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Methods of preparing aripiprazole crystalline forms - european patent office - ep 1613598 b

EP 1 613 598 B1
EUROPEAN PATENT SPECIFICATION
(45) Date of publication and mention of the grant of the patent: C07D 215/22 (2006.01)
19.10.2011 Bulletin 2011/42
(86) International application number: (21) Application number: 04815093.2
(22) Date of filing: 16.12.2004
(87) International publication number: WO 2005/058835 (30.06.2005 Gazette 2005/26)
(54) METHODS OF PREPARING ARIPIPRAZOLE CRYSTALLINE FORMS
VERFAHREN ZUR HERSTELLUNG VON KRISTALLINEN ARIPIPRAZOLFORMEN PROCEDES DE PREPARATION DE FORMES CRISTALLINES D'ARIPIPRAZOLE (84) Designated Contracting States: • IZSAK, Reuven
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
Doar Na Mizrah Binyamin (IL)
HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR
(74) Representative: Eder, Michael et al
(30) Priority: 16.12.2003 US 530297 P
30.12.2003 US 533831 P
Fünf Höfe
13.10.2004 US 618404 P
14.10.2004 US 618960 P
80333 München (DE)
(43) Date of publication of application: (56) References cited: 11.01.2006 Bulletin 2006/02
(73) Proprietor: TEVA PHARMACEUTICAL
• OSHIRO YASUO ET AL: "Novel Antipsychotic
49131 Petah Tiqva (IL)
Agents with Dopamine Autoreceptor Agonist
Properties: Synthesis and Pharmacology of
• ARONHIME, Judith
dihydro-2(1H)-quinolinone Derivatives" 1998,
76217 Rehovot (IL)
JOURNAL OF MEDICINAL CHEMISTRY,
• DOLITZKY, Ben-Zion
AMERICAN CHEMICAL SOCIETY.
Petach Tiqva 49651 (IL)
WASHINGTON, US, PAGE(S) 658-667 ,
• LUVCHICK, Eran
XP002272484 ISSN: 0022-2623 page 661; example
Azur (IL)
• HILDESHEIM, Jean
Mazkeret Batya (IL)
• EISEN-NEVO, Hagit
The file contains technical information submitted after Shoam 73142 (IL)
the application was filed and not included in this specification 13 598 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the 1 6 Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
paid. (Art. 99(1) European Patent Convention).
Printed by Jouve, 75001 PARIS (FR) EP 1 613 598 B1
RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional Application No. 60/530,297, filed December 16, 2003;
U.S. provisional Application No. 60/533,831, filed December 30, 2003; U.S. provisional Application No. 60/618,404, filed
October 13, 2004; and U.S. provisional Application No. 60/618,960, filed October 14, 2004.
FIELD OF THE INVENTION [0002] The invention encompasses crystalline forms of aripiprazole forms and methods of preparing them.
BACKGROUND OF THE INVENTION [0003] Schizophrenia is the most common type of psychosis caused by excessive neurotransmission activity of the
dopaminergic nervous system in the central nervous system. A number of drugs which block the neurotransmission of
dopaminergic receptor in the central nervous system have been developed for use in treating schizophrenia. Among
the drugs developed are phenothiazine-type compounds such as chlorpromazine, butyrophenone-type compounds such
as haloperidol, and benzamide-type compounds such as sulpiride. These drugs improve so-called positive symptoms
in the acute period of schizophrenia such as hallucinations, delusions, and excitations. Many drugs for treating schizo-phrenia, however, are not effective for improving the so-called negative symptoms which are observed in the chronicperiod of schizophrenia such as apathy, emotional depression, and hypopsychosis. The drugs currently used produceundesirable side effects such as akathisia, dystonia, Parkinsonism dyskinesia, and late dyskinesia, by blocking theneurotransmission of dopaminergic receptor in the striate body. Drugs that improve both the negative and positive symptoms of schizophrenia but diminish the undesirable side effect of schizophrenia are particularly desirable.
[0004] Aripiprazole is a pyschotropic drug that exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-
HT2A receptors; moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, α1-adrenergic and histamine H1 re- ceptors; and moderate affinity for the serotonin reuptake site. Aripiprazole has no appreciable affinity for cholinergicmuscarinic receptors. The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, is unknown. It has been proposed, however, that the efficacy of aripiprazole is mediated through a combination of partialagonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.
[0005] Japanese Patent Kokai No. 02-191256 discloses that anhydride crystals of aripiprazole are typically manufac-
tured by recrystallization of anhydride aripiprazole from ethanol or by heating aripiprazole hydrate at a temperature of
80°C. According to WO 03/26659, anhydride aripiprazole prepared by these methods is significantly hygroscopic.
[0006] The Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (October 6-8, 1996)
disclosed that aripiprazole anhydride crystals may exist as Type-I and Type-II crystals. Type-I aripiprazole crystals can
be prepared by recrystallizing aripiprazole from an ethanol solution or by heating aripiprazole hydrate at 80°C. Type-II
aripiprazole crystals can be prepared by heating the Type-I crystals at 130°C to 140°C for 15 hours. This process is not
easily applied to an industrial scale preparation of anhydride aripiprazole.
[0007] PCT publication WO 03/26659 discloses the preparation of anhydrous aripiprazole Type I and crystalline forms
Form A, B, C, and D. Typically, the process for preparing the crystalline forms comprises heating crystalline anhydrous
aripiprazole. The process, however, is cumbersome because it requires crystalline anhydrous aripiprazole as the starting
material. The process in the PCT publication can only be carried out after the preparation, isolation, and purification of
aripiprazole. Thus, only after performing the additional steps may one heat the crystalline anhydrous aripiprazole to
obtain the desired crystalline forms of aripiprazole. Additionally, drying or heating may affect the distribution of crystalline
forms and/or crystalline purity, if drying causes crystalline transformation from one crystalline form to another.
[0008] Alternate crystalline structures possessing the stability and manufacturing advantages of anhydrous aripiprazole
are highly desired. Likewise, methods for making aripiprazole without additional steps and cost also are necessary.
SUMMARY OF THE INVENTION [0009] Described here are anhydrous aripiprazole crystalline forms which are non-hygroscopic and which maintain
compound stability during storage, and methods for preparing the non-hygroscopic aripiprazole crystalline forms.
[0010] Described here are
[0011] Described is a crystalline anhydrous aripiprazole Form I characterized by X-ray powder diffraction peaks at
16.8, 19.6, 20.6, 22.3, and 25.1 degrees two-theta,  0.2 degrees two-theta.
[0012] The invention encompasses aripiprazole Form II characterized by X-ray powder diffraction peaks at 16.5, 18.7,
21.9, 22.4, and 23.5 degrees two-theta,  0.2 degrees two-theta.
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[0013] An embodiment of the invention encompasses substantially pure crystalline aripiprazole Form II. For example,
substantially pure Form II may encompass Form II having. more than 10% by weight of other crystalline aripiprazole forms.
[0014] The invention encompass Form II having no more than 20% by weight of crystalline compound 1, crystalline
compound 2, Form C, or Form D, preferably no more than 10%, and most preferably no more than 5% by weight.
[0015] Also described is a crystalline aripiprazole Form VI characterized by X-ray powder diffraction peaks at 17.6,
17.8, 20.6, and 24.9 degrees two-theta,  0.2 degrees two-theta.
[0016] Also described is a aripiprazole crystalline Form VIII characterized by X-ray powder diffraction peaks at 4.4,
8.7, 20.8, 21.6, and 26.0 degrees two-theta,  0.2 degrees two-theta.
[0017] Also described is a crystalline aripiprazole Form X characterized by X-ray powder diffraction peaks at 18.2,
22.4, 22.8, and 24.3 degrees two-theta,  0.2 degrees two-theta.
[0018] Also described is a aripiprazole crystalline Form XI characterized by X-ray powder diffraction peaks at 5.9,
18.0, 20.5, 24.5, and 25.1 degrees two-theta,  0.2 degrees two-theta.
[0019] Also described is a crystalline aripiprazole Form XIV characterized by X-ray powder diffraction peaks at 11.0,
23.6, 24.7, 25.2, and 29.0 degrees two-theta,  0.2 degrees two-theta.
[0020] Also described is a crystalline aripiprazole Form XIX characterized by X-ray powder diffraction peaks at 17.4,
18.7, 20.0, 23.3, and 24.5 degrees two-theta,  0.2 degrees two-theta.
[0021] Also described is a crystalline aripiprazole Form XX characterized by X-ray powder diffraction peaks at
19.6,20.4,20.8,22.1, and 24.5 degrees two-theta,  0.2 degrees two-theta.
[0022] Another embodiment of the invention encompasses a method of preparing Form II by slurrying crystalline
aripiprazole compound 2 in acetone at room temperature to form Form II, and collecting the Form II.
[0023] Yet another embodiment of the invention encompasses methods for preparing crystalline aripiprazole Form II
comprising dissolving aripiprazole in a solvent to form a mixture, heating the mixture from about 40°C to about 132°C,
cooling the mixture to form a aripiprazole precipitate, and collecting the precipitate.
[0024] A second method of preparing crystalline aripiprazole Form II comprises dissolving aripiprazole in a solvent to
form a mixture, heating the mixture to the solvent's boiling point until aripiprazole dissolves, adding a co-solvent to
precipitate aripiprazole, cooling the mixture to about room temperature to about 4°C, and collecting the precipitate. The
second method may further comprise cooling the aripiprazole solvent mixture to the boiling point of the co-solvent before
adding the co-solvent if the boiling point of the co-solvent is lower than the boiling point of the solvent.
[0025] Also described are methods of preparing Form I comprising providing aripiprazole crystalline Form X and drying
Form X to obtain Form I.
[0026] Another embodiment of the invention encompasses methods of preparing crystalline Form II comprising pro-
viding aripiprazole crystalline compound 1 and drying compound 1 to obtain Form II. Also described are methods of
preparing crystalline Compound 2 comprising providing at least one of aripiprazole Form D, Form X, Form XI, Form XII,
or Form XIX, and heating the aripiprazole to obtain Compound 2.
[0027] Also described are methods of preparing crystalline Compound 2 comprising providing Form X, and drying the
aripiprazole to obtain Compound 2.
[0028] Also described are methods of preparing crystalline Form C comprising providing Form II, crystalline Compound
1, or crystalline Compound 2, and heating aripiprazole to obtain Form C.
[0029] Also described are methods of preparing Form D comprising providing aripiprazole crystal ine Compound 1,
crystalline Compound 2, or Form XIV, and drying the aripiprazole to obtain Form D.
[0030] Also described are encompasses methods of preparing a mixture of crystalline Compound 2 and Compound
1 comprising providing aripiprazole Form XI and drying Form XI to obtain a mixture of aripiprazole crystal ine Compound
2 and crystalline Compound 1.
[0031] Also described are methods of preparing a mixture of Form D, Compound 1, and crystalline Compound 2
comprising providing a mixture of Form D and Compound 1, and drying the mixture to obtain a mixture of Form D,
Compound 1, and crystalline Compound 2.
[0032] Other embodiments of the invention encompass pharmaceutical compositions comprising aripiprazole crystal-
line form II of the invention and their use in methods of treating schizophrenia using these pharmaceutical compositions.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates the powder X-ray diffraction pattern for Form I.
Figure 2 illustrates the powder X-ray diffraction pattern for Form II.
Figure 3 illustrates the powder X-ray diffraction pattern for Form VI.
Figure 4 illustrates the powder X-ray diffraction pattern for Form VIII.
Figure 5 illustrates the powder X-ray diffraction pattern for Form X.
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Figure 6 illustrates the powder X-ray diffraction pattern for Form XI.
Figure 7 illustrates the powder X-ray diffraction pattern for Form XII.
Figure 8 illustrates the powder X-ray diffraction pattern for Form XIV.
Figure 9 illustrates the powder X-ray diffraction pattern for Form XIX.
Figure 10 illustrates the powder X-ray diffraction pattern for Form XX.
Figure 11 illustrates the differential scan calorimetry analysis for Form I.
Figure 12 illustrates the differential scan calorimetry analysis for Form II.
Figure 13 illustrates the differential scan calorimetry analysis for Form VI.
Figure 14 illustrates the differential scan calorimetry analysis for Form VIII.
Figure 15 illustrates the differential scan calorimetry analysis for Form X.
Figure 16 illustrates the differential scan calorimetry analysis for Form XI.
Figure 17 illustrates the differential scan calorimetry analysis for Form XIX.
Figure 18 illustrates the differential scan calorimetry analysis for Form XX.
Figure 19 illustrates the powder X-ray diffraction pattern for Form II obtained by slurrying aripiprazole crystalline Compound 2 with acetone.
Figure 20 illustrates the powder X-ray diffraction pattern for Form II having 10% of Form C.
Figure 21 illustrates the powder X-ray diffraction pattern for Form II having 20% of Form C.
Figure 22 illustrates the powder X-ray diffraction pattern for Form II having 30% of Form C.
Figure 23 illustrates the powder X-ray diffraction pattern for Form II having 40% of Form C.
Figure 24 is a staggered figure illustrating the X-ray diffraction patterns for crystal ine Compound 1 and crystallineCompound 2.
DETAILED DESCRIPTION OF THE INVENTION [0034] The time and expense required to prepare aripiprazole on an industrial scale is decreased by using the anhy-
drous aripiprazole crystals of the invention. Specifically, the anhydrous aripiprazole forms of the invention diminish the
adherence of aripiprazole to equipment during industrial preparation, which in turn diminishes the necessity of special
handling techniques to maintain the equipment and anhydrous aripiprazole. Described are aripiprazole crystalline forms
that can be prepared directly by slurrying, rather than by heating a preexisting hydrate crystal form, thereby eliminating
unnecessary process steps during manufacture. Also described are methods of preparing crystalline Compound 2 by
crystallization and shorter drying processes than the drying process for aripiprazole crystalline forms disclosed in WO
03/26659.
[0035] The aripiprazole form II of the invention and the other forms described may be characterized by at least one
of Karl Fisher or TGA, X-Ray power diffraction (XRD), or differential scan calorimetry (DSC).
[0036] As used herein, the tern "anhydrous" refers to aripiprazole crystal forms with less than about 0.5% moisture.
[0037] Also described is a crystalline anhydrous aripiprazole form, herein defined as Form I, having about 0.7%
moisture by weight as measured by Karl Fisher or TGA. Form I may be characterized by X-ray powder diffraction peaks
at 16.8, 19.6, 20.6, 22.3, and 25.1 degrees two-theta, 0.2 degrees two-theta. Form I may be characterized further by
X-ray powder diffraction peaks at 11.3, 12.3, 14.6, 15.2, 17.9, 22.8, and 23.6 degrees two-theta, 0.2 degrees two-
theta. Form I may be characterized also by a melting endotherm at about 139°C to about 140°C (about 90 J/g melting
enthalpy) as measured by differential scanning calorimetry (DSC). Form I may be substantially identified by either the
XRD pattern of Figure 1 or the DSC of Figure 11.
[0038] Subject of the invention is a crystalline aripiprazole form, herein defined as Form II, having about 0.3% moisture
by weight as measured by Karl Fisher or TGA. Form II may be characterized by X-ray powder diffraction peaks at 16.5,
18.7, 21.9, 22.4, and 23.5 degrees two-theta,  0.2 degrees two-theta. Form II may be characterized further by X-raypowder diffraction peaks at 10.2, 11.8, 20.0, 20.7, 26.2, 27.3, and 29.0 degrees two-theta,  0.2 degrees two-theta.
Form II may be characterized also by DSC showing a broad and small endotherm in the range of about 100°C to about130°C and a melting endotherm at about 148°C to about 150°C. The latter indicating a transformation to Form C. FormII may be substantially identified by either the XRD pattern of Figure 2 or the DSC of Figure 12.
[0039] Another embodiment of the invention encompasses substantially pure Form II. As used herein, the term "sub-
stantially pure" refers to Form II having less than 20% of other aripiprazole crystalline forms and more preferably no
more than 10% by weight of other aripiprazole crystalline forms.
[0040] A particular embodiment of the invention encompasses Form II having no more than 20% by weight of crystalline
Compound 1, crystalline Compound 2, Form C, or Form D. In another particular embodiment, Form II has no more than
10% by weight of crystalline Compound 1, crystalline Compound 2, Form C, or Form D, most preferably no more than
5% by weight.
[0041] As used herein, "crystalline compound 1" refers to an aripiprazole crystalline form characterized by X-ray
powder diffraction peaks at 15.5, 19.5, 22.6, 24.9, and 30.6 degrees two-theta, 0.2 degrees two-theta. As used herein,
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"crystalline compound 2" refers to an aripiprazole crystalline form characterized by X-ray powder diffraction peaks at8.8, 14.5, 17.8, 20.5, and 22.2 degrees two-theta, 0.2 degrees two-theta. As used herein, "crystalline compound C"refers to an aripiprazole crystalline form as disclosed in PCT publication WO03/026659 and characterized by X-raypowder diffraction peaks at 12.6, 13.7, 15.4, 18.1, 19.0, 20.6, 23.5 and 26.4 degrees two-theta. As used herein, "crystalline compound D" refers to an aripiprazole crystalline form as disclosed in PCT publication WO03/026659 and characterized
by X-ray powder diffraction peaks at 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4 and 25.0 degrees two-theta.
[0042] Figure 20 illustrates an X-ray diffraction pattern of Form II having 10% Form C by weight. Figure 21 illustrates
an X-ray diffraction pattern of Form II having 20% Form C by weight. Figure 22 illustrates an X-ray diffraction pattern of
Form II having 30% Form C by weight. Figure 23 illustrates an X-ray diffraction pattern Form II having 40% Form C by
weight.
[0043] Also described is a crystalline aripiprazole form, herein defined as Form VI, having about 0.2% moisture by
weight as measured by TGA. Form VI may be characterized by X-ray powder diffraction peaks at 17.6, 17.8, 20.6, and
24.9 degrees two-theta,  0.2 degrees two-theta. Form VI may be characterized further by X-ray powder diffraction
peaks at 23.7, 27.0, and 31.2 degrees two-theta, 0.2 degrees two-theta. The typical DSC of Form VI shows two
endotherm peaks, a first peak at about 105°C, and a second peak at about 110°C. Aripiprazole Form VI may be sub-
stantially identified by either the XRD pattern of Figure 3 or the DSC of Figure 13.
[0044] Also described is a crystalline aripiprazole form, herein defined as Form VIII, having a weight loss of about
28% as measured by TGA, and a Karl Fisher analysis of about 0.5%. Form VIII may be characterized by X-ray powder
diffraction peaks at 4.4, 8.7, 20.8, 21.6, and 26.0 degrees two-theta,  0.2 degrees two-theta. Form VIII may be char-
acterized further by X-ray powder diffraction peaks at 13.0, 17.3, 19.3, 24.5, 27.4, and 29.2 degrees two-theta,  0.2
degrees two-theta. The typical DSC of Form VIII shows one endotherm at about 87°C followed by a broad endotherm.
Form VIII may be substantially identified by either the XRD pattern Figure 4 or the DSC of Figure 14.
[0045] Also described is a crystalline aripiprazole form, herein defined as Form X, having about 16% moisture by
weight. Form X may be characterized by X-ray powder diffraction peaks at 18.2, 22.4, 22.8, and 24.3 degrees two-theta,
 0.2 degrees two-theta. Form X may be characterized further by X-ray powder diffraction peaks at 15.4, 19.8, 23.5,and 29.1 degrees two-theta,  0.2 degrees two-theta. The typical DSC of Form X has an endotherm below about 100°C.
Additionally, two endotherms appear at about 136°C to about 140°C and at about 147°C to about 149°C. The firstendotherm represents the transformation to crystalline Compound 2. The second endotherm represent the transformationto Form C. Form X may be substantially identified by either the XRD pattern of Figure 5 or the DSC of Figure 15.
[0046] Also described is a crystal ine aripiprazole form, herein defined as Form XI, having about 14 % moisture by
weight. Form XI may be characterized by X-ray powder diffraction peaks at 5.9, 18.0, 20.5, 24.5, and 25.1 degrees two-
theta,  0.2 degrees two-theta. Form XI may be characterized further by X-ray powder diffraction peaks at 19.0, 19.6,
22.7, 26.4, and 28.3 degrees two-theta,  0.2 degrees two-theta. The typical DSC of Form XI shows an endotherm
below about 100°C and a melting endotherm at about 140°C due to a transformation to crystalline Compound 2. Form
XI may be substantially identified by either the XRD pattern of Figure 6 or the DSC of Figure 16.
[0047] Also described is a crystalline aripiprazole form, herein defined as Form XIV, having about 9% weight loss as
measured by TGA, and about 2% water content as measured by Karl Fisher. Form XIV may be characterized by X-ray
powder diffraction peaks at 11.0,23.6, 24.7, 25.2, and 29.0 degrees two-theta,  0.2 degrees two-theta. Form XIV may
be characterized further by X-ray powder diffraction peaks at 12.9, 16.5, 18.8, 22.2, 26.3, 27.3, and 28.5 degrees two-
theta,  0.2 degrees two-theta. Form XIV may be substantially identified by the XRD pattern of Figure 8.
[0048] Also described is a crystalline aripiprazole form, herein defined as Form XIX, having about 6% or less of moisture
by weight as measured by Karl Fischer. Form XIX may be characterized by X-ray powder diffraction peaks at 17.4, 18.7,
20.0, 23.3, and 24.5 degrees two-theta,  0.2 degrees two-theta. Form XIX may be characterized further by X-ray
powder diffraction peaks at 10.8, 11.6, 27.1, 27.7, and 28.3 degrees two-theta,  0.2 degrees two-theta. The typical
DSC of Form XIX shows two endotherms, one at about 115°C, and one at about 140°C. Form XIX may be substantially
identified by either the XRD pattern of Figure 9 or the DSC of Figure 17.
[0049] Also described is a crystalline aripiprazole form, herein defined as Form XX, having about 1.4% to about 5%
moisture by weight as measured by Karl Fischer. Form XX may be characterized by X-ray powder diffraction peaks at
19.6, 20.4, 20.8, 22.1, and 24.5 degrees two-theta,  0.2 degrees two-theta. Form XX may be characterized further by
X-ray powder diffraction peaks at 10.2, 11.0, 15.6, 17.4, 18.2, 25.8, 26.6, and 28.5 degrees two-theta,  0.2 degrees
two-theta. The typical DSC of Form XX shows an endotherm at about 100°C, an endotherm at about 120°C, and multiple
transitions between 140°C and 150°C. Form XX may be substantially identified by either the XRD pattern of Figure 10
or the DSC of Figure 18.
[0050] Also described are methods of preparing Form I comprising providing Form X and drying Form X to obtain Form I.
[0051] The invention also encompasses methods of preparing Form II comprising providing crystalline Compound 1
and drying crystalline Compound 1 to obtain Form II.
[0052] The invention also encompasses a method for preparing Form II by slurrying crystalline Compound 2 in a
sufficient amount of acetone for about one to about 24 hours until to obtain Form II and col ecting Form II. Form II obtained
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by slurrying aripiprazole crystalline Compound 2 with acetone is substantially identified by the XRD of Figure 19.
[0053] One of ordinary skill in the art with little or no experimentation can easily determine the sufficient amount of
acetone depending upon the amount of aripiprazole crystalline Compound 2 used during the slurrying. Conditions that
affect the amount of acetone include, but are not limited to, the amount of Form II to be crystallized and the purity of the
starting crystalline Compound 2. Preferably, crystalline compound 2 is slurried for about three hours to about 24 hours,
and more preferably for about five hours. Optionally, the process may further comprise drying the collected Form II at 50°C.
[0054] Form II may have a maximum particle size of about 300 microns or less.
[0055] Methods for preparing aripiprazole crystalline Compound 1, crystalline Compound 2, Form D, Form I, Form II,
Form VI, Form VIII, Form X, Form XI, or Form XII comprise dissolving aripiprazole in a solvent to form a mixture, heating
the mixture to between about 40°C and 132°C, cooling the mixture to form a precipitate, and collecting the precipitate.
Preferably, the mixture is heated to about the lower of the boiling point of the solvent or aripiprazole's melting pointbefore cooling. The mixture is preferably cooled to about 4°C for a sufficient amount of time to form a precipitate. Theresulting precipitate may be collected by any method commonly known in the art. Optionally, the method may furthercomprise drying the precipitate. Example 1 exemplifies the method described above. Table 1 summarized the results of the method.
[0056] Solvents which may be used in the method of the invention include, but are not limited to, C3-6 ketones, C1-4
nitriles, C1-4 alcohols, C1-6 halogenated alkanes, C1-6 amines, C2-8 amides, C2-6 esters, C2-6 ethers, C1-6 sulfoxides, and C4-10 aromatics. Preferably, the solvent is at least one of acetone, acetonitrile, trichloroacetonitrile, methanol, ethanol, n-propanol, isobutanol, propylene glycol, methyl-ethyl-ketone, tetrahydrofuran, DMF, piperidine, pyridine, xylene, tolu- ene, cyclohexanamide, diethylamine, hexylamine, dimethylsulfoxide, ethyl acetate, butyl acetate, dichloromethane, di-
bromomethane, chloroform, 1-bromopropane, 1,4-dioxane, 1,2-diaminoethane, 1,4-dibromobutane, isopropanol, 1-bu-
tanol, 2-dimethylaminoethanol, cyclopropylmethylketone, or isobutlymethylketone.
[0057] Also described are methods for preparing crystalline compound 2 comprising dissolving aripiprazole in a solvent
to form a mixture, heating the mixture to between about 40°C and 132°C, cooling the mixture to form a precipitate, and
collecting the precipitate. Preferably, the mixture of aripiprazole and solvent is heated to about the lower of the boilingpoint of the solvent or aripiprazole's melting point before cooling. The mixture is preferably cooled to about 4°C for asufficient amount of time to form a precipitate. The resulting precipitate may be col ected by any method commonlyknown in the art. Optionally, the method may further comprise drying the precipitate. The method is exemplified inExample 1 and results are summarized in Table 1.
[0058] Solvents which may be used in the invention include, but are not limited to, C3-6 ketones, C1-4 nitriles, C1-4
alcohols, C1-6 halogenated alkanes, C1-6 amines, C2-8 amides, C2-6 esters, C2-6 ethers, C1-6 sulfoxides, and C4-10 aromatics. Preferably, the solvent is at least one of chloroform, tetrahydrofuran, diethylamine, acetone, acetonitrile,
piperidine, butylacetate, or DMF.
[0059] The amount of solvent added should be sufficient dissolve the amount of aripiprazole used. One of ordinary
skill in the art with little or no experimentation can easily determine the sufficient amount of solvent. Conditions that affect
the amount of solvent include, but are not limited to, the amount of aripiprazole to be crystallized and the purity of the
starting aripiprazole.
[0060] A second method for preparing crystalline Compound 1, crystalline Compound 2, Form II, Form XII, or Form
XIX encompasses dissolving aripiprazole in a solvent to form a mixture, heating the mixture to the solvent's boiling point
to dissolve aripiprazole, adding a co-solvent to precipitate aripiprazole, cooling the co-solvent mixture to about room
temperature to about 4°C, and collecting the precipitate. The second method may further comprise cooling the mixture
before adding the co-solvent if the boiling point of the co-solvent is lower than the boiling point of the solvent.
[0061] Preferably, the co-solvent mixture is left at about 4°C for 15 hours before collecting the precipitate. The precipitate
may be collected by any method commonly known in the art. Optionally, the process may further comprise drying the
precipitate, preferably under reduced pressure of less than about 100 mm Hg at 35 °C.
[0062] As described above, one of ordinary skil in the art can easily determine the amount of solvent necessary to
dissolve aripiprazole. Solvents that may be used in the second method of the invention include, but are not limited to,
C2-6 esters, C2-6 ethers, methylethylketones, or C1-6 halogenated alkanes. Preferably, the solvent is at least one of ethyl
acetate, methylethylketone, chloroform, or tetrahydrofuran.
[0063] The co-solvent of the second method should be added in an amount sufficient to precipitate aripiprazole from
solution. Co-solvents that may be used in the second method of the invention include, but are not limited to, at least one
of water, C1-4 alcohols, C2-6 ether, or acetone. Preferably, the co-solvent is at least one of acetone, water, methanol,
ethanol, ether, or 2-propanol.
[0064] Also described is a method of preparing aripiprazole crystalline compound 2 encompasses dissolving aripipra-
zole in a solvent to form a mixture, heating the mixture to the solvent's boiling point to dissolve aripiprazole, adding aco-solvent until aripiprazole precipitates, cooling the mixture to about room temperature to about 4°C, and collecting theprecipitated crystalline compound 2. The second method may further comprise cooling the aripiprazole solvent mixturebefore adding co-solvent if the boiling point of the co-solvent is lower than the boiling point of the solvent.
EP 1 613 598 B1
[0065] Preferably, the mixture is left at about 4°C for 15 hours before collecting the precipitated aripiprazole. The
precipitate may be collected by any method commonly known in the art. Optionally, the process may further comprise
drying the precipitate, preferably under reduced pressure of less than about 100mmHg at 35°C.
[0066] As indicated above, one of ordinary skill in the art can easily determine the amount of solvent necessary to
dissolve aripiprazole. Solvents that may be used in the second method of the invention include, but are not limited to,C2-6 esters, C2-6 ethers, methylethylketones, and C1-6 halogenated alkanes. Preferably, the solvent is tetrahydrofuran.
[0067] Co-solvent is added in an amount sufficient to precipitate aripiprazole from solution. Co-solvents that may be
used in the second method of the invention include, but are not limited to, water, C1-4 alcohols, C2-6 ether, or acetone.
Preferably, the co-solvent is at list one of acetone, ether, or 2-propanol.
[0068] The temperature at which the co-solvent is added depends on the boiling point of the co-solvent. If the boiling
point for the co-solvent is lower than the boiling point of the solvent, then the mixture is cooled to the boiling point of the
co-solvent before adding the co-solvent. If a precipitate appears while lowering the temperature prior to addition of the
co-solvent, then additional solvent should be added in an amount sufficient to dissolve the precipitate. Co-solvent is then
added in an amount sufficient to precipitate aripiprazole. Example 2 exemplifies the second method. Table 2 summarizes
the results of the second method.
[0069] Also described are methods of preparing Form I by drying Form X under a pressure of less than about 100
mm Hg at 35°C until Form I is formed.
[0070] The invention also encompasses methods of preparing Form II by drying crystalline Compound 1 at a pressure
of less than about 100 mm Hg at 35 °C until Form II is formed.
[0071] Also described are methods of preparing crystalline Compound 2 comprising providing at least one Form D,
Form X, Form XI, Form XII, or Form XIX, and heating to form crystalline Compound 2.
[0072] Preferably, the heating step is performed at about 100°C to about 130°C for about 30 to about 60 minutes. The
preparation of crystalline Compound 2 by heating crystalline Form D, Form X, Form XI, Form XII, or Form XIX may
involve an intermediate transformation to Form D. For example, crystalline Compound 1 transforms to Form D after
heating to 100°C for 60 minutes; however, additional heating at 130°C for 30 minutes completes the conversion of
crystalline Compound 1 into crystalline Compound 2.
[0073] Also described are methods of preparing crystalline Compound 2 comprising providing Form XI and drying at
a pressure of less than about 100 mm Hg at 35°C to form crystalline Compound 2.
[0074] Also described are methods of preparing crystalline Compound 2 by adding Form XII to a reactor at a temperature
of about 25°C to about 35°C at a pressure of 100 mm Hg or less, preferably at a pressure of 60 mm Hg or less, and
gradually increasing the temperature to about 100°C or less, while stirring at about 12 rpm, until crystalline Compound
2 is obtained. Preferably, the crystalline Compound 2 contains no more than 5% of crystalline Form C, Form D, or Form XII.
[0075] Also described are methods of preparing Form C comprising providing at least one of Form II, crystalline
Compound 1, or crystalline Compound 2, and heating to form Form C. Preferably, the crystalline form is heated at about
130°C to about 145°C for about 30 to about 180 minutes. Small increases in temperature may have a significant effect
on the time required for the formation of Form C.
[0076] Also described are methods of preparing Form D comprising providing at least one of crystalline Compound
1, crystalline Compound 2, or Form XIV, and drying the crystalline form at a pressure of less than about 100 mm Hg at
35°C to form Form D.
[0077] Also described are methods of preparing a mixture of crystalline Compound 2 and crystalline Compound 1
comprising providing Form XI and drying at a pressure of less than about 100 mm Hg at 35°C to form a mixture crystalline
Compound 2 and crystalline Compound 1.
[0078] Also described are methods of preparing a mixture of Form D, crystalline Compound 1, and crystalline Com-
pound 2 comprising providing a mixture of Form D and Compound 1, and drying the mixture at a pressure of less than
about 100 mm Hg 35°C to form a mixture of Form D, crystalline Compound 1, and crystalline Compound 2.
[0079] Also described are methods of preparing Form XII comprising adding aripiprazole and ethanol (95% by volume)
to form a mixture, heating the mixture at reflux until aripiprazole dissolves while mechanical y stirring the mixture at 12
rpm, filtering the mixture, cooling the mixture to 0°C over 6 hours, stirring the mixture for one hour, filtering the mixture,
and washing with one volume of ethanol (95% by volume). Form XII is obtained.
[0080] Also described are methods of preparing Form XX comprising placing Form XII into a fluidized bed dryer at
about 30°C, leaving the material for about 3.5 hours at 30°C to obtain a crystalline form, and drying the crystalline form
at about 40°C until Form XX is formed.
[0081] Tables 1, 2, and 3 summarize the conversion of crystalline form II of the invention or of the crystalline forms
described.
[0082] The invention also encompasses pharmaceutical compositions comprising aripiprazole crystalline form II of
the invention. As used herein, the term "pharmaceutical compositions" includes tablets, pills, powders, liquids, suspen-
sions, emulsions, granules, capsules, suppositories, or injection preparations. Pharmaceutical compositions containing
the aripiprazole crystalline forms of the invention may be prepared by using diluents or excipients such as fillers, bulking
EP 1 613 598 B1
agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of admin-istration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, forexample tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection prepa-rations.
[0083] Any excipient commonly known and used widely in the art can be used in the pharmaceutical composition.
Carriers used include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium car-
bonate, kaolin, crystalline cellulose, silicic acid, and the like. Binders used include, but are not limited to, water, ethanol,
propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethyl cellulose, shelac, methyl
cellulose, potassium phosphate, polyvinylpyrrolidone, and the like. Disintegrating agents used include, but are not limited
to, dried starch, sodium alginate, agar powder, laminalia powder, sodium hydrogen carbonate, calcium carbonate, fattyacid esters of polyoxyethylene sorbitan, sodium laurylsulfate, monoglyceride of stearic acid, starch, lactose, and thelike. Disintegration inhibitors used include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils,and the like. Absorption accelerators used include, but are not limited to, quaternary ammonium base, sodium lauryl-sulfate, and the like. Wetting agents used include, but are not limited to, glycerin, starch, and the like. Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like. Lubricants used
include, but are not limited to, purified talc, stearates, boric acid powder, polyethylene glycol, and the like. Tablets can
be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets,
tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multilayered tablets.
[0084] When shaping the pharmaceutical composition into pil form, any commonly known excipient used in the art
can be used. For example, carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable
oils, kaolin, talc, and the like. Binders used include, but are not limited to, gum arabic powder, tragacanth gum powder,
gelatin, ethanol, and the like. Disintegrating agents used include, but are not limited to, agar, laminalia, and the like.
[0085] For the purpose of shaping the pharmaceutical composition in the form of suppositories, any commonly known
excipient used in the art can be used. For example, excipients include, but are not limited to, polyethylene glycols,
coconut butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthesized glycerides.
[0086] When preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are
preferably made isotonic to blood. Injection preparations may use carriers commonly known in the art. For example,
carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated
isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of ordinary
skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin
necessary to make the injectable preparation isotonic.
[0087] Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents may be added. If nec-
essary, coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also
be added to the desired preparations.
[0088] The amount of aripiprazole or salt thereof contained in a pharmaceutical composition for treating schizophrenia
should be sufficient to treat, ameliorate, or reduce the symptoms associated with schizophrenia. Preferably, aripiprazole
is present in an amount of about 1% to about 70% by weight, and more preferably from about 1% to about 30% by
weight of the dose.
[0089] The pharmaceutical compositions of the invention may be administered in a variety of methods depending on
the age, sex, and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules andcapsules may be orally administered. Injection preparations may be administered individually or mixed with injectiontransfusions such as glucose solutions and amino acid solutions intravenously. If necessary, the injection preparationsmay be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories may be ad-ministered into the rectum.
[0090] The dosage of a pharmaceutical composition for treating schizophrenia according to the invention will depend
on the method of use, the age, sex, and condition of the patient. Preferably, aripiprazole is administered in an amount
from about 0.1 mg/kg to about 10 mg/kg of body weight/day. More preferably, about 1 mg to 200 mg of aripiprazole may
be contained in a dose.
[0091] The invention also encompasses methods of making a pharmaceutical formulation comprising adding aripipra-
zole crystalline Form II and a pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical formu-
lations" includes tablets, pills, powders, liquids, suspensions, solutions, emulsions, granules, capsules, suppositories,
or injection preparations.
[0092] Having described the invention with reference to certain preferred embodiments, other embodiments will be-
come apparent to one skil ed in the art from consideration of the specification. The invention is further defined by reference
to the following examples describing in detail the analysis of the aripiprazole crystalline forms and methods for preparingthe crystalline forms of the invention. It wil be apparent to those skilled in the art that many modifications, both to materialsand methods, may be practiced without departing from the scope of the invention.
EP 1 613 598 B1
[0093] X-ray powder diffraction data were obtained using a SCINTAG powder X-ray diffractometer model X'TRA
equipped with a solid state detector and copper radiation of 1.5418 A. A round aluminum sample holder with zero
background was used. Al peak positions are within 0.2 degrees two theta. Differential scan calorimetry (DSC) analysiswas performed using a Mettler 821 Stare differential scanning calorimeter. The weight of the samples was about 3 mgto about 6 mg. The samples were scanned at a rate of 10°C/min from 30°C to at least 200°C. The oven was constantlypurged with nitrogen gas at a flow rate of 40 ml/min. Standard 40 Pl aluminum crucibles covered by lids with 3 holeswere used.
[0094] Thermogravimetric analysis (TGA) was performed using a Mettler M3 thermogravimeter. The samples weighed
about 10 mg and were scanned at a rate of 10°C/min from 25°C to 200°C. The oven was constantly purged with nitrogen
gas at a flow rate of 40 ml/min. Standard 150 Pl alumina crucibles covered by lids with 1 hole were used.
[0095] Karl Fisher analysis was performed according to methods well known in the art.
Example 1: Preparation of Aripiprazole Polymorphs [0096] Aripiprazole (4 g) was dissolved in solvent in a round bottomed flask (50-250 ml), and heated to the lower of
the solvent's boiling point or to aripiprazole's melting point and stirred until the aripiprazole ful y dissolved. The immersion
obtained was cooled to room temperature, and then left at 4°C for 15 hours. The precipitated crystalline form was
collected by filtration and studied by X-Ray Diffraction Technique (XRD). The crystalline form was then dried underreduced pressure of less than about 100 mm Hg at 35°C and again studied by XRD. The results are summarized in Table 1.
Table 1. Crystallization of Aripiprazole Crystalline forms Using Method 1 Resulting Crystalline Formd Compound 1 + Compound 2 Compound 1+ Compound 2 Compound 1+ Compound 2 hydrate+ compound 2 Compound 1+ Form D Compound 1+ Form D EP 1 613 598 B1
Table 1. Crystallization of Aripiprazole Crystalline forms Using Method 1 Resulting Crystalline Formd Compound 1 + Form D Compound 1+ Form D +Compound 2 Compound 1 + Compound 2 Cyclopropylmethyl ketone Compound 1 + Compound 2 Compound 1+ Form D Compound 1 + Compound 2 Isobutylmethyl ketone Compound 1+ Compound 2 Compound 1+ Form D EP 1 613 598 B1
Table 1. Crystallization of Aripiprazole Crystalline forms Using Method 1 Resulting Crystalline Formd Compound 1+ Form D 2-Dimethylamino ethanol Compound 1+ Compound 2 Compound 1 + Compound 2 Ethanol 95% in water Ethanol 80% in water a Aripiprazole MP = 132°C.
b Solvent was immediately evaporated after aripiprazole's dissolution.
c Traces of Form B were present.
d "Compound 1" is "crystalline Compound 1" and "Compound 2" is "crystalline Compound 2."* Form XII may be characterized by X-ray powder diffraction peaks at 17.4, 18.2, 19.7, and 24.5 degrees two-theta, 0.2 degrees two-theta as depicted in the XRD of Figure 7.
Example 2: Preparation of Aripiprazole Crystalline forms Using Co-Solvent Systems [0097] Aripiprazole (4 g) was dissolved in a given solvent in a round bottomed flask (50-250 ml), and heated to the
solvent's boiling point until aripiprazole fully dissolved. The temperature was cooled to the boiling point of the co-solvent
to be used if this temperature was lower than the boiling point of the solvent used to dissolve aripiprazole. If a precipitate
formed during cooling, then additional solvent was added until the precipitate dissolved. Co-solvent was then added
until a precipitate formed.
[0098] The immersion obtained was cooled to room temperature, and left at 4°C for 15 hours. The resulting crystalline
form was collected by filtration and studied by XRD. The crystalline form was then dried under reduced pressure of lessthan about 100 mm Hg at 35°C and again studied by XRD. The results are summarized in Table 2.
EP 1 613 598 B1
Table 2. Crystallization of Aripiprazole Crystalline forms by Method 2 a Solvent B did not form a precipitate at the reflux temperature.
b "Compound 1" is "crystalline Compound 1" and "Compound 2" is "crystalline Compound 2."* Form XII may be characterized by X-ray powder diffraction peaks at 17.4, 18.2, 19.7, and 24.5 degrees two-theta,0.2 degrees two-theta as depicted in the XRD pattern of Figure 7.
EP 1 613 598 B1
Example 3: Preparation of Aripiprazole Crystalline forms by Conversion [0099] An aripiprazole crystalline form was heated to about 100°C to about 145°C for about 30 to about 180 minutes
until another crystalline form was formed. The resulting crystalline form was analyzed using X-ray diffraction. The results
are summarized below.
Table 3. Conversion of Aripiprazole Crystalline forms Heating Conditions Initial Crystalline Form Resulting Crystalline Forma Compound 1 + Form D a "Compound 1" is "crystalline Compound 1" and "Compound 2" is "crystallineCompound 2." Example 4: Preparation of Crystalline Form II by Triturating in Acetone [0100] Aripiprazole crystalline Compound 2 (3 g) and acetone (9 mol) were added to a round bottomed flask equipped
with a magnetic stirrer. The slurry was stirred at room temperature for 5 hours until a precipitate formed. The precipitate
was then isolated and identified as Form II. The Form II was dried at 50°C overnight.
Reference Example 5: Preparation of Form XII* by Crystallization in Ethanol [0101] Aripiprazole (30 g) and ethanol (300 ml of 95% by volume) were added to a 1 liter reactor equipped with a
mechanical stirrer, forming a mixture. The mixture was heated at reflux until aripiprazole dissolved, and mechanicallyfiltered. The resulting solution was cooled to 0°C over a period of 6 hours, and thereafter stirred for one hour. The solutionwas then filtered and washed with ethanol (one volume of 95% ethanol by volume) to obtain Form XII.
Reference Example 6: Preparation of Form XX by Drying Form XII* [0102] Form XII (24g) was dried in a fluidized bed dryer at 30°C for 3.5 hours. The material was then dried at 40°C
for 1.5 hours until Form XX was obtained.
Reference Example 7: Preparation of crystalline Compound 2 by Drying Form XII* [0103] Form XII (30g) was dried in a 250 ml round-bottom 3-neck flask equipped with a mechanical stirrer at 30°C
under reduced pressure of 60 mm Hg or less. After stirring for 3 hours at 30°C, the material was stirred at 40°C for two
hours, then at 70°C for 5 hours, and finally at 90°C for three hours. Crystalline Compound 2 was obtained.
Reference Example 8: Preparation of crystalline Compound 2 by Drying Form XII* [0104] Form XII (30 g) was dried in a 0.25 L reactor equipped with a mechanical stirrer at 30°C under reduced pressure
of 20 mm Hg or less. After stirring for 3 hours, the material was stirred at 40°C for two hours, then at 70°C for 5 hours,
EP 1 613 598 B1
and final y at 90°C for three hours. Crystalline compound 2 was obtained.
Reference Example 9: Preparation of crystalline Compound 2 by Drying Form XII* [0105] Aripiprazole Form XII (35 g) was added to a 0.25 liter reactor equipped with a mechanical stirrer at room
temperature under reduced pressure of 60 mm Hg or less. The temperature was increased gradually during 1 hour to
100°C, and maintained at 100°C for 1 hour. Crystalline Compound 2 was obtained.
Reference Example 10: Preparation of crystalline Compound 2 by Drying Form XII* [0106] Form XII (28g) was dried in a 0.25 L reactor equipped with a mechanical stirrer at 30°C under reduced pressure
of 60 mm Hg or less. After stirring for 3 hours, the material was stirred at 40°C for 2.5 hours, then at 70°C for 5 hours,
and finally at 90°C for 8 hours. Crystalline Compound 2 was obtained.
* Form XII may be characterized by X-ray powder diffraction peaks at 17.4, 18.2, 19.7, and 24.5 degrees two-theta,
0.2 degrees two-theta as depicted in the XRD pattern of Figure 7.
1. An aripiprazole crystalline Form II characterized by at least one of an XRD pattern having peaks at 16.5, 18.7,
21.9, 22.4, and 23.5 degrees two-theta, 0. 2 degrees two-theta, or a DSC scan showing a broad and smallendotherm in the range of about 100°C to about 130°C and a melting endotherm at about 148°C to about 150°C,and having less than 20% by weight of aripiprazole crystalline compound 1, crystalline compound 2, crystalline formC, or crystalline form D, wherein: "crystalline compound 1" is defined in claim 13 below; "crystalline compound 2" is defined in claim 6 below; "crystal ine form C" is characterized by X-ray powder diffraction peaks at 12.6, 13.7,
15.4, 18.1, 19.0, 20.6, 23.5 and 26.4 degrees two-theta and "crystalline form D" is characterized by X-ray powder
diffraction peaks at 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4 and 25.0 degrees two-theta.
2. The aripiprazole crystalline form of claim 1 further characterized by XRD peaks at 10.2,11.8,20.0,20.7, 26.2, 27.3,
and 29.0 degrees two-theta, 0.2 degrees two-theta.
3. The aripiprazole crystalline form of claim 1 or claim 2, having less than 10% by weight of aripiprazole crystalline
compound 1, crystalline compound 2, crystalline form C, or crystalline form D.
4. The aripiprazole crystalline form of claim 3, having less than 5% by weight of aripiprazole crystalline compound 1,
crystalline compound 2, crystalline form C, or crystalline form D.
5. The aripirazole crystalline form of claim 3 or 4, having no more than 10% by weight of other crystalline aripiprazole
6. A method of preparing Form II as defined in any one of claims 1-5, by slurrying crystalline Compound 2 characterized
by an XRD pattern having peaks at 8.8, 14.5, 17.8, 20.5 and 22.2 degrees two-theta 0. 2 degrees two-theta, in
acetone until Form II is formed.
7. The method of claim 6, wherein crystalline Compound 2 is slurried in acetone for about one to about 24 hours,
preferably about three to about 24 hours.
8. The method of claim 6, wherein crystalline Compound 2 is slurried in acetone for about five hours.
9. The method of any one of claims 6 to 8, wherein Form II has an average size of about 300 microns or less.
10. The method of any one of claims 6 to 9, further comprising drying the Form II at about 50°C.
11. A method of preparing crystalline Form II comprising:
dissolving aripiprazole in chloroform, tetrahydrofuran, diethylamine, acetone, acetonitrile, piperidine, butylace-tate or DMF to form a mixture, heating the mixture to the lower of the solvent's boiling point or to aripiprazole'smelting point of between about 40°C and about 132°C; cooling the mixture until aripirazole crystalline Form II EP 1 613 598 B1
precipitates; and collecting the aripiprazole.
12. A method of preparing aripiprazole crystalline form II as defined in any one of claims 1-5, comprising: dissolving
aripiprazole in tetrahydrofuran to form a mixture, heating the mixture to the solvent's boiling point until aripiprazole dissolves, cooling the mixture, adding a co-solvent selected from ether, acetone, 2-propanol or water to the mixtureof aripiprazole and solvent until aripiprazole crystalline Form II precipitates, and collecting said aripiprazole Form II.
13. A method of preparing aripiprazole crystalline form II as defined in any one of claims 1-5, comprising: providing
aripiprazole crystal ine compound 1 characterized by an XRD pattern having peaks at 15.5, 19.5, 22.6, 24.9 and
30.6 degrees two-theta 0. 2 degrees two-theta; and drying the aripiprazole to obtain aripiprazole crystalline form II.
14. The method of claim 13, wherein the drying step is performed at a temperature of about 35°C.
15. The method of claim 13 or claim 14, wherein the drying step is performed at a pressure of less than about 100 mm Hg.
16. A pharmaceutical composition comprising aripiprazole crystalline Form II as defined in any one of claims 1-5, and
at least one pharmaceutically acceptable excipient.
17. The pharmaceutical composition of claim 16, wherein the aripiprazole is present in an amount of about 1% to about
70% by weight.
18. The pharmaceutical composition of claim 17, wherein the aripiprazole is present in an amount of about 1% to about
30% by weight.
19. A method of making a pharmaceutical formulation comprising mixing aripiprazole crystalline Form II as defined in
any one of claims 1-5, and at least one pharmaceutically acceptable excipient.
20. Use of aripiprazole crystal ine Form II as defined in any one of claims 1-5, for preparing a pharmaceutical composition
for treating, ameliorating, or reducing the symptoms associated with schizophrenia.
21. The use of claim 20, wherein the pharmaceutical composition is administered in an amount of about 0.1 mg/kg to
about 10 mg/kg of body weight of the patient per day.
22. The use of claim 20 or claim 21, wherein the pharmaceutical composition is administered in an amount of about 1
mg to about 200 mg per dose.
1. Kristalline Form II von Aripiprazol, gekennzeichnet durch mindestens eines von einem Röntgen-Diffraktogrammmit
Peaks bei 16,5; 18,7; 21,9; 22,4 und 23,5 Grad 2 Theta +/- 0,2 Grad 2 Theta, oder einem DSC-Scan, der ein breitesoder ein schmales Endotherm in dem Bereich zwischen ungefähr 100°C und ungefähr 130°C und ein Schmelzen-dotherm zwischen ungefähr 148°C und ungefähr 150°C aufweist, und umfassend weniger als 20 Gew.-% derkristallinen Aripiprazol-Verbindung 1, der kristallinen Verbindung 2, der kristallinen Form C oder der kristallinen Form D, wobei die kristalline Verbindung 1 in dem unten stehenden Patentanspruch 13, die kristalline Verbindung
2 in dem unten stehenden Patentanspruch 6 definiert ist und die kristalline Form C durch die Röntgen-Pulverdif-
fraktogramm-Peaks bei 12,6; 13,7; 15,4; 18,1; 19,0; 20,6; 23,5 und 26,4 Grad 2 Theta und die kristalline Form D
durch die Röntgen-Pulverdiffraktogramm-Peaks bei 8,7; 11,6; 16,3; 17,7; 18,6; 20,3; 23,4 und 25,0 Grad 2 Theta
gekennzeichnet ist.
2. Die kristalline Form von Aripiprazol nach Anspruch 1, ferner gekennzeichnet durch die Röntgen-Diffraktogramm-
Peaks bei 10,2; 11,8; 20,0; 20,7; 26,2; 27,3 und 29 Grad 2 Theta+/- 0,2 Grad 2 Theta.
3. Die kristal ine Form von Aripiprazol nach Anspruch 1 oder 2, umfassend weniger als 10 Gew.-% der kristallinen
Aripiprazol - Verbindung 1, der kristallinen Verbindung 2, der kristallinen Form C oder der kristallinen Form D.
4. Die kristalline Form von Aripiprazol nach Anspruch 3 umfassend weniger als 5 Gew.-% der kristallinen Aripiprazol
- Verbindung 1, der kristallinen Verbindung 2, der kristallinen Form C oder der kristallinen Form D.
EP 1 613 598 B1
5. Die kristalline Form von Aripiprazol nach Anspruch 3 oder 4, umfassend nicht mehr als 10 Gew.-% anderer kristalliner
Formen von Aripiprazol.
6. Verfahren zur Herstellung der Form II wie in einem der Patentansprüche 1 bis 5 beschrieben, gekennzeichnet
dadurch, dass die die kristalline Verbindung 2, die ein Röntgen-Diffraktogramm mit Peaks bei 8,8; 14,5; 17,8; 20,5
und 22,2 Grad 2 Theta +/- 0,2 Grad 2 Theta aufweist, in Aceton geschlämmt wird, bis die Form 11 gebildet worden ist.
7. Das Verfahren nach Patentanspruch 6, wobei die kristalline Verbindung 2 in Aceton während ungefähr einer bis
ungefähr 24 Stunden, bevorzugt zwischen ungefähr drei Stunden bis ungefähr 24 Stunden geschlämmt wird.
8. Das Verfahren nach Patentanspruch 6, wobei die kristalline Verbindung 2 in Aceton während ungefähr fünf Stunden
geschlämmt wird.
9. Das Verfahren nach einem der Patentansprüche 6 bis 8, wobei die Form II eine mittlere Größe von ungefähr 300
Pm oder weniger aufweist.
10. Das Verfahren nach einem der Patentansprüche 6 bis 9, ferner umfassend Trocknen der Form II bei einer Temperatur
von ungefähr 50°C.
11. Verfahren zur Herstellung der kristallinen Form II, umfassend:
Auflösen von Aripiprazol in Chloroform, Tetrahydrofuran, Diethylamin, Aceton, Acetonitril, Piperidin, Butylacetatoder DMF, um eine Mischung zu bilden, Erhitzen der Mischung auf die niedrigere der Temperaturen des Sie-depunktes des Lösemittels oder des Schmelzpunktes von Aripiprazol zwischen ungefähr 40°C und ungefähr 132°C; Abkühlen der Mischung bis die kristalline Form II von Aripiprazol ausfällt; und Aufnehmen von Aripiprazol .
12. Verfahren zum Herstellen der kristallinen Form II von Aripiprazol wie in einem der Ansprüche 1 bis 5 beschrieben,
umfassend: Auflösen von Aripiprazol in Tetrahydrofuran um eine Mischung zu bilden, Erhitzen der Mischung aufden Siedepunkt des Lösemittels bis sich Aripiprazol auflöst, Abkühlen der Mischung, Hinzufügen eines Co-Solvens, das ausgewählt wird aus Ether, Aceton, 2-Propanol oder Wasser, zu der Mischung von Aripiprazol und dem Solvensbis die kristalline Form II von Aripiprazol ausfällt und Aufnehmen der genannten Form II von Aripiprazol.
13. Verfahren zum Herstellen der kristallinen Form II von Aripiprazol wie in einem der Ansprüche 1 bis 5 beschrieben,
umfassend: Bereitstellen der kristallinen Verbindung 1 von Aripiprazol, gekennzeichnet durch ein Röntgen-Dif-
fraktogramm mit Peaks bei 15,5; 19,5; 22,6; 24,9 und 30,6 Grad 2 Theta +/- 0,2 Grad 2 Theta; und Trocknen vonAripiprazol, um die kristalline Form II von Aripiprazol zu erhalten.
14. Das Verfahren nach Patentanspruch 13, wobei der Schritt zum Trocknen bei einer Temperatur von ungefähr 35°C
ausgeführt wird.
15. Das Verfahren nach Patentanspruch 13 oder Patentanspruch 14 , wobei der Schritt zum Trocknen bei einem Druck
von 100 mm Hg oder weniger ausgeführt wird.
16. Eine pharmazeutische Zusammensetzung umfassend die kristalline Form II von Aripiprazol , wie in einem der
Patentansprüche 1 bis 5 beschrieben, und mindestens einen pharmazeutisch verträglichen Hilfsstoff.
17. Die pharmazeutische Zusammensetzung nach Patentanspruch 16, wobei das Aripiprazol in einer Menge von un-
gefähr 1 Gew.-% bis ungefähr 70 Gew.-% vorliegt.
18. Die pharmazeutische Zusammensetzung nach Patentanspruch 17, wobei das Aripiprazol in einer Menge von un-
gefähr 1 Gew.-% bis ungefähr 30 Gew.-% vorliegt.
19. Ein Verfahren zur Herstellung einer pharmazeutischen Formulierung umfassend das Mischen der kristallinen Form
II von Aripiprazol, wie in einem der Patentansprüche 1 bis 5 beschrieben, mit mindestens einem pharmazeutisch 20. Verwendung der kristallinen Form II von Aripiprazol, wie in einem der Patentansprüche 1 bis 5 beschrieben, zur
Herstellung einer pharmazeutischen Zusammensetzung für die Behandlung, Verbesserung oder Reduzierung der EP 1 613 598 B1
Symptome, die mit der Schizophrenie verbunden sind .
21. Die Verwendung nach Patentanspruch 20, wobei die pharmazeutische Zusammensetzung in einer Menge zwischen
ungefähr 0,1 mg/kg bis ungefähr 10 mg/kg Körpergewicht des Patienten pro Tag verabreicht wird .
22. Die Verwendung nach Patentanspruch 20 oder Patentanspruch 21, wobei die pharmazeutische Zusammensetzung
in einer Menge zwischen ungefähr 1 mg bis ungefähr 200 mg pro Dosis verabreicht wird.
1. Une forme II cristalline d'aripiprazole caractérisée par au moins un diffractogramme de rayons X ayant des pics
situés à 16,5; 18,7; 21,9; 22,4 et 23,5 degrés deux thêta +/- 0,2 degrés deux thêta ou un balayage DSC montrantun endotherme large et un endotherme étroit se trouvant dans la zone entre à peu près 100°C et à peu près 130°C et un endotherme de fusion entre à peu près 148°C et à peu près 150°C, et contenant moins que 20% en poids du
composé 1 d'aripiprazole cristallin, du composé 2 cristallin, de la forme C cristalline ou de la forme D cristalline, où :
le composé 1 cristallin est défini dans la revendication 13 ci-dessous, le composé 2 cristallin est défini dans la
revendication 6 ci-dessous, la forme C cristallin est caractérisée par des pics de diffraction poudreuse de rayons
X à 12,6; 13,7; 15,4; 18,1; 19,0; 20,6; 23,5 et 26,4 degrés deux thêta et la forme D cristallin est caractérisée par
des pics de diffraction poudreuse de rayons X à 8,7; 11,6; 16,3; 17,7; 18,6; 20,3; 23,4 et 25,0 degrés deux thêta.
2. La forme cristalline d'aripiprazole selon la revendication 1, caractérisée en outre par des pics sur le diffractogramme
de rayons X situés à 10,2; 11,8; 20,0; 20,7; 26,2; 27,3 et 29 dégrées deux thêta, +/- 0,2 dégrées deux theta.
3. La forme cristalline d'aripiprazole selon la revendication 1 ou la revendication 2, comportant moins de 10% en poids
du composé 1 cristallin d'aripiprazole, du composé 2 cristallin, de la forme C cristalline, ou de la forme D cristalline.
4. La forme cristal ine d'aripiprazole selon la revendication 3, comportant moins de 5% en poids du composé 1 cristallin
d'aripiprazole, du composé 2 cristallin, et du composé 2 cristallin, de la forme C cristalline, ou de la forme D cristalline.
5. La forme cristalline d'aripiprazole selon la revendication 3 ou la revendication 4, ne comportant pas plus de 10%
en poids d'autres formes cristallines d'aripiprazole.
6. Procédé pour préparer de la forme II cristalline d'aripiprazole comme définie dans une quelconque des revendications
1 à 5, par la mise en suspension du composé 2 cristallin, caractérisé par un diffractogramme de rayons X ayant
des pics situés à 8,8; 14,5; 17,8; 20,5 et 22,2 dégrées deux thêta +/- 0,2 dégrées deux theta, dans de l'acétone
jusqu'à la formation de la forme II.
7. Le procédé selon la revendication 6, dans lequel le composé 2 cristallin est mis en suspension dans de l'acétone
pendant une durée comprise entre 1 heure et 24 heures; lequel composé 2 étant mis en suspension, de préférencependant une durée comprise entre environ 3 heures et environ 24 heures.
8. Le procédé selon la revendication 6, dans lequel le composé 2 cristallin est mis en suspension dans de l'acétone
pendant environ 5 heures.
9. Le procédé selon l'une quelconque des revendications 6 à 8, où la forme II présente une taille moyenne d'environ
300 Pm ou moins.
10. Le procédé selon l'une quelconque des revendications 6 à 9, comportant en outre le séchage de la forme II à environ
11. Procédé pour préparer une forme II cristalline comprenant :
la dissolution d'aripiprazole dans du chloroforme, dans du tetrahydrofurane, dans de la diéthylamine, dans de l'acétone, dans de l'acétonitrile, dans de la pipéridine, dans du butylacétate ou du DMF pour former un mélange,le réchauffement du mélange à la température la plus basse des points d'ébullition des solvants ou à la tem-pérature du point de fusion d'aripiprazole, située entre 40°C et environ 132°C;le refroidissement du mélange jusqu'à ce que la forme II cristalline d'aripripazole se précipite; et la collecte EP 1 613 598 B1
12. Procédé pour préparer la forme II cristalline d'aripiprazole, comme définie dans une quelconque des revendications
1 à 5, comprenant : la dissolution d'aripiprazole dans du tetrahydrofurane pour former un mélange,le réchauffement du mélange jusqu'au point d'ébullition du solvant et jusqu'à l'aripiprazole se dissolve,le refroidissement du mélange en ajoutant un co-solvant sélectionné parmi de l'éther, de l'acétone, 2-propanoleou de l'eau au mélange d'aripiprazole et de solvant jusqu'à ce que la forme II cristalline d'aripiprazole se précipite, et la collecte de ladite forme II d'aripiprazole.
13. Procédé pour préparer la forme II cristalline d'aripiprazole, comme définie dans une quelconque des revendications
1 à 5, comprenant: la mise à disposition du composé 1 cristallin d'aripiprazole, caractérisé par un diffractogramme de rayons X
ayant des pics à 15,5; 19,5; 22,6; 24,9 et 30,6 dégrées deux thêta, +/- 0,2 dégrées deux thêta; et séchage de
l'aripiprazole pour obtenir la forme II cristalline d'aripiprazole.
14. Le procédé selon la revendication 13, dans lequel l'étape de séchage est effectuée à une température d'environ 35°C.
15. Le procédé selon la revendication 13 ou la revendication 14, dans lequel l'étape de séchage est effectuée à une
pression inférieure à environ 100 mm Hg.
16. Composition pharmaceutique comprenant la forme II cristalline d'aripiprazole comme définie dans une quelconque
des revendications 1 à 5 et comprenant au moins un excipient pharmaceutiquement acceptable.
17. La composition pharmaceutique selon la revendication 16, dans laquelle l'aripiprazole est présent dans une quantité
d'environ 1% à environ 70% en poids.
18. La composition pharmaceutique selon la revendication 17, dans laquelle l'aripiprazole est présent dans une quantité
d'environ 1% à environ 30% en poids.
19. Procédé pour préparer une formulation pharmaceutique comprenant le mélange de la forme II cristalline d'aripipra-
zole, comme définie dans une quelconque des revendications 1 à 5 et comprenant au moins un excipient pharma- 20. L'utilisation de la forme II cristalline d'aripiprazole comme définie dans une quelconque des revendications 1 à 5,
dans la fabrication d'une composition pharmaceutique pour traiter, améliorer, ou réduire les symptômes associésà la schizophrénie.
21. L'utilisation selon la revendication 20, dans laquelle la composition pharmaceutique est administrée selon une
quantité d'environ 0,1 mg/kg à environ 10 mg/kg de poids du corps du patient par jour.
22. L'utilisation selon la revendication 20 ou la revendication 21, dans laquelle la composition pharmaceutique est
administrée selon une quantité d'environ 1 mg à environ 200 mg par dose.
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REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the Europeanpatent document. Even though great care has been taken in compiling the references, errors or omissions cannot beexcluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description
US 53029703 P [0001]
JP 2191256 A [0005]
US 53383103 P [0001]
WO 0326659 A [0005] [0007] [0034]
US 61840404 P [0001]
WO 03026659 A [0041]
US 61896004 P [0001]
Non-patent literature cited in the description
The Proceedings of the 4th Japanese-Korean Sym-
posium on Separation Technology, 06 October 1996
[0006]

Source: https://www.lens.org/images/patent/EP/1613598/B1/EP_1613598_B1.pdf