WO2012107890A2 - Crystalline forms of lurasidone hydrochloride - Google Patents
Crystalline forms of lurasidone hydrochloride Download PDFInfo
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- WO2012107890A2 WO2012107890A2 PCT/IB2012/050573 IB2012050573W WO2012107890A2 WO 2012107890 A2 WO2012107890 A2 WO 2012107890A2 IB 2012050573 W IB2012050573 W IB 2012050573W WO 2012107890 A2 WO2012107890 A2 WO 2012107890A2
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- Prior art keywords
- lurasidone
- crystalline form
- hydrochloride
- lurasidone hydrochloride
- base
- Prior art date
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- 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
- C07D417/08—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 carbon chain containing alicyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Definitions
- the present invention provides crystalline forms of lurasidone hydrochloride, processes for their preparation, pharmaceutical compositions comprising them and their use for the treatment of schizophrenia.
- Lurasidone hydrochloride is chemically (3aR,4S,7R,7aS)-2- ⁇ (lR,2R)-2-[4-(l,2- benzisothiazol-3 -yl)piperazin- 1 -ylmethyl]cyclohexylmethyl ⁇ hexahydro-4,7-methano-2H- isoindole-l,3-dione hydrochloride, having the structure as represented by Formula I and is known from U.S. Patent No. 5,532,372.
- U.S. Patent No. 5,532,372 describes the preparation of lurasidone hydrochloride using mixture of acetone and iso-propanol solution of hydrogen chloride.
- U.S. Patent No. 7,605,260 describes the preparation of lurasidone hydrochloride using aqueous hydrogen chloride.
- the present invention provides crystalline forms of lurasidone hydrochloride, processes for their preparation, pharmaceutical compositions comprising them and their use for the treatment of schizophrenia.
- the crystalline forms of lurasidone hydrochloride of the present invention are highly pure, easy to filter, free-flowing solids having small average particle size.
- the crystalline forms of the present invention are stable towards polymorphic conversion and show little or no variation in dissolution profile.
- a first aspect of the present invention provides crystalline Form 1 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 5.81, 5.72, 5.55, 5.26 and 4.93A.
- a second aspect of the present invention provides crystalline Form 2 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 5.83, 5.56, 5.28, 4.94 and 4.29 A.
- a third aspect of the present invention provides crystalline Form 3 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 6.50, 5.16, 5.09, 3.61 and 3.43 A.
- a fourth aspect of the present invention provides crystalline Form 4 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 9.65, 5.82, 5.74, 4.83 and 3.94 A.
- a fifth aspect of the present invention provides a process for the preparation of crystalline Form 1 of lurasidone hydrochloride comprising the steps of:
- a sixth aspect of the present invention provides a process for the preparation of crystalline Form 1 of lurasidone hydrochloride comprising the steps of:
- a seventh aspect of the present invention provides a process for the preparation of crystalline Form 2 of lurasidone hydrochloride comprising the steps of:
- An eighth aspect of the present invention provides a process for the preparation of crystalline Form 2 of lurasidone hydrochloride comprising the steps of: i) contacting lurasidone base with toluene;
- a ninth aspect of the present invention provides a process for the preparation of crystalline Form 3 of lurasidone hydrochloride comprising the steps of:
- a tenth aspect of the present invention provides a process for the preparation of crystalline Form 4 of lurasidone hydrochloride comprising the steps of:
- An eleventh aspect of the present invention provides a process for the purification of lurasidone base comprising contacting crude lurasidone base with a solvent.
- a twelfth aspect of the present invention provides lurasidone base having purity greater than 97% as determined by High Performance Liquid Chromatography (HPLC).
- a thirteenth aspect of the present invention provides pharmaceutical compositions comprising crystalline Form 1, 2, 3 or 4 of lurasidone hydrochloride and one or more pharmaceutically acceptable carriers, diluents or excipients.
- a fourteenth aspect of the present invention provides use of crystalline Form 1, 2, Brief Description of the Figures
- Figure 1 X-ray diffraction (XRPD) spectrum of crystalline Form 1 of lurasidone hydrochloride.
- FIG. 3 Differential Scanning Thermogram (DSC) of crystalline Form 1 of lurasidone hydrochloride.
- Figure 5 X-ray diffraction (XRPD) spectrum of crystalline Form 2 of lurasidone hydrochloride.
- FIG. 7 Differential Scanning Thermogram (DSC) of crystalline Form 2 of lurasidone hydrochloride.
- Figure 9 X-ray diffraction (XRPD) spectrum of crystalline Form 3 of lurasidone hydrochloride.
- Figure 1 1 X-ray diffraction (XRPD) spectrum of crystalline Form 4 of lurasidone hydrochloride.
- Figure 13 HPLC chromatogram of crude lurasidone base.
- Figure 14 HPLC chromatogram of pure lurasidone base.
- contacting may include dissolving, slurrying, stirring, or a combination thereof.
- ambient temperature refers to a temperature in the range of about 20°C to about 30°C.
- Crystalline Form 1 of lurasidone hydrochloride may be characterized by XRPD peaks at about 15.26 (d-spacing at about 5.81 A), 15.49 (5.72 A), 15.98 (5.55 A), 16.85 (5.26 A) and 18.00 (4.93 A) ⁇ 0.2° 2 ⁇ . It may be further characterized by XRPD peaks at about 9.01 (9.82 A), 14.16 (6.25 A), 18.46 (4.81 A), 20.77 (4.28 A) and 21.44 (4.14 A) ⁇ 0.2° 2 ⁇ . Crystalline Form 1 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 1.
- Crystalline Form 1 may also be characterized by DSC having endotherms at about 72.50°C and 214.67°C. It may also be characterized by a melting point in the range of about 204°C to 216°C with decomposition.
- Figures 2, 3 and 4 provide IR, DSC and TGA for crystalline Form 1 of lurasidone hydrochloride, respectively.
- Crystalline Form 1 of lurasidone hydrochloride of the present invention has purity greater than 97% as determined by High Performance Liquid Chromatography (HPLC).
- Crystalline Form 2 of lurasidone hydrochloride may be characterized by XRPD peaks at about 15.20 (d-spacing at about 5.83 A), 15.93 (5.56 A), 16.80 (5.28 A), 17.95 (4.94 A) and 20.72 (4.29 A) ⁇ 0.2° 2 ⁇ . It may be further characterized by XRPD peaks at about 8.96 (9.87 A), 14.11 (6.28 A), 15.41 (5.75 A), 21.41 (4.15 A) and 26.41 (3.38 A) ⁇ 0.2° 2 ⁇ . Crystalline Form 2 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 5.
- Crystalline Form 2 may also be characterized by DSC having endotherms at about 75.01°C and 214.99°C. It may also be characterized by a melting point in the range of about 211°C to 213°C with decomposition.
- Figures 6, 7 and 8 provide IR, DSC and TGA for crystalline Form 2 of lurasidone hydrochloride, respectively.
- Crystalline Form 2 of lurasidone hydrochloride of the present invention has purity greater than 98% as determined by HPLC.
- Crystalline Form 3 of lurasidone hydrochloride may be characterized by XRPD peaks at about 13.62 (d-spacing at about 6.50 A), 17.17 (5.16 A), 17.41 (5.09 A), 24.68 (3.61 A) and 25.99 (3.43 A) ⁇ 0.2° 20. It may be further characterized by XRPD peaks at about 4.13 (21.41 A), 12.40 (7.14 A), 13.87 (6.39 A), 15.64 (5.66 A), and 26.32 (3.39 A) ⁇ 0.2° 20. Crystalline Form 3 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 9. Table 3 summarizes the d-spacing in A and the corresponding 20 values. Crystalline Form 3 may also be characterized by IR spectrum as depicted in Figure 10. Crystalline Form 3 of lurasidone hydrochloride of the present invention has purity greater than 98% as determined by HPLC.
- Crystalline Form 4 of lurasidone hydrochloride may be characterized by XRPD peaks at about 9.16 (d-spacing at about 9.65A), 15.22 (5.82 A), 15.44 (5.74 A), 18.39 (4.83 A) and 22.54 (3.94 A) ⁇ 0.2° 2 ⁇ . It may be further characterized by XRPD peaks at about 15.88 (5.58 A), 20.18 (4.40 A), 21.46 (4.14 A), 25.38 (3.51 A), and 30.72 (2.91 A) ⁇ 0.2° 2 ⁇ . Crystalline Form 4 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 11.
- Crystalline Form 4 may also be characterized by IR spectrum as depicted in Figure 12. Crystalline Form 4 of the present invention may also be characterized by a melting point in the range of about 214°C to 216°C with
- Crystalline Form 4 of lurasidone hydrochloride of the present invention has purity greater than 98% as determined by HPLC.
- Table 4 XRPD peaks of crystalline Form 4 of lurasidone hydrochloride
- Crystalline Forms 3 and 4 of the present invention may also be characterized by their Differential Scanning Thermogram (DSC) and Thermogravimetric Analysis (TGA).
- Lurasidone base used for the preparation of crystalline forms of lurasidone hydrochloride of the present invention may be obtained by the method known in U.S. Patent No. 5,532,372, which is incorporated herein by reference. It may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation.
- lurasidone base may be obtained by refluxing a reaction mixture containing trans-3 a,7a-octahydroisoindolium-2-spiro- ⁇ - [4' -( 1 ,2-benzisothiazol-3- yl)]piperazine methane sulfonate, bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide, dibenzo-18-crown-6 and potassium carbonate in xylene or toluene for about 16 to 36 hours to obtain crude lurasidone base.
- Purification of lurasidone base may be carried out by contacting with a solvent selected from the group consisting of alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers and hydrocarbons.
- a solvent selected from the group consisting of alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers and hydrocarbons.
- alcohols are methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol and n-pentanol.
- ketones are acetone, methyl ethyl ketone and methyl isobutyl ketone.
- alkyl acetates are ethyl acetate and isopropyl acetate.
- chlorinated hydrocarbons are dichloromethane and chloroform.
- ethers are diethyl ether, diisopropyl ether and methyl butyl ether.
- hydrocarbons are xylene, toluene, hexane, heptanes and pentane.
- An anti-solvent may also be added in the purification step. The anti-solvent may be selected from water or hydrocarbons.
- hydrocarbons are xylene, toluene, hexane, heptanes and pentane. The examples cited herein are for illustrative purposes only and are not meant to limit the choice to only those solvents identified so.
- crude lurasidone base may be purified using iso-propanol.
- the purification process of the present invention provides lurasidone base having HPLC purity greater than 97%.
- Both crude and purified lurasidone base may be used for the preparation of crystalline forms of the present invention.
- Crystalline Forms 1, 2, 3 and 4 of lurasidone hydrochloride may be prepared by contacting lurasidone base with hydrogen chloride at a temperature in the range from about 0°C to about 120°C or by contacting a solution of lurasidone base in a solvent with hydrogen chloride at a temperature in the range from about 0°C to about 120°C.
- the reaction mixture may be cooled to about -5°C to ambient temperature and stirred for about 1 hour to 2 days.
- An anti-solvent may be added to the reaction mixture followed by drying. Drying may be carried out using any suitable method, such as drying under reduced pressure, drying under atmospheric pressure, air drying or drying under an inert gas atmosphere, such as under nitrogen. Preferably, drying may be carried out at ambient temperature to about 80°C.
- Crystalline Form 1 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with dry hydrogen chloride in iso-propanol. It may also be obtained by contacting a solution of lurasidone base in acetone with dry hydrogen chloride in iso-propanol.
- Crystalline Form 2 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with an alkyl acetate solvent and adding dry hydrogen chloride in iso-propanol. It may also be prepared by contacting lurasidone base with toluene and adding aqueous hydrogen chloride solution.
- Crystalline Form 3 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with acetone, adding aqueous hydrogen chloride followed by an addition of an anti-solvent selected from ethers and hydrocarbons.
- an anti-solvent selected from ethers and hydrocarbons Both acyclic and cyclic ethers may be used as anti-solvents.
- acyclic ethers may include dimethyl ether, diethyl ether or di-isopropyl ether.
- Examples of cyclic ethers may include tetrahydrofuran or 1, 4-dioxane.
- hydrocarbons may include xylene, toluene, hexane, heptanes or pentane.
- di-isopropyl ether may be used.
- Crystalline Form 4 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with ethyl acetate and adding aqueous hydrogen chloride.
- the present invention provides crystalline Form 1 of lurasidone hydrochloride prepared by contacting lurasidone base with dry hydrogen chloride in iso-propanol at a temperature of about 35°C to 55°C, cooling to ambient temperature, optionally diluting with iso-propanol, stirring for about 2 hours to 2 days followed by isolation and drying. Drying may be carried out under reduced pressure at a temperature of about 30°C to 60°C, preferably at about 40°C to 45°C.
- the present invention provides crystalline Form 1 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in acetone with dry hydrogen chloride in iso-propanol at ambient temperature, stirring the reaction mixture for about 2 hours to about 20 hours, cooling to about -15°C to -20°C, diluting with iso-propanol, stirring at ambient temperature for about 1 hour to about 5 hours followed by isolation and drying under reduced pressure at a temperature of about 30°C to about 60°C, preferably at about 40°C to about 45°C.
- the present invention provides crystalline Form 2 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in ethyl acetate with dry hydrogen chloride in iso-propanol at about 0°C to 5°C , raising the temperature to ambient temperature, stirring for about 1 to 5 hours, followed by isolation and drying. Drying may be carried out under reduced pressure at a temperature of about 30°C to 60°C, preferably at about 40°C to 45°C.
- the present invention provides crystalline Form 2 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in toluene with 4% to 5% aqueous hydrochloric acid at ambient temperature, overnight stirring followed by isolation and drying. Drying may be carried out under reduced pressure at a temperature of about 30°C to 60°C.
- the present invention provides crystalline Form 3 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in acetone with about 4% aqueous hydrogen chloride solution, stirring for about 30 minutes to 2 hours, cooling to about -5°C to 10°C, adding an anti-solvent such as ether, cooling to about -5°C to 10°C, filtering and drying under reduced pressure at ambient temperature to about 80°C, preferably at about 50°C.
- di-isopropyl ether may be added as an anti-solvent.
- the present invention provides crystalline Form 4 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in ethyl acetate with 7% aqueous hydrogen chloride solution at about 40°C, cooling to ambient temperature, diluting with ethyl acetate, filtering and drying under reduced pressure at ambient temperature to about 80°C, preferably at about 50°C.
- compositions that comprise crystalline forms of lurasidone hydrochloride of the present invention, and one or more pharmaceutically acceptable carrier(s), diluents(s) or excipients(s) and optionally other therapeutic ingredients.
- the crystalline forms of lurasidone hydrochloride of the present invention may conventionally be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, peroral or parental.
- X-ray diffraction patterns were recorded using Panalytical Expert PRO with copper radiation, Xcelerator as detector, 3-40 as scan range, 0.02 as step size and 3-40° 2 ⁇ as range.
- HPLC purity was determined using a YMC Pack ODS-AM(250x4.6)mm ⁇ m column with a flow rate: 1.5 mL/minute; column oven temperature: 45°C; Detector: UV at 230nm; Injection volume: 10 ⁇ ,; Run time: 37 minutes using buffer and acetonitrile as diluent and lmL o-phosphoric acid + 100 mL water as buffer.
- Step A Preparation of crude lurasidone base
- Step B Purification of lurasidone base
- a reaction mixture containing 2.2 g of crude lurasidone base and dry hydrogen chloride in iso-propanol (10 mL) was heated to a temperature of about 45 °C.
- the reaction mixture was cooled to ambient temperature and stirred for about 20 hours.
- the solid material was filtered, washed with iso-propanol (5 mL) and dried under reduced pressure at about 45 °C to obtain crystalline Form 1 of lurasidone hydrochloride as a white solid (1-2 g).
- a reaction mixture containing 4.0 g of pure lurasidone base and dry hydrogen chloride in iso-propanol (20 mL) was heated to a temperature of about 40°C.
- the reaction mixture was cooled to ambient temperature, diluted with iso-propanol (40 mL) and further stirred for about 5 hours.
- the solid material was filtered, washed with iso-propanol (15 mL) and dried under reduced pressure at about 45 °C to obtain crystalline Form 1 of lurasidone hydrochloride as a white solid (3.3 g).
Abstract
The present invention provides crystalline forms of lurasidone hydrochloride, processes for their preparation, pharmaceutical compositions comprising them and their use for the treatment of schizophrenia.
Description
CRYSTALLINE FORMS OF LURASIDONE HYDROCHLORIDE
Field of the Invention
The present invention provides crystalline forms of lurasidone hydrochloride, processes for their preparation, pharmaceutical compositions comprising them and their use for the treatment of schizophrenia.
Background of the Invention
Lurasidone hydrochloride is chemically (3aR,4S,7R,7aS)-2-{(lR,2R)-2-[4-(l,2- benzisothiazol-3 -yl)piperazin- 1 -ylmethyl]cyclohexylmethyl } hexahydro-4,7-methano-2H- isoindole-l,3-dione hydrochloride, having the structure as represented by Formula I and is known from U.S. Patent No. 5,532,372.
Formula I
U.S. Patent No. 5,532,372 describes the preparation of lurasidone hydrochloride using mixture of acetone and iso-propanol solution of hydrogen chloride.
U.S. Patent No. 7,605,260 describes the preparation of lurasidone hydrochloride using aqueous hydrogen chloride.
Summary of the Invention
The present invention provides crystalline forms of lurasidone hydrochloride, processes for their preparation, pharmaceutical compositions comprising them and their use for the treatment of schizophrenia. The crystalline forms of lurasidone hydrochloride of the present invention are highly pure, easy to filter, free-flowing solids having small average particle size. The crystalline forms of the present invention are stable towards polymorphic conversion and show little or no variation in dissolution profile.
A first aspect of the present invention provides crystalline Form 1 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 5.81, 5.72, 5.55, 5.26 and 4.93A.
A second aspect of the present invention provides crystalline Form 2 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 5.83, 5.56, 5.28, 4.94 and 4.29 A.
A third aspect of the present invention provides crystalline Form 3 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 6.50, 5.16, 5.09, 3.61 and 3.43 A.
A fourth aspect of the present invention provides crystalline Form 4 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 9.65, 5.82, 5.74, 4.83 and 3.94 A.
A fifth aspect of the present invention provides a process for the preparation of crystalline Form 1 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with dry hydrogen chloride in iso-propanol; and ii) isolating crystalline Form 1 of lurasidone hydrochloride.
A sixth aspect of the present invention provides a process for the preparation of crystalline Form 1 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with acetone;
ii) adding dry hydrogen chloride in iso-propanol; and
iii) isolating crystalline Form 1 of lurasidone hydrochloride.
A seventh aspect of the present invention provides a process for the preparation of crystalline Form 2 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with ethyl acetate;
ii) adding dry hydrogen chloride in iso-propanol; and
iii) isolating crystalline Form 2 of lurasidone hydrochloride.
An eighth aspect of the present invention provides a process for the preparation of crystalline Form 2 of lurasidone hydrochloride comprising the steps of: i) contacting lurasidone base with toluene;
ii) adding aqueous hydrogen chloride; and
iii) isolating crystalline Form 2 of lurasidone hydrochloride.
A ninth aspect of the present invention provides a process for the preparation of crystalline Form 3 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with acetone;
ii) adding aqueous hydrogen chloride solution;
iii) adding an anti-solvent; and iv) isolating crystalline Form 3 of lurasidone hydrochloride.
A tenth aspect of the present invention provides a process for the preparation of crystalline Form 4 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with ethyl acetate; ii) adding aqueous hydrogen chloride solution; and
iii) isolating crystalline Form 4 of lurasidone hydrochloride.
An eleventh aspect of the present invention provides a process for the purification of lurasidone base comprising contacting crude lurasidone base with a solvent.
A twelfth aspect of the present invention provides lurasidone base having purity greater than 97% as determined by High Performance Liquid Chromatography (HPLC).
A thirteenth aspect of the present invention provides pharmaceutical compositions comprising crystalline Form 1, 2, 3 or 4 of lurasidone hydrochloride and one or more pharmaceutically acceptable carriers, diluents or excipients.
A fourteenth aspect of the present invention provides use of crystalline Form 1, 2,
Brief Description of the Figures
Figure 1 : X-ray diffraction (XRPD) spectrum of crystalline Form 1 of lurasidone hydrochloride.
Figure 2: Infra-red (IR) spectrum of crystalline Form 1 of lurasidone
hydrochloride.
Figure 3: Differential Scanning Thermogram (DSC) of crystalline Form 1 of lurasidone hydrochloride.
Figure 4: Thermogravimetric Analysis (TGA) of crystalline Form 1 of lurasidone hydrochloride.
Figure 5: X-ray diffraction (XRPD) spectrum of crystalline Form 2 of lurasidone hydrochloride.
Figure 6: Infra-red (IR) spectrum of crystalline Form 2 of lurasidone
hydrochloride.
Figure 7: Differential Scanning Thermogram (DSC) of crystalline Form 2 of lurasidone hydrochloride.
Figure 8: Thermogravimetric Analysis (TGA) of crystalline Form 2 of lurasidone hydrochloride.
Figure 9: X-ray diffraction (XRPD) spectrum of crystalline Form 3 of lurasidone hydrochloride.
Figure 10: Infra-red (IR) spectrum of crystalline Form 3 of lurasidone
hydrochloride.
Figure 1 1 : X-ray diffraction (XRPD) spectrum of crystalline Form 4 of lurasidone hydrochloride.
Figure 12: Infra-red (IR) spectrum of crystalline Form 4 of lurasidone
hydrochloride.
Figure 13: HPLC chromatogram of crude lurasidone base. Figure 14: HPLC chromatogram of pure lurasidone base.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term "contacting" may include dissolving, slurrying, stirring, or a combination thereof.
The term "ambient temperature", as used herein, refers to a temperature in the range of about 20°C to about 30°C.
The term "about", as used herein with respect to XRPD peaks, refers to a d-spacing range of ±0.1 A and a 2Θ range of ±0.2°.
Crystalline Form 1 of lurasidone hydrochloride may be characterized by XRPD peaks at about 15.26 (d-spacing at about 5.81 A), 15.49 (5.72 A), 15.98 (5.55 A), 16.85 (5.26 A) and 18.00 (4.93 A) ± 0.2° 2Θ. It may be further characterized by XRPD peaks at about 9.01 (9.82 A), 14.16 (6.25 A), 18.46 (4.81 A), 20.77 (4.28 A) and 21.44 (4.14 A) ± 0.2° 2Θ. Crystalline Form 1 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 1. Table 1 summarizes the d-spacing in A and the corresponding 2Θ values. Crystalline Form 1 may also be characterized by DSC having endotherms at about 72.50°C and 214.67°C. It may also be characterized by a melting point in the range of about 204°C to 216°C with decomposition. Figures 2, 3 and 4 provide IR, DSC and TGA for crystalline Form 1 of lurasidone hydrochloride, respectively. Crystalline Form 1 of lurasidone hydrochloride of the present invention has purity greater than 97% as determined by High Performance Liquid Chromatography (HPLC).
Table 1: XRPD peaks of crystalline Form 1 of lurasidone hydrochloride
Position (°2Θ) d-spacing (A) Relative Intensity (%)
4.81 18.38 5.72
5.19 17.02 4.56
8.00 11.05 34.89
9.01 9.82 44.78
9.23 9.58 31.64
9.55 9.27 3.04
10.39 8.51 1.72
12.81 6.91 2.13
13.22 6.65 2.20
Position (°2Θ) d-spacing (A) Relative Intensity (%)
14.16 6.25 45.17
14.99 5.91 28.70
15.26 5.81 69.25
15.49 5.72 99.25
15.98 5.55 100.00
16.85 5.26 63.75
17.15 5.17 19.69
18.00 4.93 66.22
18.46 4.81 60.23
19.40 4.58 10.85
19.87 4.47 14.96
20.25 4.39 32.33
20.77 4.28 55.03
21.44 4.14 48.89
21.79 4.08 23.23
22.37 3.98 23.76
22.63 3.93 29.84
23.11 3.85 19.32
23.50 3.79 11.79
23.93 3.72 7.15
24.51 3.63 10.34
24.85 3.58 10.86
25.44 3.50 29.14
25.78 3.46 19.29
26.45 3.37 43.96
26.98 3.31 16.73
27.45 3.25 13.96
27.81 3.21 12.55
28.24 3.16 13.31
29.17 3.06 11.02
29.57 3.02 10.79
29.96 2.98 10.49
30.78 2.91 24.42
31.10 2.88 13.27
31.48 2.84 10.45
32.20 2.78 11.77
32.98 2.72 9.03
33.44 2.68 14.11
35.13 2.55 14.90
35.49 2.53 9.89
36.56 2.46 6.27
37.10 2.42 10.26
39.98 2,31 8.11
Crystalline Form 2 of lurasidone hydrochloride may be characterized by XRPD peaks at about 15.20 (d-spacing at about 5.83 A), 15.93 (5.56 A), 16.80 (5.28 A), 17.95 (4.94 A) and 20.72 (4.29 A) ± 0.2° 2Θ. It may be further characterized by XRPD peaks at about 8.96 (9.87 A), 14.11 (6.28 A), 15.41 (5.75 A), 21.41 (4.15 A) and 26.41 (3.38 A) ± 0.2° 2Θ. Crystalline Form 2 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 5. Table 2 summarizes the d-spacing in A and the corresponding 2Θ values. Crystalline Form 2 may also be characterized by DSC having endotherms at about 75.01°C and 214.99°C. It may also be characterized by a melting point in the range of about 211°C to 213°C with decomposition. Figures 6, 7 and 8 provide IR, DSC and TGA for crystalline Form 2 of lurasidone hydrochloride, respectively. Crystalline Form 2 of lurasidone hydrochloride of the present invention has purity greater than 98% as determined by HPLC.
Table 2: XRPD peaks of crystalline Form 2 of lurasidone hydrochloride
Position (°2Θ) d-spacing (A) Relative Intensity (%)
4.77 18.53 7.98
7.96 11.11 34.52
8.96 9.87 50.12
9.5 9.30 2.79
10.41 8.50 1.91
13.39 6.61 2.59
14.11 6.28 53.60
14.30 6.20 12.50
15.20 5.83 58.77
15.41 5.75 38.36
15.93 5.56 100.00
16.26 5.45 7.90
16.80 5.28 62.30
17.95 4.94 78.15
19.34 4.59 11.88
20.31 4.37 21.06
20.72 4.29 62.37
21.41 4.15 49.06
22.32 3.98 24.81
22.74 3.91 10.12
23.40 3.80 9.35
24.79 3.59 13.43
25.27 3.52 12.11
26.41 3.38 48.11
26.88 3.32 12.56
Position (°2Θ) d-spacing (A) Relative Intensity (%)
27.42 3.25 14.90
28.18 3.17 15.43
29.12 3.07 10.38
29.55 3.02 10.68
29.91 2.99 9.83
30.53 2.93 12.07
31.43 2.85 10.55
32.17 2.78 8.65
32.94 2.72 8.51
33.54 2.67 11.73
34.86 2.57 14.53
37.01 2.43 9.74
38.56 2.33 4.72
39.38 2.29 5.55
Crystalline Form 3 of lurasidone hydrochloride may be characterized by XRPD peaks at about 13.62 (d-spacing at about 6.50 A), 17.17 (5.16 A), 17.41 (5.09 A), 24.68 (3.61 A) and 25.99 (3.43 A) ± 0.2° 20. It may be further characterized by XRPD peaks at about 4.13 (21.41 A), 12.40 (7.14 A), 13.87 (6.39 A), 15.64 (5.66 A), and 26.32 (3.39 A) ± 0.2° 20. Crystalline Form 3 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 9. Table 3 summarizes the d-spacing in A and the corresponding 20 values. Crystalline Form 3 may also be characterized by IR spectrum as depicted in Figure 10. Crystalline Form 3 of lurasidone hydrochloride of the present invention has purity greater than 98% as determined by HPLC.
Table 3: XRPD peaks of crystalline Form 3 of lurasidone hydrochloride
Position (°2Θ) d-spacing (A) Relative Intensity (%)
4.13 21.41 61.99
8.25 10.72 8.53
9.13 9.68 25.72
10.84 8.16 35.79
12.40 7.14 56.82
13.62 6.50 65.30
13.87 6.39 63.43
15.64 5.66 56.77
15.85 5.59 46.71
17.17 5.16 99.15
17.41 5.09 100.00
17.82 4.98 13.78
Position (°2Θ) d-spacing (A) Relative Intensity (%)
18.32 4.84 19.17
19.20 4.62 27.28
19.67 4.51 50.60
20.68 4.29 31.84
21.79 4.08 35.02
22.56 3.94 16.50
23.96 3.71 26.99
24.68 3.61 86.84
24.94 3.57 39.1
25.99 3.43 70.04
26.32 3.39 30.08
26.90 3.31 61.10
27.48 3.25 13.41
28.11 3.17 26.18
28.47 3.13 29.16
28.89 3.09 11.23
29.90 2.99 23.50
30.77 2.91 15.60
32.69 2.74 26.76
34.42 2.60 14.41
36.76 2.44 6.69
38.26 2.35 5.98
Crystalline Form 4 of lurasidone hydrochloride may be characterized by XRPD peaks at about 9.16 (d-spacing at about 9.65A), 15.22 (5.82 A), 15.44 (5.74 A), 18.39 (4.83 A) and 22.54 (3.94 A) ± 0.2° 2Θ. It may be further characterized by XRPD peaks at about 15.88 (5.58 A), 20.18 (4.40 A), 21.46 (4.14 A), 25.38 (3.51 A), and 30.72 (2.91 A) ± 0.2° 2Θ. Crystalline Form 4 of lurasidone hydrochloride may also be characterized by XRPD pattern as depicted in Figure 11. Table 4 summarizes the d-spacing in A and the corresponding 2Θ values. Crystalline Form 4 may also be characterized by IR spectrum as depicted in Figure 12. Crystalline Form 4 of the present invention may also be characterized by a melting point in the range of about 214°C to 216°C with
decomposition. Crystalline Form 4 of lurasidone hydrochloride of the present invention has purity greater than 98% as determined by HPLC.
Table 4: XRPD peaks of crystalline Form 4 of lurasidone hydrochloride
Crystalline Forms 3 and 4 of the present invention may also be characterized by their Differential Scanning Thermogram (DSC) and Thermogravimetric Analysis (TGA).
Lurasidone base used for the preparation of crystalline forms of lurasidone hydrochloride of the present invention may be obtained by the method known in U.S. Patent No. 5,532,372, which is incorporated herein by reference. It may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation.
In general, lurasidone base may be obtained by refluxing a reaction mixture containing trans-3 a,7a-octahydroisoindolium-2-spiro- Γ - [4' -( 1 ,2-benzisothiazol-3- yl)]piperazine methane sulfonate, bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide, dibenzo-18-crown-6 and potassium carbonate in xylene or toluene for about 16 to 36 hours to obtain crude lurasidone base.
Purification of lurasidone base may be carried out by contacting with a solvent selected from the group consisting of alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers and hydrocarbons. Examples of alcohols are methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol and n-pentanol. Examples of ketones are acetone, methyl ethyl ketone and methyl isobutyl ketone. Examples of alkyl acetates are ethyl acetate and isopropyl acetate. Examples of chlorinated hydrocarbons are dichloromethane and chloroform. Examples of ethers are diethyl ether, diisopropyl ether and methyl butyl ether. Examples of hydrocarbons are xylene, toluene, hexane, heptanes and pentane. An anti-solvent may also be added in the purification step. The anti-solvent may be selected from water or hydrocarbons. Examples of hydrocarbons are xylene, toluene, hexane, heptanes and pentane. The examples cited herein are for illustrative purposes only and are not meant to limit the choice to only those solvents identified so.
In a preferred embodiment of the present invention, crude lurasidone base may be purified using iso-propanol.
The purification process of the present invention provides lurasidone base having HPLC purity greater than 97%.
Both crude and purified lurasidone base may be used for the preparation of crystalline forms of the present invention.
Crystalline Forms 1, 2, 3 and 4 of lurasidone hydrochloride may be prepared by contacting lurasidone base with hydrogen chloride at a temperature in the range from about 0°C to about 120°C or by contacting a solution of lurasidone base in a solvent with
hydrogen chloride at a temperature in the range from about 0°C to about 120°C. The reaction mixture may be cooled to about -5°C to ambient temperature and stirred for about 1 hour to 2 days. An anti-solvent may be added to the reaction mixture followed by drying. Drying may be carried out using any suitable method, such as drying under reduced pressure, drying under atmospheric pressure, air drying or drying under an inert gas atmosphere, such as under nitrogen. Preferably, drying may be carried out at ambient temperature to about 80°C.
Crystalline Form 1 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with dry hydrogen chloride in iso-propanol. It may also be obtained by contacting a solution of lurasidone base in acetone with dry hydrogen chloride in iso-propanol.
Crystalline Form 2 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with an alkyl acetate solvent and adding dry hydrogen chloride in iso-propanol. It may also be prepared by contacting lurasidone base with toluene and adding aqueous hydrogen chloride solution.
Crystalline Form 3 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with acetone, adding aqueous hydrogen chloride followed by an addition of an anti-solvent selected from ethers and hydrocarbons. Both acyclic and cyclic ethers may be used as anti-solvents. Examples of acyclic ethers may include dimethyl ether, diethyl ether or di-isopropyl ether. Examples of cyclic ethers may include tetrahydrofuran or 1, 4-dioxane. Examples of hydrocarbons may include xylene, toluene, hexane, heptanes or pentane. Preferably, di-isopropyl ether may be used.
Crystalline Form 4 of lurasidone hydrochloride of the present invention may be obtained by contacting lurasidone base with ethyl acetate and adding aqueous hydrogen chloride.
In one embodiment, the present invention provides crystalline Form 1 of lurasidone hydrochloride prepared by contacting lurasidone base with dry hydrogen chloride in iso-propanol at a temperature of about 35°C to 55°C, cooling to ambient temperature, optionally diluting with iso-propanol, stirring for about 2 hours to 2 days
followed by isolation and drying. Drying may be carried out under reduced pressure at a temperature of about 30°C to 60°C, preferably at about 40°C to 45°C.
In another embodiment, the present invention provides crystalline Form 1 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in acetone with dry hydrogen chloride in iso-propanol at ambient temperature, stirring the reaction mixture for about 2 hours to about 20 hours, cooling to about -15°C to -20°C, diluting with iso-propanol, stirring at ambient temperature for about 1 hour to about 5 hours followed by isolation and drying under reduced pressure at a temperature of about 30°C to about 60°C, preferably at about 40°C to about 45°C.
In another embodiment, the present invention provides crystalline Form 2 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in ethyl acetate with dry hydrogen chloride in iso-propanol at about 0°C to 5°C , raising the temperature to ambient temperature, stirring for about 1 to 5 hours, followed by isolation and drying. Drying may be carried out under reduced pressure at a temperature of about 30°C to 60°C, preferably at about 40°C to 45°C.
In another embodiment, the present invention provides crystalline Form 2 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in toluene with 4% to 5% aqueous hydrochloric acid at ambient temperature, overnight stirring followed by isolation and drying. Drying may be carried out under reduced pressure at a temperature of about 30°C to 60°C.
In another embodiment, the present invention provides crystalline Form 3 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in acetone with about 4% aqueous hydrogen chloride solution, stirring for about 30 minutes to 2 hours, cooling to about -5°C to 10°C, adding an anti-solvent such as ether, cooling to about -5°C to 10°C, filtering and drying under reduced pressure at ambient temperature to about 80°C, preferably at about 50°C. In a preferred embodiment, di-isopropyl ether may be added as an anti-solvent.
In another embodiment, the present invention provides crystalline Form 4 of lurasidone hydrochloride prepared by contacting a solution of lurasidone base in ethyl acetate with 7% aqueous hydrogen chloride solution at about 40°C, cooling to ambient
temperature, diluting with ethyl acetate, filtering and drying under reduced pressure at ambient temperature to about 80°C, preferably at about 50°C.
The crystalline forms of the present invention may be administered as part of a pharmaceutical composition for the treatment of schizophrenia. Accordingly, in a further aspect, there are provided pharmaceutical composition(s) that comprise crystalline forms of lurasidone hydrochloride of the present invention, and one or more pharmaceutically acceptable carrier(s), diluents(s) or excipients(s) and optionally other therapeutic ingredients. The crystalline forms of lurasidone hydrochloride of the present invention may conventionally be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, for example, peroral or parental.
In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Methods
X-ray diffraction patterns were recorded using Panalytical Expert PRO with copper radiation, Xcelerator as detector, 3-40 as scan range, 0.02 as step size and 3-40° 2Θ as range.
IR spectrum was recorded using Perkin Elmer Spectrum one FT-IR spectrometer.
Melting points were recorded using Buchi melting point B-545.
HPLC purity was determined using a YMC Pack ODS-AM(250x4.6)mm^m column with a flow rate: 1.5 mL/minute; column oven temperature: 45°C; Detector: UV at 230nm; Injection volume: 10 μΐ,; Run time: 37 minutes using buffer and acetonitrile as diluent and lmL o-phosphoric acid + 100 mL water as buffer.
EXAMPLES
Example 1: Preparation of Lurasidone base
Step A: Preparation of crude lurasidone base
A reaction mixture containing tra«5,-3a,7a-oc1^ydroisoindolium-2-spiro-r-[4'- (l,2-benzisothiazol-3-yl)]piperazine methane sulfonate (3.0 g), bicyclo[2.2.1]heptane-2- exo-3-exo-dicarboximide (1.7 g), dibenzo-18-crown-6 (0.03 g) and potassium carbonate (1.4 g) in xylene (40 mL) was refluxed for about 24 hours. The contents were filtered at about 50°C and concentrated under reduced pressure at a temperature of about 70°C to obtain crude lurasidone base as a sticky solid (4.0 g).
HPLC Purity: 95.35%
Step B: Purification of lurasidone base
2.8 g of the crude lurasidone base was treated with iso-propanol (20 mL) to isolate pure lurasidone base as a free-flowing white solid (1.9 g).
Yield: 70%
HPLC Purity: 97.42%
Melting point: 126.3°C
Example 2: Preparation of Crystalline Form 1 of Lurasidone Hydrochloride from Crude Lurasidone base
A reaction mixture containing 2.2 g of crude lurasidone base and dry hydrogen chloride in iso-propanol (10 mL) was heated to a temperature of about 45 °C. The reaction mixture was cooled to ambient temperature and stirred for about 20 hours. The solid material was filtered, washed with iso-propanol (5 mL) and dried under reduced pressure at about 45 °C to obtain crystalline Form 1 of lurasidone hydrochloride as a white solid (1-2 g).
Yield: 50.5%
HPLC purity: 97.05%
Melting point: 204°C -211°C with decomposition
Example 3: Preparation of Crystalline Form 1 of Lurasidone Hydrochloride from Pure Lurasidone base
A reaction mixture containing 4.0 g of pure lurasidone base and dry hydrogen chloride in iso-propanol (20 mL) was heated to a temperature of about 40°C. The reaction mixture was cooled to ambient temperature, diluted with iso-propanol (40 mL) and further stirred for about 5 hours. The solid material was filtered, washed with iso-propanol (15 mL) and dried under reduced pressure at about 45 °C to obtain crystalline Form 1 of lurasidone hydrochloride as a white solid (3.3 g).
Yield: 77%
HPLC purity: 98.84%
Melting point: 214°C -216°C with decomposition
Example 4: Preparation of Crystalline Form 1 of Lurasidone Hydrochloride from Pure Lurasidone base
Dry hydrogen chloride in iso-propanol (5 mL) was added to a solution of pure lurasidone base (1 g) in acetone (5 mL) at ambient temperature. The reaction mixture was stirred for about 8 hours and cooled to about -15°C to -20°C. The reaction mass was diluted with iso-propanol (5 mL), stirred for about 3 hours at ambient temperature, filtered, washed with acetone (3 mL) and dried under reduced pressure at about 45°C to obtain crystalline Form 1 of lurasidone hydrochloride as a white solid (0.35 g).
Yield: 32.6%
Example 5: Preparation of Crystalline Form 2 of Lurasidone Hydrochloride from Crude Lurasidone base
0.5 g of crude lurasidone base was dissolved in ethyl acetate (5 mL) by heating at a temperature of about 40°C. The solution was cooled to about 0°C to 5°C. Dry hydrogen chloride in iso-propanol (2 mL) was added drop-wise. The temperature was raised to ambient temperature and the contents were stirred for about 2.5 hours. The solid material
was filtered, washed with ethyl acetate (3 mL) and dried under reduced pressure at about 45 °C to obtain crystalline Form 2 of lurasidone hydrochloride as a white solid.
Yield: 47%
HPLC purity: 99.03%
Example 6: Preparation of Crystalline Form 2 of Lurasidone Hydrochloride from Pure Lurasidone base
4.0 g of pure lurasidone base was dissolved in ethyl acetate (40 mL) by heating at a temperature of about 40°C. The solution was cooled to about 0°C to 5°C. Dry hydrogen chloride in iso-propanol (20 mL) was added drop-wise. The temperature was raised to ambient temperature and the contents were stirred for about 3.5 hours. The solid material was filtered, washed with ethyl acetate (10 mL) and dried under reduced pressure at about 45°C to obtain crystalline Form 2 of lurasidone hydrochloride as a white solid (4.0 g).
Yield: 93%
HPLC purity: 98.65%
Melting point: 211°C -213°C with decomposition
Example 7: Preparation of Crystalline Form 2 of Lurasidone Hydrochloride from Pure Lurasidone base
4%-5% aqueous hydrochloric acid (2.5 mL) was added to a solution of pure lurasidone base (0.25 g) in toluene (4 mL) at ambient temperature. The reaction mixture was stirred overnight, diluted with toluene (4 mL), filtered, washed with toluene (3 mL) and dried under reduced pressure at about 50°C to obtain crystalline Form 2 of lurasidone base (0.17 g).
Yield: 63%
Example 8: Preparation of Crystalline Form 3 of Lurasidone Hydrochloride from Crude Lurasidone base
3.0 g of crude lurasidone base was dissolved in acetone (30 mL) by heating the reaction mixture at a temperature of about 55 °C followed by drop- wise addition of 4% aqueous hydrochloric acid solution (6 mL). The reaction mixture was stirred for about 1 hour and then cooled to about 0°C. Solvent was recovered completely from the reaction mixture. Fresh acetone (50 mL) was added and the reaction mixture was dried over anhydrous sodium sulphate (1.0 g). Di-isopropyl ether (5mL) was added drop-wise to the reaction mixture. Turbidity was observed. The reaction mixture was cooled to about 0°C to -5°C and filtered. Solid material was dried under reduced pressure at about 50°C to obtain crystalline Form 3 of lurasidone hydrochloride as a white solid (1.2 g).
Yield: 37%
HPLC purity: 98.09%
Example 9: Preparation of Crystalline Form 4 of Lurasidone Hydrochloride from Pure Lurasidone base
1.0 g of pure lurasidone base was dissolved in ethyl acetate (10 mL) by heating the reaction mixture at a temperature of about 40°C followed by drop-wise addition of about 7% aqueous hydrogen chloride solution (5 mL). The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (15 mL) and stirred for about 2 hours. The solid material was filtered, washed with ethyl acetate (10 mL) and dried under reduced pressure at about 45 °C to obtain crystalline Form 4 of lurasidone hydrochloride as a white solid (1.0 g).
Yield: 93%
HPLC purity: 98.98%
Melting point: 214°C -216°C with decomposition
Claims
1. A crystalline form of lurasidone hydrochloride characterized by having at least one X-ray diffraction peak with a relative intensity of not less than 2% at d-spacing in the range 17.0-22.0.
2. Crystalline Form 1 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 5.81, 5.72, 5.55, 5.26 and 4.93 A.
3. Crystalline Form 1 of lurasidone hydrochloride of claim 2 further characterized by XRPD peaks at about 9.82, 6.25, 4.81, 4.28 and 4.14 A.
4. Crystalline Form 1 of lurasidone hydrochloride of claim 2 characterized by XRPD pattern as depicted in Figure 1.
5. Crystalline Form 1 of lurasidone hydrochloride of claim 2 characterized by IR spectrum as depicted in Figure 2.
6. Crystalline Form 1 of lurasidone hydrochloride of claim 2 characterized by DSC having endotherms at about 72.50°C and 214.67°C.
7. Crystalline Form 1 of lurasidone hydrochloride of claim 2 characterized by DSC as depicted in Figure 3.
8. Crystalline Form 1 of lurasidone hydrochloride of claim 2 characterized by TGA as depicted in Figure 4.
9. A process for the preparation of crystalline Form 2 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with dry hydrogen chloride in iso-propanol; and ii) isolating crystalline Form 1 of lurasidone hydrochloride.
10. The process according to claim 9, wherein lurasidone base is contacted with dry hydrogen chloride in iso-propanol at about 35°C to 55°C.
1 1. The process according to claim 9, wherein the reaction mixture is stirred for about 2 hours to 20 hours.
12. Crystalline Form 2 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 5.83, 5.56, 5.28, 4.94 and 4.29 A.
13. Crystalline Form 2 of lurasidone hydrochloride of claim 12 further characterized by XRPD peaks at about 9.87, 6.28 A, 5.75, 4.15 and 3.38 A.
14. Crystalline Form 2 of lurasidone hydrochloride of claim 12 characterized by XRPD pattern as depicted in Figure 5.
15. Crystalline Form 2 of lurasidone hydrochloride of claim 12 characterized by IR spectrum as depicted in Figure 6.
16. Crystalline Form 2 of lurasidone hydrochloride of claim 12 characterized by DSC having endotherms at about 75.01°C and 214.99°C.
17. Crystalline Form 2 of lurasidone hydrochloride of claim 12 characterized by DSC as depicted in Figure 7.
18. Crystalline Form 2 of lurasidone hydrochloride of claim 12 characterized by TGA as depicted in Figure 8.
19. A process for the preparation of crystalline Form 2 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with ethyl acetate;
ii) adding dry hydrogen chloride in iso-propanol; and
iii) isolating crystalline Form 2 of lurasidone hydrochloride.
20. The process according to claim 19, wherein a solution of lurasidone base in ethyl acetate is contacted with dry hydrogen chloride in iso-propanol at about 0°C to about 5°C.
21. The process according to claim 19, wherein the reaction mixture is stirred for about 1 hour to 5 hours.
22. A process for the preparation of crystalline Form 2 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with toluene;
ii) adding aqueous hydrogen chloride; and
iii) isolating crystalline Form 2 of lurasidone hydrochloride.
23. The process according to claim 22, wherein a solution of lurasidone base in toluene is contacted with 4% to 5% aqueous hydrogen chloride.
24. The process according to claim 22, wherein a solution of lurasidone base in toluene is contacted with 4% to 5% aqueous hydrogen chloride at ambient temperature.
25. Crystalline Form 3 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 6.50, 5.16, 5.09, 3.61 and 3.43 A.
26. Crystalline Form 3 of lurasidone hydrochloride of claim 25 further characterized by XRPD peaks at about 21.41, 7.14, 6.39, 5.66 and 3.39 A.
27. Crystalline Form 3 of lurasidone hydrochloride of claim 25 characterized by XRPD pattern as depicted in Figure 9.
28. Crystalline Form 3 of lurasidone hydrochloride of claim 25 characterized by IR spectrum as depicted in Figure 10.
29. A process for the preparation of crystalline Form 3 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with acetone;
ii) adding aqueous hydrogen chloride solution;
iii) adding an anti-solvent; and
iv) isolating crystalline Form 3 of lurasidone hydrochloride.
30. The process according to claim 29, wherein a solution of lurasidone base in acetone is contacted with about 4% aqueous hydrogen chloride solution.
31. The process according to claim 29, wherein the reaction mixture is stirred for about 30 minutes to 2 hours.
32. The process according to claim 29, wherein ether is added as anti-solvent.
33. The process according to claim 29, wherein di-isopropyl ether is added as anti- solvent.
34. Crystalline Form 4 of lurasidone hydrochloride characterized by X-ray diffraction peaks at d-spacing of about 9.65, 5.82, 5.74, 4.83 and 3.94 A.
35. Crystalline Form 4 of lurasidone hydrochloride of claim 34 further characterized by XRPD peaks at about 5.58, 4.40, 4.14, 3.51 and 2.91 A.
36. Crystalline Form 4 of lurasidone hydrochloride of claim 34 characterized by XRPD pattern as depicted in Figure 11.
37. Crystalline Form 4 of lurasidone hydrochloride of claim 34 characterized by IR spectrum as depicted in Figure 12.
38. A process for the preparation of crystalline Form 4 of lurasidone hydrochloride comprising the steps of:
i) contacting lurasidone base with ethyl acetate;
ii) adding aqueous hydrogen chloride solution; and
iii) isolating crystalline Form 4 of lurasidone hydrochloride.
39. The process according to claim 38, wherein a solution of lurasidone base in ethyl acetate is contacted with about 7% aqueous hydrogen chloride solution.
40. The process according to claim 38, wherein a solution of lurasidone base in ethyl acetate is contacted with about 7% aqueous hydrogen chloride solution at about 40°C.
41. A process for the purification of lurasidone base comprising contacting crude lurasidone base with a solvent selected from alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers and hydrocarbons.
42. The process according to claim 41, wherein an alcohol is used as solvent.
43. The process according to claim 41, wherein iso-propanol is used as solvent.
44. Lurasidone base having purity greater than 97% as determined by High
Performance Liquid Chromatography (HPLC).
45. Pharmaceutical composition(s) comprising crystalline Form 1, 2, 3 or 4 of lurasidone hydrochloride and one or more pharmaceutically acceptable carrier(s), diluents(s) or excipient(s).
46. Use of crystalline Form 1 , 2, 3 or 4 of lurasidone hydrochloride for the treatment of schizophrenia.
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| CN104031041A (en) * | 2013-03-06 | 2014-09-10 | 江苏恩华药业股份有限公司 | New crystal forms of lurasidone hydrochloride and preparation method thereof |
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| WO2013121440A1 (en) | 2012-02-13 | 2013-08-22 | Cadila Healthcare Limited | Process for preparing benzisothiazol-3-yl-peperazin-l-yl-methyl-cyclo hexyl-methanisoindol-1,3-dione and its intermediates |
| CN102863437A (en) * | 2012-09-04 | 2013-01-09 | 济南百诺医药科技开发有限公司 | Preparation method of lurasidone |
| WO2014064714A2 (en) * | 2012-10-22 | 2014-05-01 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of lurasidone hydrochloride |
| WO2014064714A3 (en) * | 2012-10-22 | 2014-06-05 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of lurasidone hydrochloride |
| CN102911170A (en) * | 2012-11-15 | 2013-02-06 | 苏州第壹制药有限公司 | Method for preparing imide compound hydrochloride |
| WO2014102834A3 (en) * | 2012-12-31 | 2015-03-12 | Hetero Research Foundation | Process for lurasidone |
| CN104031041A (en) * | 2013-03-06 | 2014-09-10 | 江苏恩华药业股份有限公司 | New crystal forms of lurasidone hydrochloride and preparation method thereof |
| CN105524057A (en) * | 2013-03-06 | 2016-04-27 | 江苏恩华药业股份有限公司 | Lurasidone hydrochloride new crystal form and preparation method thereof |
| 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 |
| WO2019213286A1 (en) * | 2018-05-02 | 2019-11-07 | LifeMax Laboratories, Inc. | Extended release suspension formulation of lurasidone |
| US10987303B2 (en) | 2018-05-02 | 2021-04-27 | LifeMax Laboratories, Inc. | Extended release suspension formulation of lurasidone |
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| WO2012107890A3 (en) | 2012-11-01 |
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