrum with peaks at about 211, 429, 518, 649, 715, 793, 916, 1028, 1135, 1185, 1274, 1326, 1386, 1455, 1565, 1765, 2868, 2884, 2944, 2980, 3072, and 3480 cm "1
  • Figure 26 shows a characteristic NMR spectrum. The NMR spectrum shows 0.36% residual MeOH.
  • Example 6 Amorphous Lurasidone HCl (Method V) General method V was performed.
  • the solvents/mixture of solvents were then removed by rotary evaporator below 50 °C.
  • Figures 27 (panels A-C) and 28 (panels A-D) show characteristic XRPD of the amorphous form obtained by this method.
  • Figure 29 illustrates a characteristic DSC profile of a sample obtained from a MeOH solution. The glass transition temperature of the amorphous form obtained by this method is 110.36 °C.
  • Figure 30 illustrates a characteristic TGA profile with a weight loss of about 4.5% between 37 and 150 °C (residual solvent) and weight loss of 5.9% between 150 and 260 °C.
  • Figure 31 illustrates a characteristic IR spectrum with peaks at about 738, 776, 963, 1029, 1143, 1181, 1283, 1288, 1314, 1367, 1381, 1423, 1493, 1687, 1761, 2435, 2848, 2879, 2929, and 3417 cm "1 .
  • Figure 32 illustrates a characteristic FT-Raman spectrum with peaks at about 204, 426, 525, 649, 715, 836, 920, 1025, 1132, 1181, 1268, 1326, 1383, 1458, 1565, 1768, 2887, 2944, 3072, and 3480 cm " '
  • Figure 33 shows a characteristic NMR spectrum. The NMR spectrum shows 0.33 % residual MeOH.
  • Method V was scaled up. About 100 mg/ml solution of Lurasidone HC1 was prepared with MeOH at room temperature. Then the solvent was removed by rotary evaporator at 50 °C. The powder was dried in vacuum oven at 40 °C for 24 hrs. The dry powder was characterized by XRPD (Figure 34), DSC (Figure 35), TGA ( Figure 36) and NMR ( Figure 37). The results are consistent with Figures 28, 29, 30 and 33. As per the DSC (topem) results, the glass transition temperature of the amorphous form is 110.4 °C. The residual MeOH is less than 0.3 % based on NMR result.
  • Example 7 Hygroscopicity of Form I and amorphous Lurasidone HC1
  • Hygroscopic increase in mass is less than 15 % and equal to or greater than 2 %.
  • Testing media used was: water, pH 1.2, 4.5, 6.8, 7.4 USP buffers, 0.01 N HCl, 0.1 N
  • Form I showed a little better solubility than amorphous form in most of the media except water and 0.0 IN HC1.
  • amorphous Lurasidone HC1 has high solubility rate in water and acidic media suggests improved bioavailability of the amorphous form in comparison with the known crystalline form.

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Abstract

La présente invention concerne une nouvelle forme amorphe de HC1 de lurasidone, des compositions pharmaceutiques la comprenant, leurs procédés de préparation et d'utilisation comme agent antipsychotique.
PCT/IL2011/050009 2010-11-11 2011-11-10 Forme amorphe du chlorhydrate de lurasidone Ceased WO2012063246A1 (fr)

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WO2013121440A1 (fr) 2012-02-13 2013-08-22 Cadila Healthcare Limited Procédé de préparation de benzisothiazol-3-yl-pépérazin-l-yl-méthyl-cyclohexyl-méthanisoindol-1,3-dione et de ses intermédiaires
WO2013132511A1 (fr) * 2012-03-09 2013-09-12 Hetero Research Foundation Nouveau polymorphe de chlorhydrate de lurasidone
CN103446071A (zh) * 2012-05-29 2013-12-18 江苏豪森药业股份有限公司 一种口服片剂及其制备方法和用途
WO2014013465A3 (fr) * 2012-07-18 2014-04-24 Shasun Pharmaceuticals Limited Sels et hydrates de composés antipsychotiques
CN104059061A (zh) * 2014-07-04 2014-09-24 中国药科大学 一种难溶性药物的共无定形物
WO2014076712A3 (fr) * 2012-11-14 2015-03-12 Hetero Research Foundation Dispersion solide de chlorhydrate de lurasidone
CN106512011A (zh) * 2016-11-04 2017-03-22 中国药科大学 一种缓慢释放药物的方法
CN107163037A (zh) * 2017-07-05 2017-09-15 中国药科大学 一种盐酸鲁拉西酮氨基酸的共无定形物
US9790237B2 (en) 2014-06-16 2017-10-17 Johnson Matthey Public Limited Company Processes for making alkylated arylpiperazine and alkylated arylpiperidine compounds including novel intermediates
CN111454256A (zh) * 2020-04-29 2020-07-28 湖北中医药大学 一种帕莫酸鲁拉西酮无定形物及其制备方法与应用
CN111978315A (zh) * 2020-09-02 2020-11-24 中国药科大学 盐酸鲁拉西酮色氨酸/l-脯氨酸共无定形物及其制备方法和应用
WO2021107967A1 (fr) * 2019-01-10 2021-06-03 Slayback Pharma Llc Compositions pharmaceutiques de lurasidone
CN115960108A (zh) * 2021-10-09 2023-04-14 山东新时代药业有限公司 一种无定型盐酸纳呋拉啡及其制备方法
CN115960108B (en) * 2021-10-09 2026-02-03 山东新时代药业有限公司 Amorphous nalfurorphine hydrochloride and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013121440A1 (fr) 2012-02-13 2013-08-22 Cadila Healthcare Limited Procédé de préparation de benzisothiazol-3-yl-pépérazin-l-yl-méthyl-cyclohexyl-méthanisoindol-1,3-dione et de ses intermédiaires
US9409899B2 (en) 2012-02-13 2016-08-09 Cadila Healthcare Limited Process for preparing benzisothiazol-3-yl-piperazin-1-yl-methyl-cyclo hexylmethanisoindol-1,3-dione and its intermediates
WO2013132511A1 (fr) * 2012-03-09 2013-09-12 Hetero Research Foundation Nouveau polymorphe de chlorhydrate de lurasidone
CN103446071A (zh) * 2012-05-29 2013-12-18 江苏豪森药业股份有限公司 一种口服片剂及其制备方法和用途
US9580414B2 (en) 2012-07-18 2017-02-28 Shasun Pharmaceuticals Limited Salts and hydrates of antipsychotics
WO2014013465A3 (fr) * 2012-07-18 2014-04-24 Shasun Pharmaceuticals Limited Sels et hydrates de composés antipsychotiques
WO2014076712A3 (fr) * 2012-11-14 2015-03-12 Hetero Research Foundation Dispersion solide de chlorhydrate de lurasidone
US9790237B2 (en) 2014-06-16 2017-10-17 Johnson Matthey Public Limited Company Processes for making alkylated arylpiperazine and alkylated arylpiperidine compounds including novel intermediates
US9957283B1 (en) 2014-06-16 2018-05-01 Johnson Matthey Public Limited Company Processes for making alkylated arylpiperazine and alkylated arylpiperidine compounds including novel intermediates
CN104059061A (zh) * 2014-07-04 2014-09-24 中国药科大学 一种难溶性药物的共无定形物
CN106512011A (zh) * 2016-11-04 2017-03-22 中国药科大学 一种缓慢释放药物的方法
CN107163037A (zh) * 2017-07-05 2017-09-15 中国药科大学 一种盐酸鲁拉西酮氨基酸的共无定形物
CN107163037B (zh) * 2017-07-05 2020-04-21 中国药科大学 一种盐酸鲁拉西酮氨基酸的共无定形物
US11103503B2 (en) 2019-01-10 2021-08-31 Slayback Pharma Llc Pharmaceutical compositions of Lurasidone
WO2021107967A1 (fr) * 2019-01-10 2021-06-03 Slayback Pharma Llc Compositions pharmaceutiques de lurasidone
US11103502B2 (en) 2019-01-10 2021-08-31 Slayback Pharma Llc Pharmaceutical compositions of lurasidone
CN111454256A (zh) * 2020-04-29 2020-07-28 湖北中医药大学 一种帕莫酸鲁拉西酮无定形物及其制备方法与应用
CN111978315A (zh) * 2020-09-02 2020-11-24 中国药科大学 盐酸鲁拉西酮色氨酸/l-脯氨酸共无定形物及其制备方法和应用
CN111978315B (zh) * 2020-09-02 2023-03-24 中国药科大学 盐酸鲁拉西酮色氨酸/l-脯氨酸共无定形物及其制备方法和应用
CN115960108A (zh) * 2021-10-09 2023-04-14 山东新时代药业有限公司 一种无定型盐酸纳呋拉啡及其制备方法
CN115960108B (en) * 2021-10-09 2026-02-03 山东新时代药业有限公司 Amorphous nalfurorphine hydrochloride and preparation method thereof

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