WO2013132511A1 - Novel polymorph of lurasidone hydrochloride - Google Patents

Novel polymorph of lurasidone hydrochloride Download PDF

Info

Publication number
WO2013132511A1
WO2013132511A1 PCT/IN2012/000548 IN2012000548W WO2013132511A1 WO 2013132511 A1 WO2013132511 A1 WO 2013132511A1 IN 2012000548 W IN2012000548 W IN 2012000548W WO 2013132511 A1 WO2013132511 A1 WO 2013132511A1
Authority
WO
WIPO (PCT)
Prior art keywords
lurasidone hydrochloride
amorphous form
solvent
mixture
lurasidone
Prior art date
Application number
PCT/IN2012/000548
Other languages
French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Itiyala Srinivas Reddy
Bandi Vamsi Krishna
Original Assignee
Hetero Research Foundation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2013132511A1 publication Critical patent/WO2013132511A1/en

Links

Classifications

    • 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

  • the present invention provides a novel amorphous Form of lurasidone hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
  • Lurasidone hydrochloride is chemically, (3a/?,45',7i?,7a 1 S)-2-[((li?,2i?)-2- ⁇ [4-(l ,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl ⁇ cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l,3-dione hydrochloride and has the structural formula:
  • Lurasidone hydrochloride is a typical antipsychotic developed by Dainippon Sumitomo Pharma under the trade name Latuda ® .
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
  • polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules.
  • Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
  • Lurasidone and its salts can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • lurasidone hydrochloride crystalline Form I The powdered x-ray diffractogram (PXRD) of lurasidone hydrochloride crystalline Form I is shown in figure 1. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 1 1.4, 13.9, 15.1, 15.5, 16.4, 17.1, 19.5, 20.8 and 21.9 ⁇ 0.2 degrees.
  • novel amorphous Form of lurasidone hydrochloride has been found to be stable, reproducible and so, suitable for pharmaceutical preparations.
  • the novel amorphous Form of lurasidone hydrochloride of the present invention is different from the prior art amorphous Form of lurasidone hydrochloride as disclosed in '246 patent, specifically in the pattern of Powdered X-Ray Diffractogram.
  • an object of the present invention is to provide a novel amorphous Form of lurasidone hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention provides an amorphous Form of lurasidone hydrochloride.
  • the present invention provides a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
  • the present invention provides a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
  • the present invention provides a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous Form of lurasidone hydrochloride and pharmaceutically acceptable excipients.
  • Figure 1 is an X-ray powder diffraction spectrum of lurasidone hydrochloride crystalline Form I.
  • Figure 2 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 3 and example 4.
  • Figure 3 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 7.
  • Figure 4 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 1 1.
  • Figure 5 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 13.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 10.6 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • room temperature refers to temperature at about 25 to 35°C.
  • an amorphous Form of lurasidone hydrochloride there is provided an amorphous Form of lurasidone hydrochloride.
  • the powdered x-ray diffractogram (PXRD) of lurasidone hydrochloride amorphous Form is shown in figures 2, 3, 4 and 5.
  • the lurasidone hydrochloride amorphous Form obtained may have water content of up to 20.0% by weight.
  • a process for the preparation of lurasidone hydrochloride amorphous Form which comprises:
  • Lurasidone hydrochloride used in step (a) may preferably be lurasidone hydrochloride obtained by the known process.
  • the alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.
  • Lyophilization refers to a sublimation process that removes free water or other solvent in the form of solid.
  • a process for the preparation of lurasidone hydrochloride amorphous Form which comprises:
  • Lurasidone hydrochloride used in step (a) may preferably be lurasidone hydrochloride obtained by the known process.
  • the alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is ethanol.
  • the chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene chloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.
  • Spray drying refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
  • a process for the preparation of lurasidone hydrochloride amorphous Form which comprises:
  • Lurasidone hydrochloride used in step (a) may preferably be lurasidone hydrochloride obtained by the known process.
  • the alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.
  • the chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene chloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.
  • the ether solvent used in step (a) may preferably be a solvent or mixture of solvents selected from tetrahydrofuran, 1 ,4-dioxane, methyl tert-butyl ether and diethyl ether, and more preferably the ether solvent is methyl tert-butyl ether.
  • the solvent may be removed from the solution in step (b) by known methods, for example, distillation.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure.
  • the distillation may preferably be carried out until the solvent is almost completely distilled off.
  • reduced pressure refers to a pressure of less than 100 mmHg.
  • a pharmaceutical composition comprising amorphous Form of lurasidone hydrochloride and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
  • the amorphous Form may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • Trans- l ,2-bis(hydroxymethyl)cyclohexane 50 gm was dissolved in methylene chloride (1000 ml) and then added triethylamine (136 ml). The contents were then cooled to 0°C and then added methylsulfonyl chloride (51 ml) slowly at 0 to 5°C. The temperature of the reaction mass was raised to room temperature and stirred for 16 hours. Water (500 ml) was added to the reaction mass and stirred for 15 minutes at room temperature. The layers were separated and the aqueous layer was extracted with methylene chloride. Combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid.
  • Acetonitrile 300 ml was added to trans-1 ,2- bis(methanesulfonyloxymethyl)cyclohexane (20 gm) under stirring at room temperature.
  • a mixture of l-(l ,2-benzoisothiazol-3-yl)-piperazine (13.2 gm), sodium carbonate (6.6 gm) and tetrabutyiammonium hydrogen sulfate (200 mg) was added to the solution under stirring.
  • the temperature of the reaction mass was raised to 85°C and then heated to reflux.
  • the reaction mass was maintained for 48 hours at reflux and then cooled to 70°C.
  • the reaction mass was filtered and then concentrated to obtain a residual solid.
  • Toluene (225 ml) was added to trans-3a,7a-octahydroisoindolium-2-spiro-T-[4'- (l,2-benisothiazol-3-yl)]piperazine methane sulfonate (15 gm) and then added potassium carbonate (7.5 gm) under stirring.
  • To the reaction mixture was added bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (10 gm) and 18-crown ether (1.1 gm). The contents were heated to reflux and maintained for 4 hours.
  • To the reaction mass was added water (500 ml) and then the separated aqueous layer was extracted with toluene.
  • Lurasidone (4 gm) as obtained in example 1 was dissolved in acetone (200 ml) and stirred for 30 minutes at room temperature to obtain a clear solution. To the solution was added a solution of hydrochloric acid in isopropyl alcohol (4 ml) slowly and then cooled to 0 to 5°C. The contents were maintained for 1 hour at 0 to 5°C and filtered. The solid obtained was dried at 50°C under vacuum for 6 hours to give 3 gm of lurasidone hydrochloride crystalline Form I.
  • Example 3 Example 3:
  • Lurasidone hydrochloride crystalline Form 1 (2.5 gm) as obtained in example 2 was dissolved in methanol (169 ml) and water (955 ml) under stirring. The solution was treated with activated carbon and filtered. The filtrate thus obtained containing 15% of methanol and 85% of water was lyophilized at room temperature for 24 hours to obtain 2.5 gm of lurasidone hydrochloride amorphous Form.
  • Lurasidone hydrochloride (10 gm) was dissolved in methanol (675 ml) and water (3800 ml) under stirring. The solution was treated with activated carbon and filtered. The filtrate thus obtained containing 15% of methanol and 85% of water was lyophilized at room temperature for 24 hours to obtain 9.8 gm of lurasidone hydrochloride amorphous Form.
  • Example 3 was repeated using ethanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.
  • Example 3 was repeated using n-butanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.
  • Example 7 was repeated using n-butanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.
  • Lurasidone hydrochloride (10 gm) was dissolved in ethanol (125 ml) and methylene dichloride (125 ml) at room temperature. The solution was treated with carbon and filtered through hi-flow bed. The resulting filtrate was subjected to spray drying at 60 to 65°C to obtain 9.5 gm of lurasidone hydrochloride amorphous Form.
  • Example 7 was repeated using methanol solvent instead of ethanol solvent to obtain lurasidone hydrochloride amorphous Form.
  • Example 7 was repeated using n-butanol solvent instead of ethanol solvent to obtain lurasidone hydrochloride amorphous Form.
  • Example 7 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain lurasidone hydrochloride amorphous Form.
  • Lurasidone hydrochloride (10 gm) was dissolved in methanol (675 ml) under stirring at room temperature to obtain a clear solution. The solution was treated with carbon and filtered through hi-flow bed. The resulting filtrate was subjected to spray drying at 60 to 65°C to obtain 9.5 gm of lurasidone hydrochloride amorphous Form.
  • Example 11 was repeated using ethanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.
  • Example 13 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain lurasidone hydrochloride amorphous Form.
  • Example 13 was repeated using 1,4-dioxane solvent instead of methyl tert-butyl ether solvent to obtain lurasidone hydrochloride amorphous Form.
  • Example 13 was repeated using ethanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.

Abstract

The present invention provides a novel amorphous Form of lurasidone hydrochloride, process for its preparation and pharmaceutical compositions comprising it. In one aspect, the present invention provides an amorphous form of lurasidone hydrochloride. In another aspect, the present invention provides a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises: a) dissolving lurasidone hydrochloride in a mixture of alcoholic solvent and water; and b) subjecting the resulting solution to lyophilization to obtain lurasidone hydrochloride amorphous form.

Description

NOVEL POLYMORPH OF LURASIDONE HYDROCHLORIDE
This application claims the benefit of Indian Provisional Patent Application No. 893/CHE/2012, filed on March 09, 2012, which is incorporated herein by reference.
Filed of the Invention
The present invention provides a novel amorphous Form of lurasidone hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
Background of the Invention
Lurasidone hydrochloride is chemically, (3a/?,45',7i?,7a1S)-2-[((li?,2i?)-2-{[4-(l ,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l,3-dione hydrochloride and has the structural formula:
Figure imgf000003_0001
Lurasidone hydrochloride is a typical antipsychotic developed by Dainippon Sumitomo Pharma under the trade name Latuda®.
Lurasidone and its salts were disclosed in US patent No. 5,532,372 ('372 patent).
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
Lurasidone and its salts can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
Process for the preparation of lurasidone hydrochloride was described in '372 patent. According to the patent, crystalline solid of lurasidone hydrochloride was obtained by dissolving crude lurasidone in acetone at 20 to 30°C and then added a solution of hydrogen chloride in 2-propanol, and isolating. The crystalline lurasidone hydrochloride obtained by the process of the prior art is herein after designated as lurasidone hydrochloride crystalline Form I. The powdered x-ray diffractogram (PXRD) of lurasidone hydrochloride crystalline Form I is shown in figure 1. Crystalline Form I is characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 1 1.4, 13.9, 15.1, 15.5, 16.4, 17.1, 19.5, 20.8 and 21.9 ± 0.2 degrees.
Crystalline Form of lurasidone free base was reported in IP.com Journal (2011), 1 1(4A), 26.
International patent application publication no. WO 2012/063246 ('246 patent) disclosed amorphous Form of lurasidone hydrochloride.
We have found a novel amorphous Form of lurasidone hydrochloride. The novel Form has been found to be stable, reproducible and so, suitable for pharmaceutical preparations. The novel amorphous Form of lurasidone hydrochloride of the present invention is different from the prior art amorphous Form of lurasidone hydrochloride as disclosed in '246 patent, specifically in the pattern of Powdered X-Ray Diffractogram.
Thus, an object of the present invention is to provide a novel amorphous Form of lurasidone hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
Summary of the Invention
In one aspect, the present invention provides an amorphous Form of lurasidone hydrochloride.
In another aspect, the present invention provides a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
a) dissolving lurasidone hydrochloride in a mixture of alcoholic solvent and water; and
b) subjecting the resulting solution to lyophilization to obtain lurasidone hydrochloride amorphous Form.
In another aspect, the present invention provides a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
a) dissolving lurasidone hydrochloride in an alcoholic solvent, a chlorinated solvent or a mixture thereof; and
b) subjecting the resulting solution to spray drying to obtain lurasidone hydrochloride amorphous Form.
In another aspect, the present invention provides a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
a) dissolving lurasidone hydrochloride in a mixture of alcoholic solvent, a chlorinated solvent and an ether solvent; and
b) removing the solvent to obtain lurasidone hydrochloride amorphous Form.
In another aspect, the present invention provides a pharmaceutical composition comprising amorphous Form of lurasidone hydrochloride and pharmaceutically acceptable excipients. Brief Description of the Drawings
Figure 1 is an X-ray powder diffraction spectrum of lurasidone hydrochloride crystalline Form I.
Figure 2 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 3 and example 4.
Figure 3 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 7.
Figure 4 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 1 1.
Figure 5 is an X-ray powder diffraction spectrum of lurasidone hydrochloride amorphous Form obtained by the example 13.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper-Κα radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 10.6 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
Detailed Description of the Invention
The term "room temperature" refers to temperature at about 25 to 35°C.
According to one aspect of the present invention, there is provided an amorphous Form of lurasidone hydrochloride. The powdered x-ray diffractogram (PXRD) of lurasidone hydrochloride amorphous Form is shown in figures 2, 3, 4 and 5.
The lurasidone hydrochloride amorphous Form obtained may have water content of up to 20.0% by weight.
According to another aspect of the present invention, there is provided a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
a) dissolving lurasidone hydrochloride in a mixture of alcoholic solvent and water; and
b) subjecting the resulting solution to lyophilization to obtain lurasidone hydrochloride amorphous Form. Lurasidone hydrochloride used in step (a) may preferably be lurasidone hydrochloride obtained by the known process.
The alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.
The term "Lyophilization" refers to a sublimation process that removes free water or other solvent in the form of solid.
According to another aspect of the present invention, there is provided a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
a) dissolving lurasidone hydrochloride in an alcoholic solvent, a chlorinated solvent or a mixture thereof; and
b) subjecting the resulting solution to spray drying to obtain lurasidone hydrochloride amorphous Form.
Lurasidone hydrochloride used in step (a) may preferably be lurasidone hydrochloride obtained by the known process.
The alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is ethanol.
The chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene chloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.
The term "Spray drying" refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
According to another aspect of the present invention, there is provided a process for the preparation of lurasidone hydrochloride amorphous Form, which comprises:
a) dissolving lurasidone hydrochloride in a mixture of alcoholic solvent, a chlorinated solvent and an ether solvent; and
b) removing the solvent to obtain lurasidone hydrochloride amorphous Form.
Lurasidone hydrochloride used in step (a) may preferably be lurasidone hydrochloride obtained by the known process. The alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol. More preferably the alcoholic solvent is methanol.
The chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, ethylene chloride, chloroform and carbon tetrachloride, and more preferably the chlorinated solvent is methylene chloride.
The ether solvent used in step (a) may preferably be a solvent or mixture of solvents selected from tetrahydrofuran, 1 ,4-dioxane, methyl tert-butyl ether and diethyl ether, and more preferably the ether solvent is methyl tert-butyl ether.
The solvent may be removed from the solution in step (b) by known methods, for example, distillation.
The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
As used herein, "reduced pressure" refers to a pressure of less than 100 mmHg.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous Form of lurasidone hydrochloride and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The amorphous Form may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 :
Preparation of lurasidone
Stage-I: Preparation of trans- l,2-bis(methanesulfonyloxymethyl)cyclohexane
Trans- l ,2-bis(hydroxymethyl)cyclohexane (50 gm) was dissolved in methylene chloride (1000 ml) and then added triethylamine (136 ml). The contents were then cooled to 0°C and then added methylsulfonyl chloride (51 ml) slowly at 0 to 5°C. The temperature of the reaction mass was raised to room temperature and stirred for 16 hours. Water (500 ml) was added to the reaction mass and stirred for 15 minutes at room temperature. The layers were separated and the aqueous layer was extracted with methylene chloride. Combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid. To the residual solid was added methylene chloride (50 ml) and cyclohexane (250 ml). The contents were stirred for 30 minutes at room temperature, filtered and then dried to obtain 62 gm of trans- 1,2- bis(methanesulfonyloxymethyl)cyclohexane.
Stage-II: Preparation of trans-ia a-octahvdroisoindolium-2-spiro-l '-f4'-(L2- benisothiazol-3-yl)lpiperazine methane sulfonate
Acetonitrile (300 ml) was added to trans-1 ,2- bis(methanesulfonyloxymethyl)cyclohexane (20 gm) under stirring at room temperature. A mixture of l-(l ,2-benzoisothiazol-3-yl)-piperazine (13.2 gm), sodium carbonate (6.6 gm) and tetrabutyiammonium hydrogen sulfate (200 mg) was added to the solution under stirring. The temperature of the reaction mass was raised to 85°C and then heated to reflux. The reaction mass was maintained for 48 hours at reflux and then cooled to 70°C. The reaction mass was filtered and then concentrated to obtain a residual solid. To the residual solid was added ethyl acetate (40 ml) and stirred for 15 minutes. The separated solid was filtered and then dried to obtain 15 gm of trans-3a,7a-octahydroisoindolium-2- spiro-1 '-[4'-(l ,2-benisothiazol-3-yl)]piperazine methane sulfonate.
Stage-Ill: Preparation oflurasidone
Toluene (225 ml) was added to trans-3a,7a-octahydroisoindolium-2-spiro-T-[4'- (l,2-benisothiazol-3-yl)]piperazine methane sulfonate (15 gm) and then added potassium carbonate (7.5 gm) under stirring. To the reaction mixture was added bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (10 gm) and 18-crown ether (1.1 gm). The contents were heated to reflux and maintained for 4 hours. To the reaction mass was added water (500 ml) and then the separated aqueous layer was extracted with toluene. Combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid. The residual solid obtained was dissolved in ethyl acetate (45 ml) and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 12 gm of lurasidone. Example 2:
Preparation of lurasidone hydrochloride crystalline Form I
Lurasidone (4 gm) as obtained in example 1 was dissolved in acetone (200 ml) and stirred for 30 minutes at room temperature to obtain a clear solution. To the solution was added a solution of hydrochloric acid in isopropyl alcohol (4 ml) slowly and then cooled to 0 to 5°C. The contents were maintained for 1 hour at 0 to 5°C and filtered. The solid obtained was dried at 50°C under vacuum for 6 hours to give 3 gm of lurasidone hydrochloride crystalline Form I. Example 3:
Preparation of lurasidone hydrochloride amorphous Form
Lurasidone hydrochloride crystalline Form 1 (2.5 gm) as obtained in example 2 was dissolved in methanol (169 ml) and water (955 ml) under stirring. The solution was treated with activated carbon and filtered. The filtrate thus obtained containing 15% of methanol and 85% of water was lyophilized at room temperature for 24 hours to obtain 2.5 gm of lurasidone hydrochloride amorphous Form.
Example 4:
Preparation of lurasidone hydrochloride amorphous Form
_ Lurasidone hydrochloride (10 gm) was dissolved in methanol (675 ml) and water (3800 ml) under stirring. The solution was treated with activated carbon and filtered. The filtrate thus obtained containing 15% of methanol and 85% of water was lyophilized at room temperature for 24 hours to obtain 9.8 gm of lurasidone hydrochloride amorphous Form.
Example 5:
Preparation of lurasidone hydrochloride amorphous Form
Example 3 was repeated using ethanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.
Example 6: Preparation of lurasidone hydrochloride amorphous Form
Example 3 was repeated using n-butanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form. Example 7:
Preparation of lurasidone hydrochloride amorphous Form
Lurasidone hydrochloride (10 gm) was dissolved in ethanol (125 ml) and methylene dichloride (125 ml) at room temperature. The solution was treated with carbon and filtered through hi-flow bed. The resulting filtrate was subjected to spray drying at 60 to 65°C to obtain 9.5 gm of lurasidone hydrochloride amorphous Form.
Example 8:
Preparation of lurasidone hydrochloride amorphous Form
Example 7 was repeated using methanol solvent instead of ethanol solvent to obtain lurasidone hydrochloride amorphous Form.
Example 9:
Preparation of lurasidone hydrochloride amorphous Form
Example 7 was repeated using n-butanol solvent instead of ethanol solvent to obtain lurasidone hydrochloride amorphous Form.
Example 10:
Preparation of lurasidone hydrochloride amorphous Form
Example 7 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain lurasidone hydrochloride amorphous Form.
Example 1 1 :
Preparation of lurasidone hydrochloride amorphous Form
Lurasidone hydrochloride (10 gm) was dissolved in methanol (675 ml) under stirring at room temperature to obtain a clear solution. The solution was treated with carbon and filtered through hi-flow bed. The resulting filtrate was subjected to spray drying at 60 to 65°C to obtain 9.5 gm of lurasidone hydrochloride amorphous Form.
Example 12:
Preparation of lurasidone hydrochloride amorphous Form
Example 11 was repeated using ethanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.
Example 13:
Preparation of lurasidone hydrochloride amorphous Form
To a lurasidone hydrochloride (10 gm) was added methanol (350 ml), methylene chloride (300 ml) and methyl tert-butyl ether (350 ml) at room temperature under stirring to obtain a clear solution. The solution was maintained for 2 hours at room temperature and then treated with carbon. The solution was filtered through h-flow bed and the solvents were distilled off under reduced pressure at below -50°C to obtain a solid. The solid obtained was then dried to obtain 9.5 gm of lurasidone hydrochloride amorphous Form.
Example 14:
Preparation of lurasidone hydrochloride amorphous Form
Example 13 was repeated using ethylene chloride solvent instead of methylene chloride solvent to obtain lurasidone hydrochloride amorphous Form.
Example 15:
Preparation of lurasidone hydrochloride amorphous Form
Example 13 was repeated using 1,4-dioxane solvent instead of methyl tert-butyl ether solvent to obtain lurasidone hydrochloride amorphous Form.
Example 16:
Preparation of lurasidone hydrochloride amorphous Form Example 13 was repeated using tetrahydrofuran solvent instead of methyl tert- butyl ether solvent to obtain lurasidone hydrochloride amorphous Form.
Example 17:
Preparation of lurasidone hydrochloride amorphous Form
Example 13 was repeated using ethanol solvent instead of methanol solvent to obtain lurasidone hydrochloride amorphous Form.

Claims

We claim:
1. An amorphous Form of lurasidone hydrochloride.
2. The lurasidone hydrochloride amorphous Form of claim 1, having a powder X-ray diffractogram as shown in figures 2, 3, 4 and 5.
3. A process for the preparation of lurasidone hydrochloride amorphous Form of claim 1, which comprises:
a. dissolving lurasidone hydrochloride in a mixture of alcoholic solvent and water; and
b. subjecting the resulting solution to lyophilization to obtain lurasidone hydrochloride amorphous Form.
4. The process as claimed in claim 3, wherein the alcoholic solvent used in step (a) is a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol.
5. A process for the preparation of lurasidone hydrochloride amorphous Form of claim 1 , which comprises:
a. dissolving lurasidone hydrochloride in an alcoholic solvent, a chlorinated solvent or a mixture thereof; and
b. subjecting the resulting solution to spray drying to obtain lurasidone hydrochloride amorphous Form.
6. The process as claimed in claim 5, wherein the alcoholic solvent used in step (a) is a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol.
7. The process as claimed in claim 5, wherein the chlorinated solvent used in step (a) is a solvent or a mixture of solvents selected from methylene chloride, ethylene chloride, chloroform and carbon tetrachloride.
8. A process for the preparation of lurasidone hydrochloride amorphous Form of claim 1, which comprises:
a. dissolving lurasidone hydrochloride in a mixture of alcoholic solvent, a chlorinated solvent and an ether solvent; and
b. removing the solvent to obtain lurasidone hydrochloride amorphous Form.
9. The process as claimed in claim 8, wherein the alcoholic solvent used in step (a) is a solvent or a mixture of solvents selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, n-butanol and isobutyl alcohol.
10. The process as claimed in claim 8, wherein the chlorinated solvent used in step (a) is a solvent or a mixture of solvents selected from methylene chloride, ethylene chloride, chloroform and carbon tetrachloride.
11. The process as claimed in claim 8, wherein the ether solvent used in step (a) is a solvent or mixture of solvents selected from tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether and diethyl ether.
12. A pharmaceutical composition that comprises amorphous Form of lurasidone hydrochloride and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.
13. The pharmaceutical composition as claimed in claim 12, wherein the amorphous Form of lurasidone hydrochloride is formulated into tablets, capsules, suspensions, dispersions or injectables.
PCT/IN2012/000548 2012-03-09 2012-08-10 Novel polymorph of lurasidone hydrochloride WO2013132511A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN893/CHE/2012 2012-03-09
IN893CH2012 2012-03-09

Publications (1)

Publication Number Publication Date
WO2013132511A1 true WO2013132511A1 (en) 2013-09-12

Family

ID=49116043

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2012/000548 WO2013132511A1 (en) 2012-03-09 2012-08-10 Novel polymorph of lurasidone hydrochloride

Country Status (1)

Country Link
WO (1) WO2013132511A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104059061A (en) * 2014-07-04 2014-09-24 中国药科大学 Co-amorphous substance of indissolvable drug
ITMI20131737A1 (en) * 2013-10-17 2015-04-18 Procos Spa PROCESS FOR THE INDUSTRIAL SYNTHESIS OF LURASIDONE
CN106512011A (en) * 2016-11-04 2017-03-22 中国药科大学 A method of slowly releasing a medicine
EP3207041A4 (en) * 2014-10-14 2018-09-26 Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) An improved process for the preparation of lurasidone hydrochloride
CN110003195A (en) * 2019-05-21 2019-07-12 湖北中医药大学 Lurasidone crystal and preparation method thereof and the application in injection delivery systems
CN111366645A (en) * 2018-12-26 2020-07-03 上海科胜药物研发有限公司 Method for determining and analyzing content of chloroethane in lurasidone
WO2021107967A1 (en) * 2019-01-10 2021-06-03 Slayback Pharma Llc Pharmaceutical compositions of lurasidone
CN113024535A (en) * 2019-12-24 2021-06-25 上海科胜药物研发有限公司 Preparation method of lurasidone hydrochloride

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040254223A1 (en) * 2001-08-03 2004-12-16 Yatendra Kumar Process for the preparation of amorphous form of torsemide
US20060004207A1 (en) * 2003-01-30 2006-01-05 Ljubomir Antoncic Preparation of new pharmaceutically suitable salt of losartan and forms thereof with new purification and isolation methods
WO2006109324A2 (en) * 2005-04-13 2006-10-19 Lupin Limited Processes for preparation of amorphous cefepime acid addition salts
US20100093875A1 (en) * 2006-10-25 2010-04-15 Dainippon Sumitomo Pharma Co., Ltd. Granular preparation prevented from caking
WO2012063246A1 (en) * 2010-11-11 2012-05-18 Mapi Pharma Ltd. Amorphous form of lurasidone hydrochloride

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040254223A1 (en) * 2001-08-03 2004-12-16 Yatendra Kumar Process for the preparation of amorphous form of torsemide
US20060004207A1 (en) * 2003-01-30 2006-01-05 Ljubomir Antoncic Preparation of new pharmaceutically suitable salt of losartan and forms thereof with new purification and isolation methods
WO2006109324A2 (en) * 2005-04-13 2006-10-19 Lupin Limited Processes for preparation of amorphous cefepime acid addition salts
US20100093875A1 (en) * 2006-10-25 2010-04-15 Dainippon Sumitomo Pharma Co., Ltd. Granular preparation prevented from caking
WO2012063246A1 (en) * 2010-11-11 2012-05-18 Mapi Pharma Ltd. Amorphous form of lurasidone hydrochloride

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATTERSON ET AL.: "The Influence of Thermal and Mechanical Preparative Techniques on the Amorphous state of Four Poorly Soluble Compounds", J. PHARM SCI., vol. 94, no. 9, 2005, pages 1998 - 2012, XP055111748, DOI: doi:10.1002/jps.20424 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20131737A1 (en) * 2013-10-17 2015-04-18 Procos Spa PROCESS FOR THE INDUSTRIAL SYNTHESIS OF LURASIDONE
WO2015056205A1 (en) * 2013-10-17 2015-04-23 Procos S.P.A. Process for the industrial synthesis of lurasidone
US9518047B2 (en) 2013-10-17 2016-12-13 Procos S.P.A. Process for the industrial synthesis of lurasidone
CN104059061A (en) * 2014-07-04 2014-09-24 中国药科大学 Co-amorphous substance of indissolvable drug
EP3207041A4 (en) * 2014-10-14 2018-09-26 Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) An improved process for the preparation of lurasidone hydrochloride
CN106512011A (en) * 2016-11-04 2017-03-22 中国药科大学 A method of slowly releasing a medicine
CN111366645A (en) * 2018-12-26 2020-07-03 上海科胜药物研发有限公司 Method for determining and analyzing content of chloroethane in lurasidone
WO2021107967A1 (en) * 2019-01-10 2021-06-03 Slayback Pharma Llc Pharmaceutical compositions of lurasidone
US11103503B2 (en) 2019-01-10 2021-08-31 Slayback Pharma Llc Pharmaceutical compositions of Lurasidone
US11103502B2 (en) 2019-01-10 2021-08-31 Slayback Pharma Llc Pharmaceutical compositions of lurasidone
CN110003195B (en) * 2019-05-21 2020-05-26 湖北中医药大学 Lurasidone crystal, preparation method thereof and application thereof in injection drug delivery system
CN110003195A (en) * 2019-05-21 2019-07-12 湖北中医药大学 Lurasidone crystal and preparation method thereof and the application in injection delivery systems
CN113024535A (en) * 2019-12-24 2021-06-25 上海科胜药物研发有限公司 Preparation method of lurasidone hydrochloride
CN114728952A (en) * 2019-12-24 2022-07-08 浙江华海药业股份有限公司 Preparation method of lurasidone hydrochloride

Similar Documents

Publication Publication Date Title
WO2013132511A1 (en) Novel polymorph of lurasidone hydrochloride
WO2011095059A1 (en) Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof
WO2014076712A2 (en) Lurasidone hydrochloride solid dispersion
KR20170057441A (en) Crystal Form of Bisulfate of JAK Inhibitor and Preparation Method Therefor
US9624207B2 (en) Polymorphs of azilsartan medoxomil
WO2019003249A1 (en) Polymorphic forms of baricitinib
US20130131090A1 (en) Salts of lapatinib
KR20180003542A (en) Polymorphs of afatinib and its salts and process for the preparation of quinazolinyl derivatives
EP2646457A1 (en) Optimized synthesis of pure, non-polymorphic, crystalline bile acids with defined particle size
WO2018078392A1 (en) Polymorphs of dasatinib
WO2013150544A2 (en) Ivabradine hydrochloride solid dispersion
US20140112992A1 (en) Process for febuxostat
US20130137868A1 (en) Salts of raltegravir
CA2837266A1 (en) Amorphous ritonavir co-precipitated
EP2393786B1 (en) Novel polymorphs of lopinavir
WO2014195977A2 (en) Novel polymorphs of vismodegib
US20130190368A1 (en) Novel polymorphs of febuxostat
WO2016157136A1 (en) Crystalline forms of idelalisib
WO2014013505A2 (en) Amorphous vildagliptin
WO2014013511A2 (en) Rufinamide solid dispersion
WO2012046245A1 (en) Novel polymorph of lacosamide
WO2022224269A1 (en) Co-crystals, salts and solid forms of niraparib
US9381199B2 (en) Linagliptin solid dispersion
CA2829186A1 (en) Amorphous form of lopinavir and ritonavir mixture
US20150291574A1 (en) Novel polymorphs of azilsartan

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12870560

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12870560

Country of ref document: EP

Kind code of ref document: A1