US20080086005A1 - Novel crystalline forms of aripiprazole - Google Patents

Novel crystalline forms of aripiprazole Download PDF

Info

Publication number
US20080086005A1
US20080086005A1 US11/870,090 US87009007A US2008086005A1 US 20080086005 A1 US20080086005 A1 US 20080086005A1 US 87009007 A US87009007 A US 87009007A US 2008086005 A1 US2008086005 A1 US 2008086005A1
Authority
US
United States
Prior art keywords
aripiprazole
hydrochloride
ray powder
powder diffraction
diffraction pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/870,090
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Kesireddy Subash Chander Reddy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Drugs Ltd
Original Assignee
Hetero Drugs Ltd
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 Drugs Ltd filed Critical Hetero Drugs Ltd
Priority to US11/870,090 priority Critical patent/US20080086005A1/en
Assigned to HETERO DRUGS LIMITED reassignment HETERO DRUGS LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MURALIDHARA REDDY, DASARI, PARTHASARADHI REDDY, BANDI, RAJI REDDY, RAPOLU, RATHNAKAR REDDY, KURA, SUBASH CHANDER REDDY, KESIREDDY
Publication of US20080086005A1 publication Critical patent/US20080086005A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention provides novel crystalline forms of aripiprazole and aripiprazole hydrochloride, processes for their preparation and pharmaceutical compositions containing them.
  • Aripiprazole of Formula (I): or 7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone and its salts are useful for treating schizophrenia and their therapeutic uses were disclosed in U.S. Pat. No. 5,006,528.
  • the object of the present invention is to provide stable novel crystalline forms of aripiprazole, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.
  • Another object of the present invention is to provide stable novel crystalline forms of aripiprazole hydrochloride, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.
  • a novel crystalline form of aripiprazole designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4, 24.9 degrees.
  • FIG. 1 shows typical Form I x-ray powder diffraction pattern.
  • the suitable solvent is selected from the group consisting of acetone, ethyl acetate, methanol or ethanol.
  • a novel crystalline form of aripiprazole designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 12.7, 15.1, 17.5, 18.2, 18.8, 19.5, 20.6, 21.2, 22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6, 35.8 degrees.
  • FIG. 2 shows typical Form II x-ray powder diffraction pattern.
  • a process for preparation of the Form II of aripiprazole which comprises dissolving aripiprazole in tetrahydrofuran and vacuum drying at about 25° C. or spray drying.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form A, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 6.2, 8.5, 11.5, 15.2, 15.5, 16.8, 17.2, 18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1, 24.7, 25.9, 27.5, 28.3, 28.9, 32.8 degrees.
  • FIG. 3 shows typical Form A x-ray powder diffraction pattern.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form B, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 9.3, 14.8, 16.4, 17.4, 18.7, 19.7, 21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees.
  • FIG. 4 shows typical Form B x-ray powder diffraction pattern.
  • the ketonic solvent is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form C, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 3.3, 10.3, 14.2, 14.6, 15.1, 16.4, 16.6, 19.4, 20.3, 20.8, 24.5, 24.9, 25.5, 26.4, 26.7, 28.5, 29.3, 30.1 degrees.
  • FIG. 5 shows typical Form C x-ray powder diffraction pattern.
  • the ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, ethyl formate and tert-butyl acetate.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form D, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 9.0, 14.7, 16.4, 17.4, 19.0, 19.3, 19.8, 21.4, 23.4, 24.7, 25.4 degrees.
  • FIG. 6 shows typical Form D x-ray powder diffraction pattern.
  • a pharmaceutical composition comprising crystalline Form I or Form II of aripiprazole.
  • a pharmaceutical composition comprising novel crystalline form of aripiprazole hydrochloride.
  • FIG. 1 is a x-ray powder diffraction pattern of crystalline Form I of aripiprazole.
  • FIG. 2 is a x-ray powder diffraction pattern of crystalline Form II of aripiprazole.
  • FIG. 3 is a x-ray powder diffraction pattern of crystalline Form A of aripiprazole hydrochloride.
  • FIG. 4 is a x-ray powder diffraction pattern of crystalline Form B of aripiprazole hydrochloride.
  • FIG. 5 is a x-ray powder diffraction pattern of crystalline Form C of aripiprazole hydrochloride.
  • FIG. 6 is a x-ray powder diffraction pattern of crystalline Form D of aripiprazole hydrochloride.
  • a novel crystalline form of aripiprazole designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4, 24.9 degrees.
  • FIG. 1 shows typical Form I x-ray powder diffraction pattern.
  • a process for preparation of the Form I of aripiprazole is dissolved in a suitable solvent.
  • the suitable solvent is selected from the group consisting of acetone, ethyl acetate, methanol and ethanol.
  • Aripiprazole obtained by a known method or crystalline Form II of aripiprazole obtained by the process described below may be used.
  • the solution is refluxed for about 30 minutes to 1 hour.
  • the solution is then cooled slowly to about 15° C. to 25° C. in about 1 hour and maintained for about 2 hour to 4 hours at the same temperature.
  • the separated crystals are filtered and dried to give Form I of aripiprazole.
  • a novel crystalline form of aripiprazole designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 12.7, 15.1, 17.5, 18.2, 18.8, 19.5, 20.6, 21.2, 22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6, 35.8 degrees.
  • FIG. 2 shows typical Form II x-ray powder diffraction pattern.
  • a process for preparation of the Form II of aripiprazole which comprises dissolving aripiprazole in tetrahydrofuran and vacuum drying at about 25° C. or spray drying.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form A, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 6.2, 8.5, 11.5, 15.2, 15.5, 16.8, 17.2, 18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1, 24.7, 25.9, 27.5, 28.3, 28.9, 32.8 degrees.
  • FIG. 3 shows typical Form A x-ray powder diffraction pattern.
  • a process for preparation of the Form A of aripiprazole hydrochloride is provided.
  • aripiprazole is dissolved in ethanol or isopropyl alcohol. If necessary, the solvent may be heated to effect dissolution of aripiprazole.
  • Hydrochloric acid is added to the solution. Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole. Then the contents are maintained for about 1 hour to 3 hours at about 15° C. to 25° C. and the separated crystals are filtered and dried to yield Form A of aripiprazole hydrochloride.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form B, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 9.3, 14.8, 16.4, 17.4, 18.7, 19.7, 21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees.
  • FIG. 4 shows typical Form B x-ray powder diffraction pattern.
  • a process for preparation of the Form B of aripiprazole hydrochloride is provided.
  • aripiprazole is dissolved in a ketonic solvent.
  • the solvent may be heated to dissolve aripiprazole.
  • the ketonic solvent is acetone or methyl isobutyl ketone or methyl ethyl ketone; or mixture thereof.
  • Hydrochloric acid is added to the solution. Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole. Then the contents are maintained for about 1 hour to 4 hours at about 15° C. to 25° C. and the separated crystals are filtered and dried to yield Form B of aripiprazole hydrochloride.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form C, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 3.3, 10.3, 14.2, 14.6, 15.1, 16.4, 16.6, 19.4, 20.3, 20.8, 24.5, 24.9, 25.5, 26.4, 26.7, 28.5, 29.3, 30.1 degrees.
  • FIG. 5 shows typical Form C x-ray powder diffraction pattern.
  • a process for preparation of the Form C of aripiprazole hydrochloride is provided.
  • aripiprazole is dissolved in an ester solvent.
  • the solvent may be heated to effect dissolution of aripiprazole.
  • the ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, ethyl formate and tert-butyl acetate.
  • Hydrochloric acid is added to the solution. Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole. Then the contents are maintained for about 1 hour to 4 hours at about 15° C. to 25° C. and the separated solid is filtered and dried to obtain Form C of aripiprazole hydrochloride.
  • a novel crystalline form of aripiprazole hydrochloride designated as Form D, characterized by an x-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 9.0, 14.7, 16.4, 17.4, 19.0, 19.3, 19.8, 21.4, 23.4, 24.7, 25.4 degrees.
  • FIG. 6 shows typical Form D x-ray powder diffraction pattern.
  • a process for preparation of the Form D of aripiprazole hydrochloride is provided.
  • aripiprazole is dissolved in tetrahydrofuran.
  • Hydrochloric acid is added to the solution.
  • Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole.
  • the contents are maintained for 2 hour to 4 hours at about 15° C. to 25° C. and the separated crystals are filtered and dried to produce Form D of aripiprazole hydrochloride.
  • aripiprazole hydrochloride obtained by the processes described above are very pure. So, aripiprazole with high purity can be obtained by basifying a solution of aripiprazole hydrochloride crystalline form and isolating aripiprazole from the solution by usual processes known in the art.
  • a pharmaceutical composition comprising Form I or Form II of aripiprazole and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising crystalline form of aripiprazole hydrochloride and a pharmaceutically acceptable carrier.
  • the crystalline form may be Form A, Form B, Form C or Form D.
  • aripiprazole or aripiprazole hydrochloride may be formulated in a form suitable for oral administration or injection.
  • the examples of pharmaceutical compositions are tablets, capsules, powders, suspensions, emulsions, injections and the like.
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in acetone (42 ml) and refluxed for 30 minutes. The solution is slowly cooled to 25° C. in 1 hour and maintained at 25° C. for 3 hours. The separated crystals are filtered and dried to give 1 gm of Form I of aripiprazole.
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in tetrahydrofuran and the solvent is removed by vacuum drying at 25° C. for 6 hours to give Form II of aripiprazole in quantitative yield.
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in tetrahydrofuran and the solvent is removed by spray drying at 25° C. for 6 hours to give Form II of aripiprazole in quantitative yield.
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in methanol (12 ml) and conc. hydrochloric acid (1 ml) is added to the solution. The contents are maintained for 2 hours at 25° C. and the separated solid is filtered to give 2 gm of Form A of aripiprazole hydrochloride.
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in acetone (12 ml) and conc. hydrochloric acid (1 ml) is added to the solution. The contents are maintained for 3 hours at 25° C. and the separated solid is filtered to give 1.9 gm of Form B of aripiprazole hydrochloride.
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in ethyl acetate (12 ml). 10% W/V HCl in ethyl acetate (4 ml) is added to the solution. The solution is maintained at 25° C. for 2 hours and the separated crystals are collected by filtration to give 2 gm of Form C of aripiprazole hydrochloride.
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in tetrahydrofuran (12 ml) and conc. hydrochloric acid (1 ml) is added to the solution. The contents are maintained for 3 hours at 25° C. and the separated solid is collected by filtration to give 2 gm of Form D of aripiprazole hydrochloride.
  • Example 1 is repeated using Form II of aripiprazole instead of aripiprazole to give Form I of aripiprazole.
  • Example 2 is repeated using Form I of aripiprazole instead of aripiprazole to give Form II of aripiprazole.
  • Example 5 is repeated using Form I of aripiprazole instead of aripiprazole to give Form B of aripiprazole hydrochloride.
  • Example 7 is repeated using Form II of aripiprazole instead of aripiprazole to give Form D of aripiprazole hydrochloride.

Abstract

The present invention provides novel crystalline forms of aripiprazole and aripiprazole hydrochloride, processes for their preparation and pharmaceutical compositions containing them.

Description

    FIELD OF THE INVENTION
  • The present invention provides novel crystalline forms of aripiprazole and aripiprazole hydrochloride, processes for their preparation and pharmaceutical compositions containing them.
    • BACKGROUND OF THE INVENTION
  • Aripiprazole of Formula (I):
    Figure US20080086005A1-20080410-C00001
    or 7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone and its salts are useful for treating schizophrenia and their therapeutic uses were disclosed in U.S. Pat. No. 5,006,528.
  • Processes for the preparation of aripiprazole and its salts were described in U.S. Pat. No. 5,006,528. These processes do not produce well defined, reproducible crystalline forms.
  • Thus there is a need for stable and reproducible crystalline forms of aripiprazole and its salts.
  • We have discovered two novel crystalline forms of aripiprazole and four novel crystalline forms of aripiprazole hydrochloride. The novel forms have been found to be stable over the time and reproducible and so, suitable for pharmaceutical preparations.
  • Thus, the object of the present invention is to provide stable novel crystalline forms of aripiprazole, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.
  • Another object of the present invention is to provide stable novel crystalline forms of aripiprazole hydrochloride, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.
  • Since the novel crystalline forms of aripiprazole hydrochloride are obtained with high purity, preparation of aripiprazole via the crystalline forms of aripiprazole hydrochloride serves as a means of producing pure aripiprazole.
    • SUMMARY OF THE INVENTION
  • According to one aspect of the present invention, there is provided a novel crystalline form of aripiprazole, designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4, 24.9 degrees. FIG. 1 shows typical Form I x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form I of aripiprazole comprising the steps of:
  • a) dissolving aripiprazole in a suitable solvent;
  • b) refluxing for about 30 minutes to 1 hour;
  • c) cooling slowly to about 15° C. to 25° C.;
  • d) maintaining for about 2 hour to 4 hours at about 15° C. to 25° C.; and
  • e) filtering the solid separated.
  • The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methanol or ethanol.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole, designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 12.7, 15.1, 17.5, 18.2, 18.8, 19.5, 20.6, 21.2, 22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6, 35.8 degrees. FIG. 2 shows typical Form II x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form II of aripiprazole, which comprises dissolving aripiprazole in tetrahydrofuran and vacuum drying at about 25° C. or spray drying.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form A, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 6.2, 8.5, 11.5, 15.2, 15.5, 16.8, 17.2, 18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1, 24.7, 25.9, 27.5, 28.3, 28.9, 32.8 degrees. FIG. 3 shows typical Form A x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form A of aripiprazole hydrochloride comprising the steps of:
  • a) dissolving aripiprazole in methanol or isopropyl alcohol;
  • b) adding hydrochloric acid;
  • c) maintaining for about 1 hour to 3 hours at about 15° C. to 25° C.;
  • d) filtering the solid separated.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form B, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 9.3, 14.8, 16.4, 17.4, 18.7, 19.7, 21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees. FIG. 4 shows typical Form B x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form B of aripiprazole hydrochloride comprising the steps of:
  • a) dissolving aripiprazole in a ketonic solvent;
  • b) adding hydrochloric acid;
  • c) maintaining for about 1 hour to 4 hours at about 15° C. to 25° C.;
  • d) filtering the solid separated.
  • The ketonic solvent is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form C, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 3.3, 10.3, 14.2, 14.6, 15.1, 16.4, 16.6, 19.4, 20.3, 20.8, 24.5, 24.9, 25.5, 26.4, 26.7, 28.5, 29.3, 30.1 degrees. FIG. 5 shows typical Form C x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form C of aripiprazole hydrochloride comprising the steps of:
  • a) dissolving aripiprazole in an ester solvent;
  • b) adding hydrochloric acid;
  • c) maintaining for about 1 hour to 4 hours at about 15° C. to 25° C.;
  • d) filtering the separated solid.
  • The ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, ethyl formate and tert-butyl acetate.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form D, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 9.0, 14.7, 16.4, 17.4, 19.0, 19.3, 19.8, 21.4, 23.4, 24.7, 25.4 degrees. FIG. 6 shows typical Form D x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form D of aripiprazole hydrochloride comprising the steps of:
  • a) dissolving aripiprazole in tetrahydrofuran;
  • b) adding hydrochloric acid;
  • c) maintaining for about 2 hour to 4 hours at about 15° C. to 25° C.;
  • d) filtering the solid separated.
  • According to another aspect of the present invention there is provided a pharmaceutical composition comprising crystalline Form I or Form II of aripiprazole.
  • According to another aspect of the present invention there is provided a pharmaceutical composition comprising novel crystalline form of aripiprazole hydrochloride.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a x-ray powder diffraction pattern of crystalline Form I of aripiprazole.
  • FIG. 2 is a x-ray powder diffraction pattern of crystalline Form II of aripiprazole.
  • FIG. 3 is a x-ray powder diffraction pattern of crystalline Form A of aripiprazole hydrochloride.
  • FIG. 4 is a x-ray powder diffraction pattern of crystalline Form B of aripiprazole hydrochloride.
  • FIG. 5 is a x-ray powder diffraction pattern of crystalline Form C of aripiprazole hydrochloride.
  • FIG. 6 is a x-ray powder diffraction pattern of crystalline Form D of aripiprazole hydrochloride.
      • x-Ray powder diffraction spectrum was measured on a Siemens diffractometer.
    DETAILED DESCRIPTION OF THE INVENTION
  • According to one aspect of the present invention, there is provided a novel crystalline form of aripiprazole, designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4, 24.9 degrees. FIG. 1 shows typical Form I x-ray powder diffraction pattern.
  • According to another aspect of the present invention, there is provided a process for preparation of the Form I of aripiprazole. Thus aripiprazole is dissolved in a suitable solvent. The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methanol and ethanol. Aripiprazole obtained by a known method or crystalline Form II of aripiprazole obtained by the process described below may be used. The solution is refluxed for about 30 minutes to 1 hour. The solution is then cooled slowly to about 15° C. to 25° C. in about 1 hour and maintained for about 2 hour to 4 hours at the same temperature. The separated crystals are filtered and dried to give Form I of aripiprazole.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole, designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 12.7, 15.1, 17.5, 18.2, 18.8, 19.5, 20.6, 21.2, 22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6, 35.8 degrees. FIG. 2 shows typical Form II x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form II of aripiprazole, which comprises dissolving aripiprazole in tetrahydrofuran and vacuum drying at about 25° C. or spray drying.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form A, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 6.2, 8.5, 11.5, 15.2, 15.5, 16.8, 17.2, 18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1, 24.7, 25.9, 27.5, 28.3, 28.9, 32.8 degrees. FIG. 3 shows typical Form A x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form A of aripiprazole hydrochloride. Thus aripiprazole is dissolved in ethanol or isopropyl alcohol. If necessary, the solvent may be heated to effect dissolution of aripiprazole. Hydrochloric acid is added to the solution. Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole. Then the contents are maintained for about 1 hour to 3 hours at about 15° C. to 25° C. and the separated crystals are filtered and dried to yield Form A of aripiprazole hydrochloride.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form B, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 9.3, 14.8, 16.4, 17.4, 18.7, 19.7, 21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees. FIG. 4 shows typical Form B x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form B of aripiprazole hydrochloride. Thus aripiprazole is dissolved in a ketonic solvent. If necessary, the solvent may be heated to dissolve aripiprazole. The ketonic solvent is acetone or methyl isobutyl ketone or methyl ethyl ketone; or mixture thereof. Hydrochloric acid is added to the solution. Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole. Then the contents are maintained for about 1 hour to 4 hours at about 15° C. to 25° C. and the separated crystals are filtered and dried to yield Form B of aripiprazole hydrochloride.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form C, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 3.3, 10.3, 14.2, 14.6, 15.1, 16.4, 16.6, 19.4, 20.3, 20.8, 24.5, 24.9, 25.5, 26.4, 26.7, 28.5, 29.3, 30.1 degrees. FIG. 5 shows typical Form C x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form C of aripiprazole hydrochloride. Thus aripiprazole is dissolved in an ester solvent. If necessary, the solvent may be heated to effect dissolution of aripiprazole. The ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, ethyl formate and tert-butyl acetate. Hydrochloric acid is added to the solution. Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole. Then the contents are maintained for about 1 hour to 4 hours at about 15° C. to 25° C. and the separated solid is filtered and dried to obtain Form C of aripiprazole hydrochloride.
  • According to another aspect of the present invention, there is provided a novel crystalline form of aripiprazole hydrochloride, designated as Form D, characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 9.0, 14.7, 16.4, 17.4, 19.0, 19.3, 19.8, 21.4, 23.4, 24.7, 25.4 degrees. FIG. 6 shows typical Form D x-ray powder diffraction pattern.
  • According to another aspect of the present invention there is provided a process for preparation of the Form D of aripiprazole hydrochloride. Thus aripiprazole is dissolved in tetrahydrofuran. Hydrochloric acid is added to the solution. Hydrochloric acid may be added as an aqueous solution or as a solution in any other solvent; or hydrochloric acid gas may be passed through the solution of aripiprazole. Then the contents are maintained for 2 hour to 4 hours at about 15° C. to 25° C. and the separated crystals are filtered and dried to produce Form D of aripiprazole hydrochloride.
  • The novel crystalline forms of aripiprazole hydrochloride obtained by the processes described above are very pure. So, aripiprazole with high purity can be obtained by basifying a solution of aripiprazole hydrochloride crystalline form and isolating aripiprazole from the solution by usual processes known in the art.
  • According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form I or Form II of aripiprazole and a pharmaceutically acceptable carrier.
  • According to another aspect of the present invention there is provided a pharmaceutical composition comprising crystalline form of aripiprazole hydrochloride and a pharmaceutically acceptable carrier. The crystalline form may be Form A, Form B, Form C or Form D.
  • The forms of aripiprazole or aripiprazole hydrochloride may be formulated in a form suitable for oral administration or injection. The examples of pharmaceutical compositions are tablets, capsules, powders, suspensions, emulsions, injections and the like.
  • The following examples will serve to further illustrate the invention.
    • EXAMPLE 1
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in acetone (42 ml) and refluxed for 30 minutes. The solution is slowly cooled to 25° C. in 1 hour and maintained at 25° C. for 3 hours. The separated crystals are filtered and dried to give 1 gm of Form I of aripiprazole.
    • EXAMPLE 2
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in tetrahydrofuran and the solvent is removed by vacuum drying at 25° C. for 6 hours to give Form II of aripiprazole in quantitative yield.
    • EXAMPLE 3
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in tetrahydrofuran and the solvent is removed by spray drying at 25° C. for 6 hours to give Form II of aripiprazole in quantitative yield.
    • EXAMPLE 4
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in methanol (12 ml) and conc. hydrochloric acid (1 ml) is added to the solution. The contents are maintained for 2 hours at 25° C. and the separated solid is filtered to give 2 gm of Form A of aripiprazole hydrochloride.
    • EXAMPLE 5
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in acetone (12 ml) and conc. hydrochloric acid (1 ml) is added to the solution. The contents are maintained for 3 hours at 25° C. and the separated solid is filtered to give 1.9 gm of Form B of aripiprazole hydrochloride.
    • EXAMPLE 6
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in ethyl acetate (12 ml). 10% W/V HCl in ethyl acetate (4 ml) is added to the solution. The solution is maintained at 25° C. for 2 hours and the separated crystals are collected by filtration to give 2 gm of Form C of aripiprazole hydrochloride.
    • EXAMPLE 7
  • Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No. 5,006,528) is dissolved in tetrahydrofuran (12 ml) and conc. hydrochloric acid (1 ml) is added to the solution. The contents are maintained for 3 hours at 25° C. and the separated solid is collected by filtration to give 2 gm of Form D of aripiprazole hydrochloride.
    • EXAMPLE 8
  • Example 1 is repeated using Form II of aripiprazole instead of aripiprazole to give Form I of aripiprazole.
    • EXAMPLE 9
  • Example 2 is repeated using Form I of aripiprazole instead of aripiprazole to give Form II of aripiprazole.
    • EXAMPLE 10
  • Example 5 is repeated using Form I of aripiprazole instead of aripiprazole to give Form B of aripiprazole hydrochloride.
    • EXAMPLE 11
  • Example 7 is repeated using Form II of aripiprazole instead of aripiprazole to give Form D of aripiprazole hydrochloride.

Claims (7)

1-13. (canceled)
14. A crystalline Form B of aripiprazole hydrochloride characterized by an x-ray powder diffraction pattern having peaks expressed as 2θ at about 9.3, 14.8, 16.4, 17.4, 18.7, 19.7, 21.4, 21.9, 23.8, 25.1, 25.9, 29.7 degrees.
15. A crystalline aripiprazole hydrochloride, characterized by an x-ray powder diffraction pattern as in FIG. 4.
16. A process for preparation of Form B of aripiprazole hydrochloride of claim 14, comprising the steps of:
a) dissolving aripiprazole in a ketonic solvent;
b) adding hydrochloric acid;
c) maintaining for about 1 hour to 4 hours at about 15° C. to 25° C.; and
d) filtering the solid separated;
wherein the ketonic solvent is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone.
17. A process according to claim 16, wherein the ketone is acetone.
18. A process according to claim 16, wherein the ketone is methyl isobutyl ketone.
19-30. (canceled)
US11/870,090 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole Abandoned US20080086005A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/870,090 US20080086005A1 (en) 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/IN2003/000064 WO2004083183A1 (en) 2003-03-21 2003-03-21 Novel crystalline forms of aripiprazole
US10/508,498 US7491726B2 (en) 2003-03-21 2003-03-21 Crystalline forms of aripiprazole
US11/870,090 US20080086005A1 (en) 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/IN2003/000064 Division WO2004083183A1 (en) 2003-03-21 2003-03-21 Novel crystalline forms of aripiprazole
US10/508,498 Division US7491726B2 (en) 2003-03-21 2003-03-21 Crystalline forms of aripiprazole

Publications (1)

Publication Number Publication Date
US20080086005A1 true US20080086005A1 (en) 2008-04-10

Family

ID=33017818

Family Applications (4)

Application Number Title Priority Date Filing Date
US10/508,498 Expired - Fee Related US7491726B2 (en) 2003-03-21 2003-03-21 Crystalline forms of aripiprazole
US11/870,067 Abandoned US20080085903A1 (en) 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole
US11/870,090 Abandoned US20080086005A1 (en) 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole
US11/870,108 Abandoned US20080182856A1 (en) 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US10/508,498 Expired - Fee Related US7491726B2 (en) 2003-03-21 2003-03-21 Crystalline forms of aripiprazole
US11/870,067 Abandoned US20080085903A1 (en) 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/870,108 Abandoned US20080182856A1 (en) 2003-03-21 2007-10-10 Novel crystalline forms of aripiprazole

Country Status (4)

Country Link
US (4) US7491726B2 (en)
EP (1) EP1606262A1 (en)
AU (1) AU2003230192A1 (en)
WO (1) WO2004083183A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080085903A1 (en) * 2003-03-21 2008-04-10 Hetero Drugs Limited Novel crystalline forms of aripiprazole

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI371274B (en) * 2003-10-23 2012-09-01 Bristol Myers Squibb Co Process for making sterile aripiprazole of desired mean particle size
US7714129B2 (en) 2003-12-16 2010-05-11 Teva Pharmaceutical Industries Ltd. Methods of preparing anhydrous aripiprazole form II
ATE529409T1 (en) 2003-12-16 2011-11-15 Teva Pharma METHOD FOR PRODUCING CRYSTALLINE FORMS OF ARIPIPRAZOLE
CN1914176A (en) 2004-02-05 2007-02-14 特瓦制药工业有限公司 Process for preparing aripiprazole
EP1711466A1 (en) * 2004-02-05 2006-10-18 Teva Pharmaceutical Industries Ltd Process for preparing aripiprazole
AU2006208628B2 (en) * 2005-01-27 2010-08-12 Sandoz Ag Salts of aripiprazole
EP1686126A1 (en) * 2005-01-27 2006-08-02 Sandoz AG Salts of aripiprazole
CZ300352B6 (en) * 2005-02-15 2009-04-29 Zentiva, A. S. Process for preparing aripiprazole phosphate
ES2526415T3 (en) * 2005-03-17 2015-01-12 Synthon B.V. Pharmaceutical tablets of crystalline aripiprazole type II
AU2006224759A1 (en) * 2005-03-17 2006-09-21 Synthon B.V. Process of making crystalline Type II aripiprazole
EP1879865A1 (en) * 2005-04-15 2008-01-23 Medichem S.A. Syntheses and preparations of polymorphs of crystalline aripiprazole
JP2008537540A (en) * 2005-12-22 2008-09-18 テバ ファーマシューティカル インダストリーズ リミティド A method for reducing the particle size of aripiprazole
PT1808164E (en) * 2006-01-05 2009-03-17 Teva Pharma Wet granulation method for preparing pharmaceutical compositions of aripiprazole
CA2627695A1 (en) * 2006-01-05 2007-07-19 Teva Pharmaceutical Industries Ltd. Dry formulations of aripiprazole
US20060223820A1 (en) * 2006-03-21 2006-10-05 Chemagis Ltd. Crystalline aripiprazole salts and processes for preparation and purification thereof
DE602007003024D1 (en) 2006-06-27 2009-12-10 Sandoz Ag NEW PROCESS FOR SALT PRODUCTION
US7799790B2 (en) 2006-07-20 2010-09-21 Helm Ag Amorphous aripiprazole and process for the preparation thereof
EP1880714A1 (en) 2006-07-20 2008-01-23 Helm AG Amorphous Aripiprazole and Process for the Preparation thereof
EP2082735B1 (en) 2008-01-23 2010-09-29 Helm AG Amorphous Aripiprazole and Process for the Preparation thereof
WO2008020453A2 (en) * 2006-08-17 2008-02-21 Unichem Laboratories Limited A process for the preparation of a novel crystalline polymorph of aripiprazole
GB0618879D0 (en) 2006-09-26 2006-11-01 Zysis Ltd Pharmaceutical compositions
US8199003B2 (en) 2007-01-30 2012-06-12 At&T Intellectual Property I, Lp Devices and methods for detecting environmental circumstances and responding with designated communication actions
EP2233471A1 (en) 2009-02-06 2010-09-29 Adamed Sp. z o.o. A salt of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4.dihydro-2(1h)-quinolinone with 5-sulfosalicylic acid and its preparation process
US9156822B2 (en) 2010-07-02 2015-10-13 The University Of North Carolina At Chapel Hill Functionally selective ligands of dopamine D2 receptors
CN102850268B (en) * 2011-06-27 2015-07-15 上海中西制药有限公司 Aripiprazole I-type crystallite, aripiprazole solid preparation and preparation methods thereof
CN106474058B (en) 2015-08-31 2020-01-07 南京诺瑞特医药科技有限公司 Injectable aripiprazole suspension formulations with extended shelf life
WO2017139971A1 (en) * 2016-02-19 2017-08-24 诺瑞特国际药业股份有限公司 New crystal form of aripiprazole

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006528A (en) * 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
US20040102523A1 (en) * 2002-08-09 2004-05-27 Michel Broquaire Modafinil polymorphic forms
US20080085903A1 (en) * 2003-03-21 2008-04-10 Hetero Drugs Limited Novel crystalline forms of aripiprazole

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006528A (en) * 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
US20040102523A1 (en) * 2002-08-09 2004-05-27 Michel Broquaire Modafinil polymorphic forms
US20080085903A1 (en) * 2003-03-21 2008-04-10 Hetero Drugs Limited Novel crystalline forms of aripiprazole
US20080182856A1 (en) * 2003-03-21 2008-07-31 Hetero Drugs Limited Novel crystalline forms of aripiprazole

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080085903A1 (en) * 2003-03-21 2008-04-10 Hetero Drugs Limited Novel crystalline forms of aripiprazole
US20080182856A1 (en) * 2003-03-21 2008-07-31 Hetero Drugs Limited Novel crystalline forms of aripiprazole

Also Published As

Publication number Publication date
US7491726B2 (en) 2009-02-17
US20050159429A1 (en) 2005-07-21
EP1606262A1 (en) 2005-12-21
WO2004083183A1 (en) 2004-09-30
US20080182856A1 (en) 2008-07-31
AU2003230192A1 (en) 2004-10-11
US20080085903A1 (en) 2008-04-10

Similar Documents

Publication Publication Date Title
US20080086005A1 (en) Novel crystalline forms of aripiprazole
US7655798B2 (en) Process of making crystalline Type II aripiprazole
US7956048B2 (en) Polymorphs of eltrombopag and eltrombopag salts and processes for preparation thereof
US7300938B2 (en) Polymorphs of imatinib mesylate
US7902198B2 (en) Crystalline aripiprazole solvates
WO2012027543A1 (en) Solid state forms of dabigatran etexilate, dabigatran etexilate mesylate and processes for preparation thereof
US7989618B2 (en) Linezolid crystalline hydrate form and linezolid salts
WO2007004061A1 (en) Syntheses and preparations of polymorphs of crystalline aripiprazole
EP0304941B1 (en) Pharmaceutically useful polymorphic modification of buspirone
EP0683167B1 (en) Terazosin monohydrochloride and processes and intermediate for its production
EP1789412B1 (en) Crystalline alfuzosin base
US6130218A (en) Polymorphic form of doxazosin mesylate (Form I)
WO2012098501A1 (en) Febuxostat co-crystals
EP1858855B2 (en) Process of making crystalline type ii aripiprazole
US20100113784A1 (en) Process for preparing crystalline aripiprazole
CA2224884A1 (en) New polymorphous form of doxazosine mesylate (form 11)
WO2004099183A1 (en) Novel polymorphs of pantoprazole sodium
WO2019099761A1 (en) Solid state forms of elafibranor
WO2011085130A1 (en) Solid state forms of fosamprenavir calcium salt and process for preparation thereof
EP3656768A1 (en) Beraprost-314d crystals and methods for preparation thereof
EP1082304B1 (en) NEW CRYSTALLINE POLYMORPHIC FORM OF 1-METHYL-5-p-TOLUOYLPYRROLE-2-ACETAMIDOACETIC ACID GUAIACYL ESTER (MED 15)
WO2005108395A1 (en) Ziprasidone hydrochloride polymorph and process for its preparation
EP1785411A1 (en) Protriptyline hydrochloride crystalline form

Legal Events

Date Code Title Description
AS Assignment

Owner name: HETERO DRUGS LIMITED, INDIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PARTHASARADHI REDDY, BANDI;RATHNAKAR REDDY, KURA;RAJI REDDY, RAPOLU;AND OTHERS;REEL/FRAME:020198/0411

Effective date: 20041224

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE