Indian Patents. 262892:PROCESS FOR PREPARATION OF ARIPIPRAZOLE FORM X

Title of Invention	PROCESS FOR PREPARATION OF ARIPIPRAZOLE FORM X
Abstract	The present invention relates to novel polymorphic forms of aripiprazole and processes for producing them. It further relates to pharmaceutical compositions comprising the novel forms and to the use of the novel forms in the treatment of schizophrenia.

Full Text	Organic Compounds FIELD OF THE INVENTION The present invention relates to novel polymorphic forms of aripiprazoie and processes for their production, it further relates to pharmaceutical compositions comprising the novel forms and to the use of the novel forms in the treatment of schizophrenia. BACKGROUND OF THE INVENTION Aripiprazoie, 7-[4-{4-.(2J3-dichlorophenyl)-1-piperazinyl]butoxy3-3)4-dihydrO'2(1H)-quinolinone, is an antipsychotic drug useful m the treatment of schizophrenia (Merck Index, monograph number 00791, CAS registry number 129722-12-9). Synthesis and isolation of aripiprazoie are described in EP 367141 B1 and US 5006528. Additional crystalline anhydrous or hydrous forms are disclosed in WO 03/026659 {conventional hydrate, hydrate A. conventional anhydrate, anhydrate B, anhydrate C, anhydrate D, anhydrate E, anhydrate F5 anhydrate G). Nevertheless, there remains a need for alternative polymorphic forms of aripiprazoie which have properties suitable for pharmaceutical processing on a commercial scale. The present invention satisfies these needs by providing novel polymorphic forms of aripiprazoie and processes for their production. SUMMARY OF THE INVENTION The present invention relates to form X of aripiprazoie characterized by an X-ray powder diffraction pattern withi peaks at 10.0,11.6,15.7,16.3,18.5,20.4,21.8, 22.2,and 23.3 degrees 29. The present invention further relates to aripiprazoie ethanoi hemisoivate characterized by an X-ray powder diffraction pattern with peaks at 17.4, 18.1, 19.6, 23.3 and 27.9 degrees 29. The present invention also relates to aripiprazoie methanol solvate characterized by an X-ray powder diffraction pattern with peaks at 11.5,17.3, 18.5, 19.8, 23.1, 24.4 and 26.9 degrees 26, The present invention provides a process for preparing form X of aripiprazole, comprising the steps of: a) dissolving aripiprazole in a suitable solvent by heating b) slowly cooling the solution to room temperature or below to effect crystallization . c) optionally isolating crystalline form X of aripiprazole. * The present invention also provides a process for preparing form X of aripiprazole characterized in that a suspension of aripiprazole in a suitable solvent is seeded with crystals of form X and the suspension is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazole into form X. in another aspect the invention provides a process for preparing aripiprazole ethanol hemisolvate, comprising the steps of; -a) dissolving aripiprazole In ethanol by heating b) slowly cooling the solution to room temperature or below to effect crystallization c) isolating the crystalline ethanol hemisolvate d) drying the ethanol hemisolvate at a temperature below about 60°C. In a further aspect the invention provides a process for preparing aripiprazole ethanol hemisolvate, comprising the steps of: a) dissolving aripiprazole in a solvent in which aripiprazole is soluble at room temperature b) diluting the solution with ethanol c) isolating the crystalline ethanol hemisolvate d) drying the ethanol hemisolvate at a temperature below about 60°C. In a further aspect the invention provides a process for preparing aripiprazole ethanol hemisolvate characterized in that a suspension of aripiprazole in ethanol is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazole into aripiprazole ethanol hemisolvate. In another aspect the invention provides a process for preparing aripiprazole methanol solvate, comprising the steps of: a) dissolving aripiprazole in methanol by heating b) slowly cooling the solution to room temperature or beiow to effect crystallization c) isolating the crystalline methanol solvate d) drying the methanol solvate at a temperature below about 60°C. In a further aspect the invention provides a process for preparing aripiprazole methanol solvate, comprising the steps of: a) dissolving aripiprazole in a solvent in which aripiprazole is soluble at room temperature b) diluting the solution with methanol c) isolating the crystalline methanol solvate d) drying the methanol solvate at a temperature beiow about 60DC. in a further aspect the invention provides a process for preparing aripiprazole methanol solvate characterized in that a suspension of aripiprazole in methanol is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazole into aripiprazole methanol solvate. The present invention also relates to form X=of aripiprazole or aripiprazole ethanoi hemisolvate for use as a medicament. In another aspect the present invention relates to the use of form X of aripiprazole or aripiprazole ethanoi hemisolvate for the preparation of a medicament for the treatment of schizophrenia. In a further aspect the present invention relates to a pharmaceutical composition comprising an effective amount of form X of aripiprazole or aripiprazole ethanoi hemisolvate and a pharmaceutical acceptable carrier^-. Other objects, features, advantages and aspects of the present invention will become apparent to those of skill from the following description, it should be understood, however, that the description and the following specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent ip.,those skilled in the art from reading the description and from reading the other parts of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: infrared spectrum of form X of aripiprazoie. Figure 2: Infrared spectrum of aripiprazoie ethanoi hemisoivate. Figure 3: infrared spectrum of aripiprazoie methanol solvate. Figure 4: X-ray powder diffraction pattern of form X of aripiprazoie. Figure 5: X-ray powder diffraction pattern of aripiprazoie ethanoi hemisoivate. Figure 6: X-ray powder diffraction pattern of aripiprazoie methanol solvate. Figure 7: Thermogravimetric and differential scanning caiorimetric curve of form X of aripiprazoie. Figure 8: Thermogravimetric and differentia! scanning caiorimetric curve of aripiprazoie ethanoi hemisoivate. Figure 9: Thermogravimetric and differential scanning caiorimetric curve of aripiprazoie methanol solvate. Figure 10: Moisture sorption isotherm of form X of aripiprazoie. DETAILED DESCRIPTION OF THE INVENTION As used herein the term "crude" refers to crystals of aripiprazoie that have not been washed and/or recrystaliized to remove impurities that may be present. As used herein the term "crystalline" refers to crystals of aripiprazoie that have been washed and recrystaliized to remove impurities. As used herein the term "amorphous1' relates to solid material which lacks a regular crystalline structure. The term "room temperature" as used herein indicates that the applied temperature is not critical and that no exact temperature value has to be kept. Usually, "room temperature" is understood to mean temperatures of about 15°C to about 25°C (see e.g. EU Pharmacopeia 5.0, page 6). The inventors of the present invention have identified novel polymorphs of aripiprazoie. The novel polymorphs have distinct physical properties and may be characterized e.g. by a typical X-ray powder diffraction pattern, infrared spectrum or a characteristic thermogravimetric (TGA) and differential scanning caiorimetric (DSC) curve. Each of these characteristics on its own is sufficient to unambiguously define and identify the new polymorphs but they also may be combined with each other. The present invention relates to a novel form X of aripiprazoie characterized by an X-ray powder diffraction pattern with peaks at 10.0, 11.6, 15.7,16.3, 18.5, 20.4, 21.8, 22.2 and 23.3 degrees 20 (2-theta). A characteristic X-ray powder diffraction pattern of form X of aripiprazoie is shown in Figure 4 and some characteristic peaks are listed in Table 1. Accordingly, in a preferred embodiment, the present invention relates to a novel form X of aripiprazoie characterized by an X-ray powder diffraction pattern substantially in accordance with Table 1 and Figure 4. Form X of aripiprazoie may be also characterized by a typical infrared spectrum as shown in Figure 1. Accordingly, in a further preferred embodiment, the present invention relates to form X of aripiprazoie characterized by an infrared spectrum substantially in accordance with Figure 1. Characteristic bands are present at 2939, 2803, 1677, 1374, 1191,1168, 1045, 868, 822 and 736 cm"1. In addition, form X of aripiprazoie shows a typical DSC curve at a heating rate of of 5°K/min and practically no mass loss in the TGA analysis. Typical thermograms of form X of aripiprazoie are shown in Figure 7. It can be seen that the DSC curve of form X shows two specific endothermic peaks with onset temperatures of about 119°C and 149°C. Accordingly, in a further preferred embodiment, the present invention relates to form X of aripiprazoie characterized by two endothermic peaks with onset temperatures of about 119°C and 14G°C at a heating rate of 5°K/min in differential scanning calorimetry. Form X of aripiprazoie is a novel anhydrous form, hereinafter also referred to as "form X", which is particularly stable and hence is suitable for bulk preparation and handling. Form X of aripiprazoie has been found to be of low hygroscopicity and does not substantially convert into a hydrated form of aripiprazoie. This can be seen from the moisture sorption isotherm of form X which is shown in Figure 10. The present invention further relates \Q anpiprazole ethanol hemisolvate characterized by an X-ray powder diffraction pattern with peaks at 17.4, 18.1, 19.6, 23.3 and 27.9 degrees 29. A characteristic X-ray powder diffraction pattern of aripiprazole ethanol hemisoivate is shown in Figure 5 and some characteristic peaks are listed in Table 2. Accordingly, in a preferred embodiment, the present invention relates to aripiprazole ethanol hemisoivate characterized by an X-ray powder diffraction pattern substantially in accordance with Table 2 and Figure 5. Aripiprazole ethanol hemisoivate may be also characterized by a typical infrared spectrum as shown in Figure 2. Accordingly, in a further preferred embodiment, the present invention relates to aripiprazole ethanol hemisoivate characterized by an infrared spectrum substantially in accordance with Figure 2. Characteristic bands are present at 2949, 2816, 1670, 1378: 1192, 1171, 1047, 854, 830 and 746 cm"1. In addition, aripiprazole ethanol hemisoivate shows a typical step in the TGA curve and a characteristic DSC curve at a heating rate of of 5°K/min. Typical thermograms of aripiprazole ethanol hemisoivate are shown in Figure 8. It can be seen that the DSC curve of aripiprazole ethanol hemisoivate (sample pan with pinhole) shows an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic peaks with onset temperatures of about 139°C and 148DC. Accordingly, in a further preferred embodiment, the present invention relates to aripiprazole ethanol hemisoivate characterized by an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic peaks with onset temperatures of about 139°C and 148°C at a heating rate of 5°K/min in differential scanning calorimetry. In another aspect, the present invention relates to aripiprazole methanol solvate characterized by an X-ray powder diffraction pattern with peaks at 11.5,.17.3, 18.5, 19.3, 23.1, 24.4 and 26.9 degrees 26. A characteristic X-ray powder diffraction pattern of aripiprazole methanol solvate is shown in Figure 6 and some characteristic peaks are listed in Table 3. Accordingly, in a preferred embodiment, the present invention relates to aripiprazole methanol solvate characterized by an X-ray powder diffraction pattern substantially in accordance with Table 3 and Figure 6. Anpiprazole methanol solvate may be also characterized by a typical infrared spectrum as shown in Figure 3. Accordingly, in a further preferred embodiment, the present invention rslaies to anpiprazole methanol solvate characterized by an infrared spectrum substantially in accordance with Figure 3. Characteristic bands are present at 2942. 2814, 1671, 1377, 1199f 1174, 1 -337, 857; 824 and 746 cm'1. hi additiorL arpiorazofe methanol solvate shows a typical step in the TGA curve and a diasacfef^c DSC carve at a heating rate of of 5°K/min. Typical thermograms of aripiprazole osetenot soiveie are shown in Figure 9. It can be seen that the DSC curve of aripiprazole rae&tanot sot^a^ (sample pan with pinhole) shows an endothermic peak with an onset temperature of about 113°C followed by an exothermic event and two endothermic peaks «tt> oossi temperatures of about 139°C and 148°C. Accordingly, in a further preferred embodiment, the present invention relates to aripiprazole methanol solvate characterized by an endothermic peak with an onset temperature of about 113°C toiowed by an exothermic event and two endothermic peaks with onset temperatures of about 139~C and 148°C at a heating rate of 5DK/min in differential scanning calorimetry. As said before, each of the above mentioned data alone are sufficient to characterize each of the new polymorphs of aripiprazole. Therefore, further embodiments of the present invention relate to each polymorph being characterized by its typical X-ray powder diffraction pattern or its typical \n1rared spectrum or its typical thermogravimetric/differential scanning caiorimetnc curse. In one embodiment the preseaUnventi^^^ X of anpiprazoie, comprising the steps of: a) dissolving aripiprazole in a suitable solvent by heating b) slowly cooling the solution to room temperature or below to effect crystallization c) optionaify isolating crystalline form X of aripiprazole. For preparing form X of aripiprazole according to the above first process, any other form of aripiprazole may be used, e.g. the forms disclosed in WO 03/026659 (conventional hydrate, hydrate A, conventional anhydride, anhydrate B, anhydrate C, anhydrate D, anhydrate E, anhydrate F, anhydrate G). In addition, also non-crystalline forms of aripiprazole such as the amorphous form and forms of low crystalline order or crude aripiprazole may be used. in parEJcuiar, the other novel forms of aripiprazoie of the present invention described above. i.e. ariprprazGie ethanol bemtsolvate and aripiprazole methanol solvate or an aripiprazoie hydrate may oe used to prepare form X of aripiprazole. Of course, also mixtures of two or more zMef&wt forms of aripiprazoie may be used. Therefore, in a preferred embodiment, the form used in ihe above first process In step a) is aripiprazole ethanol hemisolvate and/or ^KrazQie melhanof solvate and/or aripiprazole hydrate. Acrartfeg to ihe above first process a suitable solvent is a solvent in which the substance is not nighty settle. Unsuitable solvents are pure water, ethanol or methanol because the Gonrespoficing solvate is formed, in a preferred embodiment, the solvent used in step a) of the above first process is acetone, tetrahydrofuran or 2-propanol. The even more preferred solvent is 2-propanoi. The heating temperature applied in order to dissolve aripiprazole depends on the boiling point of the solvent used but usually will be in the range of 50°C to iOQ°C. A preferred temperature is the boiling temperature of the solvent. If 2-propanol is used, the aripiprazoie Is dissolved preferably in a concentration of about 20 g to about 40 g per liter 2-propanol by heating, most preferably in a concentration of about 30 g to about 35 g aripiprazole per liter 2-propanoL The crystallization step b) of the above first process may be facilitated by adding seed crystals In another embodiment, the present invention provides a second process for preparing form X of aripiprazoie characterized in that a suspension of aripiprazoie in a suitable solvent is seeded with crystals of form X and the suspension is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazoie into form X. Just as for the first process described above also for this second process for preparing form X of »pprazoie any other form of aripiprazoie, i.e. any crystalline unsolvated or solvated tern, ocn* cns^oe or amorphous form or crude aripiprazoie may be used. Preferably, the ater ocwi fonss of aripprazoje of the present invention, i.e. aripiprazoie ethanol nenasoivs&£ and aripiprazoie methanol solvate or an aripiprazoie hydrate may be used. Hom&iBf, this second process is based on the solution mediated transformation of any form of mv&mzz^e wiiieh is thermodynamicaiiy less stable under given conditions than form X. Therefore, the transformation into form X is a thermodynamicaiiy controlled process due to Ire fact that form X has the lowest Gibbs free energy at temperatures at and below about 6CTC. Consequently, all known solid crystalline or non-crystalline forms, of aripiprazoie may be used in the present process. Accorfng to the above second process a suitable solvent is a solvent or solvent mixture which does not form a crystalline solvate with aripiprazoie and in which the substance is not highly soluble, in a preferred embodiment, the solvent used in the above second process for preparing form X of aripiprazoie is selected from 2-propanol, acetone, 1-butanoI or 1-propanoi. The-tempera&ire^t^hicixibe^^ susoended form of aripiprazoie into form X depends on the form of aripiprazoie and the solvent used. Room temperature or an elevated temperature may be applied but usually it wtfl be in the range of 10CC to 60°C. However, it is crucial that solvent and temperature are chosen such that the used form of aripiprazoie remains in the condition of a suspension and does not become dissolved. It is well within the general knowledge of a person skilled in the art to determine a suitable solvent and temperature accordingly. In a preferred embodiment the solvent is 2-propanol and the preferred temperature range is about 10QC to about 80°C, preferably at a temperature of about 60°C to about 40°C, most preferable at a temperature of about 60°C to about 50°C for a time to form form X of aripiprazole. . Aripiprazole is then isolated after cooling the solution. A time sufficient for the formation of form X varies from a view minutes , e.g. 15 to 30 min to several days, e.g. 2 to 6 days. Optionally In intervals the suspension may be cooled to a lower temperature, e.g. to a temperature ro about ambient temperature and the suspension is then reheated to the desrred temperature. In a hriier enijoeirnent, the present invention provides a first process for preparing anpioarazole ethanol hemssoJvate, comprising the steps of- a) &mcfamig a^ppcazoie in ethanol by heating b) sfawiy cocfeig fse solution to room temperature or below to effect crystallization cf iscfeSrag me crysEaBne ethanol hemisolvate d) drying the eshanol hemisolvate at a temperature below about 60DC. Jus! as for the processes for preparing form X of aripiprazole described above also for this first process for preparing aripiprazole ethanol hemisolvate any other form of aripiprazole, Le. any crystalline unsolvated or soivated form, any non-crystalline or amorphous form and crude aripiprazole may be used. Preferably, the other novel forms of aripiprazole of the present invention, i.e. form X of aripiprazole and aripiprazole methanol solvate or an aripiprazole hydrate may be used. The heating temperature applied in order to dissolve aripiprazole depends on the boiling pant of the soh/ent used but usually will be in the range of 50°C to 100°C. A preferred temperature is the boiling temperature of the solvent. Dryrng^he^thranof hemisolvateat atemperatunsrbetow about 60°C may be performed in different ways under different suitable conditions. Drying time and drying temperature are inversely related, so that for example the drying time will be longer the lower the drying temperature, and shorter the higher the drying temperature. Particularly suitable and preferred are air drying at room temperature, drying under vacuum at room temperature over night or drying at 50°C for 2 hours. Alternatively, instead of using pure ethanol as solvent for preparing the ethanol hemisolvate, aripiprazole may be dissolved \n a solvent in which aripiprazole is soluble at room temperature such as e.g. methylene choride, tetrahydrofuran or amides like e.g. dimethyiformamide, dimethyiacetamide or N-methylpyrrolidone. A suitable solvent is a solvent which allows dissolving one gram aripiprazoie in a volume of approximately 10 ml solvent or less at room temperature. Due to the good solubility only a little quantity of the sotvenx is neeaed. The concentrated solution is then diluted with ethanol resulting in the crystalfizstjcc? of aripiprazoie ethanol hemisolvate. 7b© process provides high yields of aripiprazoie ethanol hemisolvate and also represents a piBcfeai meted for purification of crude aripiprazoie, because most of the impurities of cnjde arpiprazase are mere soluble than aripiprazoie ethanol hemisolvate and remain in sokiiorL Accordingly, m a further embodiment, the present invention provides a second process for preparing anp^pcazoie ethanol hemisolvate, comprising the steps of: a) dissolving anpiprazole in a solvent in which aripiprazoie is soluble at room temperature b\ tiftiSng the solution with ethanol c) ssciaBog the crystalline ethanol hemisolvate d) drying tt^e ethanol hemisolvate at a temperature below about 60DC. In a preferred embodiment, the solvent used in the above second process for preparing aripiprazoie ethano! hemisolvate is selected from methylene chloride, tetrahydrofuran, dlmethyiformamide, dimethylacetamide or N-methylpyrrolidone. With respect to the aripiprazoie form used in step a) and the performance of drying step d) the same applies as said above for the first process for preparing aripiprazoie ethanol • hemisotyate^— — „^_^„,,___- .^^.^^^--^ -^—-^-=—-- --— - m a further embodiment, the present invention provides a third process for preparing aripiprazoie ethano! hemisolvate characterized in that a suspension of aripiprazoie in ethanol is stirred at a suitable temperature in order to effect transformation of the used form of anpiprazole into aripiprazoie ethanol hemisolvate. With respect to the aripiprazoie form used the same applies as said above for the first and-. second process for preparing aripiprazoie ethanol hemisolvate. The temperature at which the suspension is stirred in order to effect transformation of the suspended form of aripiprazole into aripiprazole ethanoi hemisolvate may be room temperature or an elevated temperature. Usually, it will be in the range of 10DC to 40DC. However, it is crucial that the temperature is chosen such that the used form of aripiprazole remains in the condition of a suspension and does not become dissolved. It is well within the general knowledge of a person skilled in the art to determine a suitable temperature The p&esenr wwen&an also relates to a first process for preparing aripiprazole methanol sohraae conpds@ng the steps of: aj sfesofvirag arbfxazoie in methanol by heating b) mom&g cocfeg the solution to room temperature or below to effect crystallization c\| ©dating the crystalline methanol solvate o) drying tie methanol solvate at a temperature below about 60°C. Also for tfus first process for preparing aripiprazole methanol solvate any form of aripipcazote, i.e. any crystalline unsolvated or solvated form, any non-crystalline or amorphous form and crude aripiprazole may be used. Preferably, the other novel forms of aripiprazole of the present invention, i.e. form X of aripiprazole and aripiprazole ethano! hemisolvate or an aripiprazole hydrate may be used. Drying the methanol solvate at a temperature below about 60°C may be performed in eifferent ways under different suitable conditions. Drying time and drying temperature are inversely related, so that for example the diying time will be longer the lower the drying temperaturerand shorter the higher the drying temperature. Particularly suitable and preferred are air drying at room temperature, drying under vacuum at room temperature over night or drying at 50°C for 2 hours. Alternatively, instead of using pure methanol as solvent for preparing the methanol solvate, anp^prazole may be dissolved in a soivent in which aripiprazole is soluble at room temperature such as e.g. methylene choride, tetrahydrofuran or amides like e.g. dimethyfformarnide, dimethylacetamide or N-methylpyrrolidone. A suitable solvent is a solvent which allows dissolving one gram aripiprazole in a volume of approximately 10 mflSiitres solvent or less at room temperature. Due to the good solubility only a little quantity of the solvent is needed. The concentrated solution is then diluted with methanol resulting in the crystallization of aripiprazole methanol solvate. Hits process provides high yields of aripiprazole methanol solvate and also represents a practical metrod for purification of crude aripiprazole, because most of the impurities of crude anqpramle are more soluble than aripiprazole methanol solvate and remain in solution. Accosting, n another aspect the present invention relates to a second process for prspsi^ig arpw-azDte methanol soivate, comprising the steps of: m dssofving arac^azo^e in a solvent in which aripiprazole is soluble at room temperature t) cfikjiang the solution with methanol c) isolating the crystafisne methanol soivate d) drying the methanol solvate at a temperature below about 60°C. k\ a preferred embodiment, the solvent used in the above second process for preparing aripiprazote methanol soivate is selected from methylene chloride, tetrahydrofuran, cftrnetrry1tormarn»deT dimethylacetamide or N-methylpyrrolidone. With respect to the aripiprazole form used in step a) and the performance of drying step d) the same sopites, as said above for the first process for preparing aripiprazole methanol soh/aie. in a further embodiment, the present invention provides a third process for preparing anpft^YOfein^ in methanol is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazote into aripiprazole methanol solvate. With respect to the aripiprazole form used the same applies as said above for the first and second process for preparing aripiprazole methanol solvate. Toe temperature at which the suspension is stirred in order to effect transformation of the suspended form of aripiprazole into aripiprazole methanol solvate may be room temperature or an elevated temperature. Usually, it will be in the range of 10°C to 40°C. However, it is crucial that the temperature is chosen such that the used form of aripiprazole remains in the concftion of a suspension and does not become dissolved. It is well within the general knowledge of a person skilled in the art to determine a suitable temperature accordingly. The novel forms of aripiprazoie of the present invention may be used alone as antipsychotic drugs or in tr?e form of a suitable pharmaceutical composition containing the novel form togestef wriih one or more suitable pharmaceuticaiiy acceptabie carriers. The pharmaceutical conaDasifcnss canzammg the novel forms of aripiprazole of the present invention are prepared aararding ID k&cmn processes. tocwi^yr the present invention relates to form X of aripiprazole or aripiprazole ethanol bemsofVHiB for use as a medicament. The novel forms of aripiprazoie are particularly useful for the treatment of schizophrenia. Therefore, the present invention also relates to the use of form X of aripiprazole or arspiprazote ethanol hernisoivate for the preparation of a medicament for the treatment of schizophrenia. Tne present invention further relates to a pharmaceutical composition comprising an effective amount cf form X of aripiprazole or aripiprazole ethanol hernisoivate and a pharmaceuticaiiy acceptabie carrier. The pharmaceutical composition may be prepared via a wet granulation process as known in the state of the art and as described for other cr/stailne and potymorphic forms in WO 03/026659. Another suitable preparation may be forming flash-meit tablets. The invention is further described by reference to the following examples. These examples are provided for illustration purposes only and are not intended to be limiting the present invention in any way. EXAMPLES The infrared spectra are recorded using a BRUKER FTiR-Tensor 27 with diamond ATR. The XRPD ts recorded on a AXS-BRUKER X-ray powder diffractometer D-8 using the fotowing acquisition conditions: tube anode: Cu; generator tension: 40 kV; generator current: 40 mA: stan angle: 2.0° 9; end angle: 40.0° 8; step size: 0.01 ° 8; time per step: 2 seconds. Dsferen&ai scanning caionmetry (DSC) is performed with a DSC 7 (Perkin-Elmer, NorwaJk, CL, USA} usrsg tie Pyds 2.0 software. Samples are weighed into 25 fj\ Al-Pans. Dry rabogen ss used as trta purge gas (purge: 20 mi min'1). Them&gsacmtkM'ic analyst is performed with the Thermogravimetric-System TGA-7 using tie Pyns^StxtmafB far Windows NT, (Perkin-Eimer, Norwalk, Ct., USA), 50 JJL platin-pans, nteogen ptsge- gas {sample purge: 20 mL min"1, balance purge: 40 mL min"1). Exampka i 25 g os ahpgjrazoie Anhydrate Form A obtained as described in EP 367141 B1 are stirred in 250 rri isopncspanoi and heated at boiling until a clear solution is obtained. After cooling to room temperature under stirring the precipitated product is filtered and dried at room temperature under vacuum over night to give 24.12 g (96.5%) of the anhydrous polymorph referred to herein as form X. The form X crystals of aripiprazole anhydride obtained above provide an infrared spectrum with peaks at 2939, 2803, 1677, 1374, 1191, 1168, 1045, 868, 822 and 736 cm1 (Figure 1). The XRPD patlern of form X of aripiprazole with characteristic XRPD angles, d-spacings and sla&tfe intensities is shown in Table 1 and in Figure 4. Table i: X-Ray Powder Diffraction (XRPD) pattern of form X of aripiprazole. Values: interptanar spacings (dT in A, Angstroem), characteristic XRPD angles (in degrees 2-theta) and relative intensities (in %) Form X of anoiorazole shews a typical DSC curve at a heating rate of of 5°K/min and practscaly no mass toss in the TGA analysis. Typical thermograms of form X of aripiprazoie are shown In Rgyre 7. it can be seen that form X shows two specific endothermic peaks with onset temperatures of about 119CC and 149°C. Exampie 2 5 g of aripiprazoie Anhydrate Form A obtained as described in EP 367141 B1 are stirred in 20 ml tetrahydrofuran and heated at boiling until a clear solution is obtained. After cooling to room temperature the suspension is stirred for additional three hours and then allowed to sand two days in a refrigerator. The precipitated product is filtered and dried at room temperature under vacuum over night to give 2.95 g (59%) of form X of the product. Example 3 A suspension of 7 g of aripiprazoie Anhydrate Form A obtained as described in reference example 1 of WO 03/026659 is stirred in 50 m! acetone and heated to reflux for'7.5 hours. The mixture is filtered and the insoluble solid dried in an desiccator at room temperature over night to yield 4.48 g (64%) of form X of the product. Example 4 100 g crude aripiprazoie prepared as described in EP 367141 B1 are suspended in 1500 ml absolute ethanol and then heated to reflux. The resulting solution is slowly cooled to room temperature to crystallize the product. After stirring at 0°C for one hour the precipitated product is filtered and dried at room temperature under vacuum for 17 hours to give 102.7 g (97,7%) of the ethanol hemisoivate of the product. The crystals are colorless plate form. The content of ethanol in the product is about 5,0 % by weight i.e. the compound is an ethanoi heroisotvate containing half a mol of ethanol per mol aripiprazole. The e&ranof nsmtsolvaie of aripiprazole obtained above provides an infrared spectrum with peeks at 294S. 2816, 1670, 1378, 1192, 1171, 1047, 854, 830 and 746 cm'1 (Figure 2). The XF^O GatiSssr* or aripiprazole-ethanol hemisoivate with characteristic XRPD angles, d-spacaTcs and ^5Jaf&e intensities is shown in Table 2 and in Figure 5. Tafcie 2: X~Ray Pomder Diffraction (XRPD) pattern of aripiprazole ethanoi hemisoivate. Values: fmerpsanar spacrngs (d; in A, Angstroem), characteristic XRPD angles (in degrees 2-tfieta) s&td resatr&a ^itensriies (in'%) Aripiprazole ethanol hemisoivate shows a typical endothermic curve in TGA and DSC analysis at a heating rate of of 5°K/min. A typical thermogram of aripiprazole ethanol hemisoivate is shown in Figure 8. It can be seen that aripiprazole ethanol hemisoivate shows an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic peaks with onset temperatures of about 139CC and 148.5°C. Example 5 100 g crude aripiprazofe prepared as described in EP 367141 B1 are suspended in 1500 mi absolute ethanol and then heated to reflux. The resulting solution Is slowly cooled to room temperature to crystallize the product. After stirring at 0°C for one hour the precipitated product Is ^tBTBa and dried at 50°C under vacuum for 2 hours. Example 6 15 g or afp$5taztfc Anhydrate Form A obtained as described in EP 367141 B1 is added to 1900 im meShanoi and the mixture is heated to reflux to get a clear solution. The solution is ihert skmfy coded ID room temperature, stirred for another two hours and allowed to stand in a rsfsksersiDf lor several days. The precipitated crystals are isolated by suction and dried at nxm tenperaiure m vacuo to yield 15.2 g (93.7%) methanol solvate of the product. The crysfeis am cosoness plate form. Tne content of methanol in the product is about 6,7% by weighs Le. the compound is a methanol monosolvate containing one mol of methanol per rnd arpiprazoie. The methanes solvate of aripiprazole obtained above provides an infrared spectrum with peaks at 2942. 2814. 1671, -1377, 1199, 1174, 1037, 857, 824 and 746 cm'1 (Figure 3). The XRPD pattern of aripiprazole methanol solvate with characteristic XRPD angles, d-spac^>gs and relative intensities is shown in Table 3 and in Figure 6. Table 3: X-Ray Powder Diffraction (XRPD) pattern of aripiprazole methanol solvate. Values: Interplanar spadngs (d, in A, Angstroem), characteristic XRPD angles (in degrees 2-theta) and reistjve intensities (in %) A®pa&s&zx$& inefenof solvate shows a typical endothermic curve in TGA and DSC analysis M a fusing rate of of STC'min. A typical thermogram of aripiprazole methanol solvate is shamn m P«^s s. k can be seen that aripiprazole methanol solvate shows an endothermic peak wifc an onset iafm>erature of about 113°C followed by an exothermic event and two ando^erriic peate with onset temperatures of about 139°C and 148°C. Eseampe 7 Igd crude aripiprazole Anhydrate Form A obtained as described in EP 367141 B1 is dfesotved in 10 rri cfchloromethane. The solution is diluted with 40 ml methanol and then allowed to stand \n a refrigerator overnight. The precipitated crystals are isolated by suction and dried at room temperature in vacuo to yield 0.93 g (86.0%) methanol solvate of the product Example 8 5gd the ethanoi hemisolvate of example 4 are recrystallized from 55 ml isopropanol using seed crystals obtained in example 1 above. The yield is 4.5 g (94.6%) of form X of anpprazole. Example S Examotz 8 is repeated using 3 g of the methanol solvate obtained in example 5 above instead of the ethanoi hemisolvate. The yield is 2.7 g (96.8%) of form X of aripiprazole. Example 10 Example 8 is repeated but instead of using the ethano! hemisolvate as starting material 5 g erf the aripiprazole hydrate obtained as described in reference example 3 of WO 03/026659 ss used. The yield is 4.5 g (93.6%) of form X of aripiprazole. Example 11 5 g of aripiprazole Anhydrate Form A obtained as described in EP 367141 B1 and 0.5 g of form X of aripiprazole are suspended in 55 mi isopropanol and heated at 50°C overnight and then stirred at room temperature for four days. The unsoluble part of the reaction mixture is ootecSed by f3tratfc>n and dried in vacuo at room temperature over night to give 4.6 g (92%) of form X of anpiprazoie. Ex&rnpte 12 5 g rf amaprazDie Anhydrate Form A obtained as described in EP 367141 B1 are suspended mSDrru e#sano» and s^tBd at room temperature for three hours. The solid is filtered and ed ^ rtaom lemperHfure under vacuum for 17 hours to give 5.0 g (95,1 %) of the ethanol hesnssdirae of arcrarazole. Exarc^3£e 13 A suspension or 33 g of anpiprazole Anhydrate Form A obtained as described in EP 367141 B^ m 1000 rrs of isopropanol is heated to reflux temperature. The resulting clear solution is coofed down to 55^ under stirnng and then seeded with 0,3 g of aripiprazole form X. After further cooling down to 60°C a second portion of 0,3 g seeds of aripiprazole form X are added. The mixture is then sfowiy cooied down to 50°C in one hour and then from 50°C to 0°C in one hour. After stirring at 0°C for one hour, the obtained suspension is reheated to 50°C: stirred at this temperature for one or two hours, then again cooied to 0°C. After stirring foe one hour the precipitated product is filtered and dried in vacuo at room temperature over rwgtei or at 60CC for 3 hours to yield 31,8 g (94,5%) of form X of aripiprazole £;xarnpie 14 3 g anpiprazofe hydrate, obtained as described in example 22 are suspended in 80 ml isopropanol, seeded with 0,5 g aripiprazole form X and stirred at 50°C over night. The suspension is cooied to room temperature, filtered and dried at room temperature under actium for 17 hours to give 4,61 g (85,5%) aripiprazole form X . Example 15 Example 14 is repeated using 5 g of the ethanol hemisoivate as starting material instead of the hydrate. The yield is 4,51 g (84,3%) of form X of aripiprazoie. Example 16 2 g aripiprazoie methanol solvate obtained as described in example 6 are suspended in 30 ml isopropanol. seeded with 0,5 g aripiprazoie form X and stirred at 50°C over night. The suspension is coo?ea to room temperature, filtered and dried at room temperature under vacuum or 17 hours tc grve 1 f94g (77,2%) aripiprazoie form X . Claims: 1. Form X of ariprprazoJe charactenzed by an X-ray powder diffraction pattern with peaks at 10.0. 11.6, 15.7: 15.3, 18.5, 20.4, 21.8, 22.2 and 23.3 degrees 29. 2. Forr: X of anpspnazDie of daim 1 characterized by an X-ray powder diffraction pattern substernal* in accordance with Table 1 and Figure 4. 3. Form X or arcaprs2ote of daim 1 characterized by an infrared spectrum substantially in accordance with Figure 1. 4. Form X of aspprH2oie of claim 1 characterized by two endothermic peaks with onset temperatLrres of about 119°C and 149°C at a heating rate of 5°K/min in in differential scanrwig calorsraeiry. 5. Arp£razoie ethanoi hemisoivate characterized by an X-ray powder diffraction pattern with peaks at 17.4. 18.1, 19.6, 23.3 and 27.9 degrees 26. 6. Ariprprazoie ethanoi hemisoivate of claim 5 characterized by an X-ray powder diffraction pattern substantially in accordance with Table 2 and Figure 5. 7. Aripiprazofe ethanoi hemisoivate of claim 5 characterized by an infrared spectrum substanciaHy ?n accordance with Figure 2. a. Anpiprazofe ethanoi hemisoivate of claim 5 characterized by an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic zzaaks with onset temperatures of about 139°C and 148°C at a heating rate of 5°K/min in differential scanning caiorimetry. 9 AricwrazGle methanol solvate characterized by an X-ray powder diffraction pattern with peaks at 11.5, 17.3, 18.5, 19.8, 23.1, 24.4 and 26.9 degrees 29. 10. Aripipa2ote methanol solvate of claim 9 charactenzed by an X-ray powder diffraction pattern substantially in accordance with Table 3 and Figure 6. 11. Aripiprazole methanol solvate of claim 9 characterized by an infrared spectrum substandaiiy in accordance with Figure 3. 12. Aripiprazote methanol solvate of claim 9 characterized by an endothermic peak with an onset lemperaiure of about 113CC followed by an exothermic event and two endothennic peaks mfo onset lemperaiures of about 139CC and 148°C at a heating rate of 5°K/min in m tiferasiiija£ scsarmng caJorimetry. 13. Process for preparing form X of aripiprazole, comprising the steps of: a) dissolving mkm^szD^e m a suitable solvent by heating b) siowfy cocwig the soiutkm to room temperature or below to effect crystallization c) QDfcnafy teoiassng crystalline form X of aripiprazole. 14. Process acconJng to claim 13, wherein the form used in step a) is aripiprazole ethanol hemssoivate and/or aripiprazole methanol solvate and/or aripiprazole hydrate. 15. Process for preparing form X of aripiprazole according to claim 13 or claim 14, wherein the solvent rn steo a) is acetone, tetrahydrofuran or 2-propanol and/or in step b) seed crystals of iorrr X of aripiprazoie are added. 16- :>rooass according tc claim 15, wherein the solvent is 2-propanoi and the preferred anoeraiure range is about 40°C to about 70°C. 17. Process for preparing fortft-X ofaripiprazole-Gharacterizedin that a suspension of- ~--■— anptprazole in a suitable solvent is seeded with crystals of form X and the suspension is stirred at a suitable temperature in order to effect transformation of the used form of anoiprazole into form X. * a Process according to claim 17, wherein the solvent is selected from 2-propanol, acetone, "-octane! or 1-propanoL 19. Process according to claim 17. wherein the solvent is 2-propanol and the preferred temoersture ranee is about 40°C to about 60°C. 20. Process for preparing aripiprazofe ethanol hemisolvate, comprising the steps of: a) dissolving aripiprazole in ethanol by heating h) stowfy coding the solution to room temperature or below to effect crystallization c) isolating the crystalline ethanol hemisolvate cf) drying the ethanol hemisolvate at a temperature below about 60°C. 21- Process kx pRgeanog arpipcazole ethanol hemisolvate, comprising the steps of: ai dissafemg wkme&zalB in a solvent in which aripiprazofe is soluble at room temperature trt dttufeg the soiuson wfth ethanol cl asoiaing #se crys&Bne ethanol hemisolvate ri> sfcyang fie etani hemtsohrate at a temperature below about 60°C. 22 Process for pre&armg aripiprazole ethanof hemisolvate characterized in that a suspension ot an&pmzole ki ethanoj is stirred at a suitable temperature in order to effect transforrnatjon ct tine used form of aripiprazole into aripiprazole ethanol hemisolvate. 23. Process for preparing aripiprazole methanol solvate, comprising the steps of: a) cfissolving aripiprazole in methanol by heating b) slowty cooling the solution to room temperature or below to effect crystallization c) isolating the crystalline methanol solvate d^ crying the methanol solvate at a temperature below about 60DC. 2*. >~3cess for preparing aripiprazole methanol solvate, comprising the steps of: &} cissoMog arip^azoLeJa-a-Soivent-in-whrch aripiprazole is soluble at room temperature b) (Muting the solution with methanol c> isolating the crystalline methanol solvate x ±wig the methanol solvate at a temperature below about 60°C. 25.. Process according to claim 21 or claim 24, wherein the solvent is selected from rnefrryiene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide or N-rneshyipyf rolidon e. 28. Process for preparing aripiprazoie methanol solvate characterized in that a suspension of aripiprazoie in methanol is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazoie into aripiprazoie methanol solvate. 27. Form X of anp&razoie or aripiprazoie ethanol hemisoivate for use as a medicament 2& Use of ferm X or anck&szoke or aripiprazoie ethanoi hemisoivate for the preparation of a medkss&ert tor tnse treatment of schizophrenia. 2S. Ftsarmacei^3ca§ ^ornoostton comprising an effective amount of form X of aripiprazoie or assapesaDie etesid hemisofvaie and a pharmaceuticaify acceptable carrier.

Full Text

Organic Compounds
FIELD OF THE INVENTION
The present invention relates to novel polymorphic forms of aripiprazoie and processes for their production, it further relates to pharmaceutical compositions comprising the novel forms and to the use of the novel forms in the treatment of schizophrenia.
BACKGROUND OF THE INVENTION
Aripiprazoie, 7-[4-{4-.(2J3-dichlorophenyl)-1-piperazinyl]butoxy3-3)4-dihydrO'2(1H)-quinolinone, is an antipsychotic drug useful m the treatment of schizophrenia (Merck Index, monograph number 00791, CAS registry number 129722-12-9). Synthesis and isolation of aripiprazoie are described in EP 367141 B1 and US 5006528.
Additional crystalline anhydrous or hydrous forms are disclosed in WO 03/026659 {conventional hydrate, hydrate A. conventional anhydrate, anhydrate B, anhydrate C, anhydrate D, anhydrate E, anhydrate F5 anhydrate G).
Nevertheless, there remains a need for alternative polymorphic forms of aripiprazoie which have properties suitable for pharmaceutical processing on a commercial scale. The present invention satisfies these needs by providing novel polymorphic forms of aripiprazoie and processes for their production.
SUMMARY OF THE INVENTION
The present invention relates to form X of aripiprazoie characterized by an X-ray powder diffraction pattern withi peaks at 10.0,11.6,15.7,16.3,18.5,20.4,21.8, 22.2,and 23.3
degrees 29.
The present invention further relates to aripiprazoie ethanoi hemisoivate characterized by an X-ray powder diffraction pattern with peaks at 17.4, 18.1, 19.6, 23.3 and 27.9 degrees 29.
The present invention also relates to aripiprazoie methanol solvate characterized by an X-ray powder diffraction pattern with peaks at 11.5,17.3, 18.5, 19.8, 23.1, 24.4 and 26.9 degrees 26,

The present invention provides a process for preparing form X of aripiprazole, comprising the steps of:
a) dissolving aripiprazole in a suitable solvent by heating
b) slowly cooling the solution to room temperature or below to effect crystallization .
c) optionally isolating crystalline form X of aripiprazole.
*
The present invention also provides a process for preparing form X of aripiprazole characterized in that a suspension of aripiprazole in a suitable solvent is seeded with crystals of form X and the suspension is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazole into form X.
in another aspect the invention provides a process for preparing aripiprazole ethanol
hemisolvate, comprising the steps of;
-a) dissolving aripiprazole In ethanol by heating
b) slowly cooling the solution to room temperature or below to effect crystallization
c) isolating the crystalline ethanol hemisolvate
d) drying the ethanol hemisolvate at a temperature below about 60°C.
In a further aspect the invention provides a process for preparing aripiprazole ethanol hemisolvate, comprising the steps of:
a) dissolving aripiprazole in a solvent in which aripiprazole is soluble at room temperature
b) diluting the solution with ethanol
c) isolating the crystalline ethanol hemisolvate
d) drying the ethanol hemisolvate at a temperature below about 60°C.
In a further aspect the invention provides a process for preparing aripiprazole ethanol hemisolvate characterized in that a suspension of aripiprazole in ethanol is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazole into aripiprazole ethanol hemisolvate.
In another aspect the invention provides a process for preparing aripiprazole methanol solvate, comprising the steps of:
a) dissolving aripiprazole in methanol by heating
b) slowly cooling the solution to room temperature or beiow to effect crystallization

c) isolating the crystalline methanol solvate
d) drying the methanol solvate at a temperature below about 60°C.
In a further aspect the invention provides a process for preparing aripiprazole methanol solvate, comprising the steps of:
a) dissolving aripiprazole in a solvent in which aripiprazole is soluble at room temperature
b) diluting the solution with methanol
c) isolating the crystalline methanol solvate
d) drying the methanol solvate at a temperature beiow about 60DC.
in a further aspect the invention provides a process for preparing aripiprazole methanol solvate characterized in that a suspension of aripiprazole in methanol is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazole into aripiprazole methanol solvate.
The present invention also relates to form X=of aripiprazole or aripiprazole ethanoi hemisolvate for use as a medicament.
In another aspect the present invention relates to the use of form X of aripiprazole or aripiprazole ethanoi hemisolvate for the preparation of a medicament for the treatment of schizophrenia.
In a further aspect the present invention relates to a pharmaceutical composition comprising an effective amount of form X of aripiprazole or aripiprazole ethanoi hemisolvate and a pharmaceutical acceptable carrier^-.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill from the following description, it should be understood, however, that the description and the following specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent ip.,those skilled in the art from reading the description and from reading the other parts of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: infrared spectrum of form X of aripiprazoie.
Figure 2: Infrared spectrum of aripiprazoie ethanoi hemisoivate.
Figure 3: infrared spectrum of aripiprazoie methanol solvate.
Figure 4: X-ray powder diffraction pattern of form X of aripiprazoie.
Figure 5: X-ray powder diffraction pattern of aripiprazoie ethanoi hemisoivate.
Figure 6: X-ray powder diffraction pattern of aripiprazoie methanol solvate.
Figure 7: Thermogravimetric and differential scanning caiorimetric curve of form X of
aripiprazoie.
Figure 8: Thermogravimetric and differentia! scanning caiorimetric curve of aripiprazoie
ethanoi hemisoivate.
Figure 9: Thermogravimetric and differential scanning caiorimetric curve of aripiprazoie
methanol solvate.
Figure 10: Moisture sorption isotherm of form X of aripiprazoie.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "crude" refers to crystals of aripiprazoie that have not been washed
and/or recrystaliized to remove impurities that may be present.
As used herein the term "crystalline" refers to crystals of aripiprazoie that have been washed
and recrystaliized to remove impurities.
As used herein the term "amorphous1' relates to solid material which lacks a regular
crystalline structure.
The term "room temperature" as used herein indicates that the applied temperature is not
critical and that no exact temperature value has to be kept. Usually, "room temperature" is
understood to mean temperatures of about 15°C to about 25°C (see e.g. EU Pharmacopeia
5.0, page 6).
The inventors of the present invention have identified novel polymorphs of aripiprazoie. The novel polymorphs have distinct physical properties and may be characterized e.g. by a typical X-ray powder diffraction pattern, infrared spectrum or a characteristic thermogravimetric (TGA) and differential scanning caiorimetric (DSC) curve. Each of these characteristics on its own is sufficient to unambiguously define and identify the new polymorphs but they also may be combined with each other.

The present invention relates to a novel form X of aripiprazoie characterized by an X-ray powder diffraction pattern with peaks at 10.0, 11.6, 15.7,16.3, 18.5, 20.4, 21.8, 22.2 and 23.3 degrees 20 (2-theta).
A characteristic X-ray powder diffraction pattern of form X of aripiprazoie is shown in Figure 4 and some characteristic peaks are listed in Table 1. Accordingly, in a preferred embodiment, the present invention relates to a novel form X of aripiprazoie characterized by an X-ray powder diffraction pattern substantially in accordance with Table 1 and Figure 4.
Form X of aripiprazoie may be also characterized by a typical infrared spectrum as shown in Figure 1. Accordingly, in a further preferred embodiment, the present invention relates to form X of aripiprazoie characterized by an infrared spectrum substantially in accordance with Figure 1. Characteristic bands are present at 2939, 2803, 1677, 1374, 1191,1168, 1045, 868, 822 and 736 cm"1.
In addition, form X of aripiprazoie shows a typical DSC curve at a heating rate of of 5°K/min and practically no mass loss in the TGA analysis. Typical thermograms of form X of aripiprazoie are shown in Figure 7. It can be seen that the DSC curve of form X shows two specific endothermic peaks with onset temperatures of about 119°C and 149°C.
Accordingly, in a further preferred embodiment, the present invention relates to form X of aripiprazoie characterized by two endothermic peaks with onset temperatures of about 119°C and 14G°C at a heating rate of 5°K/min in differential scanning calorimetry.
Form X of aripiprazoie is a novel anhydrous form, hereinafter also referred to as "form X",
which is particularly stable and hence is suitable for bulk preparation and handling. Form X of aripiprazoie has been found to be of low hygroscopicity and does not substantially convert into a hydrated form of aripiprazoie. This can be seen from the moisture sorption isotherm of form X which is shown in Figure 10.
The present invention further relates \Q anpiprazole ethanol hemisolvate characterized by an X-ray powder diffraction pattern with peaks at 17.4, 18.1, 19.6, 23.3 and 27.9 degrees 29.

A characteristic X-ray powder diffraction pattern of aripiprazole ethanol hemisoivate is shown in Figure 5 and some characteristic peaks are listed in Table 2. Accordingly, in a preferred embodiment, the present invention relates to aripiprazole ethanol hemisoivate characterized by an X-ray powder diffraction pattern substantially in accordance with Table 2 and Figure 5.
Aripiprazole ethanol hemisoivate may be also characterized by a typical infrared spectrum as shown in Figure 2. Accordingly, in a further preferred embodiment, the present invention relates to aripiprazole ethanol hemisoivate characterized by an infrared spectrum substantially in accordance with Figure 2. Characteristic bands are present at 2949, 2816, 1670, 1378: 1192, 1171, 1047, 854, 830 and 746 cm"1.
In addition, aripiprazole ethanol hemisoivate shows a typical step in the TGA curve and a characteristic DSC curve at a heating rate of of 5°K/min. Typical thermograms of aripiprazole ethanol hemisoivate are shown in Figure 8. It can be seen that the DSC curve of aripiprazole ethanol hemisoivate (sample pan with pinhole) shows an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic peaks with onset temperatures of about 139°C and 148DC.
Accordingly, in a further preferred embodiment, the present invention relates to aripiprazole ethanol hemisoivate characterized by an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic peaks with onset temperatures of about 139°C and 148°C at a heating rate of 5°K/min in differential scanning calorimetry.
In another aspect, the present invention relates to aripiprazole methanol solvate
characterized by an X-ray powder diffraction pattern with peaks at 11.5,.17.3, 18.5, 19.3, 23.1, 24.4 and 26.9 degrees 26.
A characteristic X-ray powder diffraction pattern of aripiprazole methanol solvate is shown in Figure 6 and some characteristic peaks are listed in Table 3. Accordingly, in a preferred embodiment, the present invention relates to aripiprazole methanol solvate characterized by an X-ray powder diffraction pattern substantially in accordance with Table 3 and Figure 6.

Anpiprazole methanol solvate may be also characterized by a typical infrared spectrum as shown in Figure 3. Accordingly, in a further preferred embodiment, the present invention rslaies to anpiprazole methanol solvate characterized by an infrared spectrum substantially in accordance with Figure 3. Characteristic bands are present at 2942. 2814, 1671, 1377, 1199f 1174, 1 -337, 857; 824 and 746 cm'1.
hi additiorL arpiorazofe methanol solvate shows a typical step in the TGA curve and a diasacfef^c DSC carve at a heating rate of of 5°K/min. Typical thermograms of aripiprazole osetenot soiveie are shown in Figure 9. It can be seen that the DSC curve of aripiprazole rae&tanot sot^a^ (sample pan with pinhole) shows an endothermic peak with an onset temperature of about 113°C followed by an exothermic event and two endothermic peaks «tt> oossi temperatures of about 139°C and 148°C.
Accordingly, in a further preferred embodiment, the present invention relates to aripiprazole methanol solvate characterized by an endothermic peak with an onset temperature of about 113°C toiowed by an exothermic event and two endothermic peaks with onset temperatures of about 139~C and 148°C at a heating rate of 5DK/min in differential scanning calorimetry.
As said before, each of the above mentioned data alone are sufficient to characterize each of the new polymorphs of aripiprazole. Therefore, further embodiments of the present invention relate to each polymorph being characterized by its typical X-ray powder diffraction pattern or its typical \n1rared spectrum or its typical thermogravimetric/differential scanning caiorimetnc curse.
In one embodiment the preseaUnventi^^^ X of
anpiprazoie, comprising the steps of:
a) dissolving aripiprazole in a suitable solvent by heating
b) slowly cooling the solution to room temperature or below to effect crystallization
c) optionaify isolating crystalline form X of aripiprazole.
For preparing form X of aripiprazole according to the above first process, any other form of aripiprazole may be used, e.g. the forms disclosed in WO 03/026659 (conventional hydrate, hydrate A, conventional anhydride, anhydrate B, anhydrate C, anhydrate D, anhydrate E,

anhydrate F, anhydrate G). In addition, also non-crystalline forms of aripiprazole such as the amorphous form and forms of low crystalline order or crude aripiprazole may be used.
in parEJcuiar, the other novel forms of aripiprazoie of the present invention described above. i.e. ariprprazGie ethanol bemtsolvate and aripiprazole methanol solvate or an aripiprazoie hydrate may oe used to prepare form X of aripiprazole. Of course, also mixtures of two or more zMef&wt forms of aripiprazoie may be used. Therefore, in a preferred embodiment, the form used in ihe above first process In step a) is aripiprazole ethanol hemisolvate and/or ^KrazQie melhanof solvate and/or aripiprazole hydrate.
Acrartfeg to ihe above first process a suitable solvent is a solvent in which the substance is not nighty settle. Unsuitable solvents are pure water, ethanol or methanol because the Gonrespoficing solvate is formed, in a preferred embodiment, the solvent used in step a) of the above first process is acetone, tetrahydrofuran or 2-propanol. The even more preferred solvent is 2-propanoi.
The heating temperature applied in order to dissolve aripiprazole depends on the boiling point of the solvent used but usually will be in the range of 50°C to iOQ°C. A preferred temperature is the boiling temperature of the solvent. If 2-propanol is used, the aripiprazoie Is dissolved preferably in a concentration of about 20 g to about 40 g per liter 2-propanol by heating, most preferably in a concentration of about 30 g to about 35 g aripiprazole per liter 2-propanoL
The crystallization step b) of the above first process may be facilitated by adding seed crystals
In another embodiment, the present invention provides a second process for preparing form X of aripiprazoie characterized in that a suspension of aripiprazoie in a suitable solvent is seeded with crystals of form X and the suspension is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazoie into form X.
Just as for the first process described above also for this second process for preparing form X of »pprazoie any other form of aripiprazoie, i.e. any crystalline unsolvated or solvated tern, ocn* cn*s^oe or amorphous form or crude aripiprazoie may be used. Preferably, the ater ocwi fonss of aripprazoje of the present invention, i.e. aripiprazoie ethanol nenasoivs&£ and aripiprazoie methanol solvate or an aripiprazoie hydrate may be used.
Hom&iBf, this second process is based on the solution mediated transformation of any form of mv&mzz^e wiiieh is thermodynamicaiiy less stable under given conditions than form X. Therefore, the transformation into form X is a thermodynamicaiiy controlled process due to Ire fact that form X has the lowest Gibbs free energy at temperatures at and below about 6CTC. Consequently, all known solid crystalline or non-crystalline forms, of aripiprazoie may be used in the present process.
Accorfng to the above second process a suitable solvent is a solvent or solvent mixture which does not form a crystalline solvate with aripiprazoie and in which the substance is not highly soluble, in a preferred embodiment, the solvent used in the above second process for preparing form X of aripiprazoie is selected from 2-propanol, acetone, 1-butanoI or 1-propanoi.
The-tempera&ire^t^hicixibe^^
susoended form of aripiprazoie into form X depends on the form of aripiprazoie and the solvent used. Room temperature or an elevated temperature may be applied but usually it wtfl be in the range of 10CC to 60°C. However, it is crucial that solvent and temperature are chosen such that the used form of aripiprazoie remains in the condition of a suspension and does not become dissolved. It is well within the general knowledge of a person skilled in the art to determine a suitable solvent and temperature accordingly.
In a preferred embodiment the solvent is 2-propanol and the preferred temperature range is about 10QC to about 80°C, preferably at a temperature of about 60°C to about 40°C, most preferable at a temperature of about 60°C to about 50°C for a time to form form X of

aripiprazole. . Aripiprazole is then isolated after cooling the solution. A time sufficient for the formation of form X varies from a view minutes , e.g. 15 to 30 min to several days, e.g. 2 to 6 days. Optionally In intervals the suspension may be cooled to a lower temperature, e.g. to a temperature ro about ambient temperature and the suspension is then reheated to the desrred temperature.
In a hriier enijoeirnent, the present invention provides a first process for preparing anpioarazole ethanol hemssoJvate, comprising the steps of-
a) &mcfamig a^ppcazoie in ethanol by heating
b) sfawiy cocfeig fse solution to room temperature or below to effect crystallization cf iscfeSrag me crysEaBne ethanol hemisolvate
d) drying the eshanol hemisolvate at a temperature below about 60DC.
Jus! as for the processes for preparing form X of aripiprazole described above also for this first process for preparing aripiprazole ethanol hemisolvate any other form of aripiprazole, Le. any crystalline unsolvated or soivated form, any non-crystalline or amorphous form and crude aripiprazole may be used. Preferably, the other novel forms of aripiprazole of the present invention, i.e. form X of aripiprazole and aripiprazole methanol solvate or an aripiprazole hydrate may be used.
The heating temperature applied in order to dissolve aripiprazole depends on the boiling pant of the soh/ent used but usually will be in the range of 50°C to 100°C. A preferred temperature is the boiling temperature of the solvent.
Dryrng^he^thranof hemisolvateat atemperatunsrbetow about 60°C may be performed in
different ways under different suitable conditions. Drying time and drying temperature are inversely related, so that for example the drying time will be longer the lower the drying temperature, and shorter the higher the drying temperature. Particularly suitable and preferred are air drying at room temperature, drying under vacuum at room temperature over night or drying at 50°C for 2 hours.
Alternatively, instead of using pure ethanol as solvent for preparing the ethanol hemisolvate, aripiprazole may be dissolved \n a solvent in which aripiprazole is soluble at room temperature such as e.g. methylene choride, tetrahydrofuran or amides like e.g.

dimethyiformamide, dimethyiacetamide or N-methylpyrrolidone. A suitable solvent is a solvent which allows dissolving one gram aripiprazoie in a volume of approximately 10 ml solvent or less at room temperature. Due to the good solubility only a little quantity of the sotvenx is neeaed. The concentrated solution is then diluted with ethanol resulting in the crystalfizstjcc? of aripiprazoie ethanol hemisolvate.
7b© process provides high yields of aripiprazoie ethanol hemisolvate and also represents a
piBcfeai meted for purification of crude aripiprazoie, because most of the impurities of cnjde arpiprazase are mere soluble than aripiprazoie ethanol hemisolvate and remain in
sokiiorL
Accordingly, m a further embodiment, the present invention provides a second process for preparing anp^pcazoie ethanol hemisolvate, comprising the steps of: a) dissolving anpiprazole in a solvent in which aripiprazoie is soluble at room temperature b\ tiftiSng the solution with ethanol
c) ssciaBog the crystalline ethanol hemisolvate
d) drying tt^e ethanol hemisolvate at a temperature below about 60DC.
In a preferred embodiment, the solvent used in the above second process for preparing aripiprazoie ethano! hemisolvate is selected from methylene chloride, tetrahydrofuran, dlmethyiformamide, dimethylacetamide or N-methylpyrrolidone.
With respect to the aripiprazoie form used in step a) and the performance of drying step d) the same applies as said above for the first process for preparing aripiprazoie ethanol
• hemisotyate^— — „^_^„,,___- .^^.^^^--^ -^—-^-=—-- --— -
m a further embodiment, the present invention provides a third process for preparing aripiprazoie ethano! hemisolvate characterized in that a suspension of aripiprazoie in ethanol is stirred at a suitable temperature in order to effect transformation of the used form of anpiprazole into aripiprazoie ethanol hemisolvate.
With respect to the aripiprazoie form used the same applies as said above for the first and-.* second process for preparing aripiprazoie ethanol hemisolvate.

The temperature at which the suspension is stirred in order to effect transformation of the suspended form of aripiprazole into aripiprazole ethanoi hemisolvate may be room temperature or an elevated temperature. Usually, it will be in the range of 10DC to 40DC. However, it is crucial that the temperature is chosen such that the used form of aripiprazole remains in the condition of a suspension and does not become dissolved. It is well within the general knowledge of a person skilled in the art to determine a suitable temperature
The p&esenr wwen&an also relates to a first process for preparing aripiprazole methanol
sohraae conpds@ng the steps of:
aj sfesofvirag arbfxazoie in methanol by heating
b) mom&g cocfeg the solution to room temperature or below to effect crystallization
c| ©dating the crystalline methanol solvate
o) drying tie methanol solvate at a temperature below about 60°C.
Also for tfus first process for preparing aripiprazole methanol solvate any form of aripipcazote, i.e. any crystalline unsolvated or solvated form, any non-crystalline or amorphous form and crude aripiprazole may be used. Preferably, the other novel forms of aripiprazole of the present invention, i.e. form X of aripiprazole and aripiprazole ethano! hemisolvate or an aripiprazole hydrate may be used.
Drying the methanol solvate at a temperature below about 60°C may be performed in eifferent ways under different suitable conditions. Drying time and drying temperature are inversely related, so that for example the diying time will be longer the lower the drying temperaturerand shorter the higher the drying temperature. Particularly suitable and
preferred are air drying at room temperature, drying under vacuum at room temperature over night or drying at 50°C for 2 hours.
Alternatively, instead of using pure methanol as solvent for preparing the methanol solvate, anp^prazole may be dissolved in a soivent in which aripiprazole is soluble at room temperature such as e.g. methylene choride, tetrahydrofuran or amides like e.g. dimethyfformarnide, dimethylacetamide or N-methylpyrrolidone. A suitable solvent is a solvent which allows dissolving one gram aripiprazole in a volume of approximately 10 mflSiitres solvent or less at room temperature. Due to the good solubility only a little quantity

of the solvent is needed. The concentrated solution is then diluted with methanol resulting in the crystallization of aripiprazole methanol solvate.
Hits process provides high yields of aripiprazole methanol solvate and also represents a practical metr*od for purification of crude aripiprazole, because most of the impurities of crude anqpramle are more soluble than aripiprazole methanol solvate and remain in solution.
Accosting, n another aspect the present invention relates to a second process for prspsi^ig arpw-azDte methanol soivate, comprising the steps of:
m dssofving arac^azo^e in a solvent in which aripiprazole is soluble at room temperature t) cfikjiang the solution with methanol
c) isolating the crystafisne methanol soivate
d) drying the methanol solvate at a temperature below about 60°C.
k\ a preferred embodiment, the solvent used in the above second process for preparing aripiprazote methanol soivate is selected from methylene chloride, tetrahydrofuran, cftrnetrry1tormarn»deT dimethylacetamide or N-methylpyrrolidone.
With respect to the aripiprazole form used in step a) and the performance of drying step d) the same sopites, as said above for the first process for preparing aripiprazole methanol
soh/aie.
in a further embodiment, the present invention provides a third process for preparing
anpft^YOfein^ in methanol
is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazote into aripiprazole methanol solvate.
With respect to the aripiprazole form used the same applies as said above for the first and second process for preparing aripiprazole methanol solvate.
Toe temperature at which the suspension is stirred in order to effect transformation of the suspended form of aripiprazole into aripiprazole methanol solvate may be room temperature or an elevated temperature. Usually, it will be in the range of 10°C to 40°C. However, it is

crucial that the temperature is chosen such that the used form of aripiprazole remains in the concftion of a suspension and does not become dissolved. It is well within the general knowledge of a person skilled in the art to determine a suitable temperature accordingly.
The novel forms of aripiprazoie of the present invention may be used alone as antipsychotic drugs or in tr?e form of a suitable pharmaceutical composition containing the novel form togestef wriih one or more suitable pharmaceuticaiiy acceptabie carriers. The pharmaceutical conaDasifcnss canzammg the novel forms of aripiprazole of the present invention are prepared
aararding ID k&cmn processes.
tocwi^yr the present invention relates to form X of aripiprazole or aripiprazole ethanol
bemsofVHiB for use as a medicament.
The novel forms of aripiprazoie are particularly useful for the treatment of schizophrenia. Therefore, the present invention also relates to the use of form X of aripiprazole or arspiprazote ethanol hernisoivate for the preparation of a medicament for the treatment of schizophrenia.
Tne present invention further relates to a pharmaceutical composition comprising an effective amount cf form X of aripiprazole or aripiprazole ethanol hernisoivate and a pharmaceuticaiiy acceptabie carrier. The pharmaceutical composition may be prepared via a wet granulation process as known in the state of the art and as described for other cr/stailne and potymorphic forms in WO 03/026659. Another suitable preparation may be forming flash-meit tablets.
The invention is further described by reference to the following examples. These examples are provided for illustration purposes only and are not intended to be limiting the present
invention in any way.

EXAMPLES
The infrared spectra are recorded using a BRUKER FTiR-Tensor 27 with diamond ATR. The XRPD ts recorded on a AXS-BRUKER X-ray powder diffractometer D-8 using the fotowing acquisition conditions: tube anode: Cu; generator tension: 40 kV; generator current: 40 mA: stan angle: 2.0° 9; end angle: 40.0° 8; step size: 0.01 ° 8; time per step: 2 seconds. Dsferen&ai scanning caionmetry (DSC) is performed with a DSC 7 (Perkin-Elmer, NorwaJk, CL, USA} usrsg tie Pyds 2.0 software. Samples are weighed into 25 fj\ Al-Pans. Dry rabogen ss used as trta purge gas (purge: 20 mi min'1).
Them&gsacmtkM'ic analyst is performed with the Thermogravimetric-System TGA-7 using tie Pyns^StxtmafB far Windows NT, (Perkin-Eimer, Norwalk, Ct., USA), 50 JJL platin-pans, nteogen ptsge- gas {sample purge: 20 mL min"1, balance purge: 40 mL min"1).
Exampka i
25 g os ahpgjrazoie Anhydrate Form A obtained as described in EP 367141 B1 are stirred in
250 rri isopncspanoi and heated at boiling until a clear solution is obtained. After cooling to
room temperature under stirring the precipitated product is filtered and dried at room
temperature under vacuum over night to give 24.12 g (96.5%) of the anhydrous polymorph
referred to herein as form X.
The form X crystals of aripiprazole anhydride obtained above provide an infrared spectrum
with peaks at 2939, 2803, 1677, 1374, 1191, 1168, 1045, 868, 822 and 736 cm*1 (Figure 1).
The XRPD patlern of form X of aripiprazole with characteristic XRPD angles, d-spacings and
*sla&tfe intensities is shown in Table 1 and in Figure 4.
Table i: X-Ray Powder Diffraction (XRPD) pattern of form X of aripiprazole. Values: interptanar spacings (dT in A, Angstroem), characteristic XRPD angles (in degrees 2-theta)
and relative intensities (in %)

Form X of anoiorazole shews a typical DSC curve at a heating rate of of 5°K/min and practscaly no mass toss in the TGA analysis. Typical thermograms of form X of aripiprazoie are shown In Rgyre 7. it can be seen that form X shows two specific endothermic peaks with onset temperatures of about 119CC and 149°C.
Exampie 2
5 g of aripiprazoie Anhydrate Form A obtained as described in EP 367141 B1 are stirred in 20 ml tetrahydrofuran and heated at boiling until a clear solution is obtained. After cooling to room temperature the suspension is stirred for additional three hours and then allowed to s*and two days in a refrigerator. The precipitated product is filtered and dried at room temperature under vacuum over night to give 2.95 g (59%) of form X of the product.
Example 3
A suspension of 7 g of aripiprazoie Anhydrate Form A obtained as described in reference example 1 of WO 03/026659 is stirred in 50 m! acetone and heated to reflux for'7.5 hours. The mixture is filtered and the insoluble solid dried in an desiccator at room temperature over night to yield 4.48 g (64%) of form X of the product.
Example 4
100 g crude aripiprazoie prepared as described in EP 367141 B1 are suspended in 1500 ml
absolute ethanol and then heated to reflux. The resulting solution is slowly cooled to room

temperature to crystallize the product. After stirring at 0°C for one hour the precipitated product is filtered and dried at room temperature under vacuum for 17 hours to give 102.7 g (97,7%) of the ethanol hemisoivate of the product. The crystals are colorless plate form. The content of ethanol in the product is about 5,0 % by weight i.e. the compound is an ethanoi heroisotvate containing half a mol of ethanol per mol aripiprazole. The e&ranof nsmtsolvaie of aripiprazole obtained above provides an infrared spectrum with peeks at 294S. 2816, 1670, 1378, 1192, 1171, 1047, 854, 830 and 746 cm'1 (Figure 2). The XF^O GatiSssr* or aripiprazole-ethanol hemisoivate with characteristic XRPD angles, d-spacaTcs and ^5Jaf&*e intensities is shown in Table 2 and in Figure 5.
Tafcie 2: X~Ray Pomder Diffraction (XRPD) pattern of aripiprazole ethanoi hemisoivate. Values: fmerpsanar spacrngs (d; in A, Angstroem), characteristic XRPD angles (in degrees 2-tfieta) s&td resatr&a ^itensriies (in'%)

Aripiprazole ethanol hemisoivate shows a typical endothermic curve in TGA and DSC analysis at a heating rate of of 5°K/min. A typical thermogram of aripiprazole ethanol hemisoivate is shown in Figure 8. It can be seen that aripiprazole ethanol hemisoivate shows an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic peaks with onset temperatures of about 139CC and 148.5°C.
Example 5

100 g crude aripiprazofe prepared as described in EP 367141 B1 are suspended in 1500 mi absolute ethanol and then heated to reflux. The resulting solution Is slowly cooled to room temperature to crystallize the product. After stirring at 0°C for one hour the precipitated
product Is ^tBTBa and dried at 50°C under vacuum for 2 hours.
Example 6
15 g or afp$5taztfc Anhydrate Form A obtained as described in EP 367141 B1 is added to 1900 im meShanoi and the mixture is heated to reflux to get a clear solution. The solution is ihert skmfy coded ID room temperature, stirred for another two hours and allowed to stand in a rsfsksersiDf lor several days. The precipitated crystals are isolated by suction and dried at nxm tenperaiure m vacuo to yield 15.2 g (93.7%) methanol solvate of the product. The crysfeis am cosoness plate form. Tne content of methanol in the product is about 6,7% by weighs Le. the compound is a methanol monosolvate containing one mol of methanol per rnd arpiprazoie.
The methanes solvate of aripiprazole obtained above provides an infrared spectrum with peaks at 2942. 2814. 1671, -1377, 1199, 1174, 1037, 857, 824 and 746 cm'1 (Figure 3). The XRPD pattern of aripiprazole methanol solvate with characteristic XRPD angles, d-spac^>gs and relative intensities is shown in Table 3 and in Figure 6.
Table 3: X-Ray Powder Diffraction (XRPD) pattern of aripiprazole methanol solvate. Values: Interplanar spadngs (d, in A, Angstroem), characteristic XRPD angles (in degrees 2-theta) and reistjve intensities (in %)

A®pa&s&zx$& inefenof solvate shows a typical endothermic curve in TGA and DSC analysis M a fusing rate of of STC'min. A typical thermogram of aripiprazole methanol solvate is shamn m P«^s s. k can be seen that aripiprazole methanol solvate shows an endothermic peak wifc an onset iafm>erature of about 113°C followed by an exothermic event and two
ando^erriic peate with onset temperatures of about 139°C and 148°C.
Eseampe 7
Igd crude aripiprazole Anhydrate Form A obtained as described in EP 367141 B1 is
dfesotved in 10 rri cfchloromethane. The solution is diluted with 40 ml methanol and then
allowed to stand \n a refrigerator overnight. The precipitated crystals are isolated by suction
and dried at room temperature in vacuo to yield 0.93 g (86.0%) methanol solvate of the
product
Example 8
5gd the ethanoi hemisolvate of example 4 are recrystallized from 55 ml isopropanol using
seed crystals obtained in example 1 above. The yield is 4.5 g (94.6%) of form X of
anpprazole.
Example S
Examotz 8 is repeated using 3 g of the methanol solvate obtained in example 5 above instead of the ethanoi hemisolvate. The yield is 2.7 g (96.8%) of form X of aripiprazole.
Example 10
Example 8 is repeated but instead of using the ethano! hemisolvate as starting material 5 g erf the aripiprazole hydrate obtained as described in reference example 3 of WO 03/026659 ss used. The yield is 4.5 g (93.6%) of form X of aripiprazole.
Example 11

5 g of aripiprazole Anhydrate Form A obtained as described in EP 367141 B1 and 0.5 g of form X of aripiprazole are suspended in 55 mi isopropanol and heated at 50°C overnight and then stirred at room temperature for four days. The unsoluble part of the reaction mixture is ootecSed by f3tratfc>n and dried in vacuo at room temperature over night to give 4.6 g (92%) of form X of anpiprazoie.
Ex&rnpte 12
5 g rf amaprazDie Anhydrate Form A obtained as described in EP 367141 B1 are suspended
mSDrru e#sano» and s^tBd at room temperature for three hours. The solid is filtered and
*ed ^ rtaom lemperHfure under vacuum for 17 hours to give 5.0 g (95,1 %) of the ethanol
hesnssdirae of arcrarazole.
Exarc^3£e 13
A suspension or 33 g of anpiprazole Anhydrate Form A obtained as described in EP 367141 B^ m 1000 rrs of isopropanol is heated to reflux temperature. The resulting clear solution is coofed down to 55^ under stirnng and then seeded with 0,3 g of aripiprazole form X. After further cooling down to 60°C a second portion of 0,3 g seeds of aripiprazole form X are added. The mixture is then sfowiy cooied down to 50°C in one hour and then from 50°C to 0°C in one hour. After stirring at 0°C for one hour, the obtained suspension is reheated to 50°C: stirred at this temperature for one or two hours, then again cooied to 0°C. After stirring foe one hour the precipitated product is filtered and dried in vacuo at room temperature over rwgtei or at 60CC for 3 hours to yield 31,8 g (94,5%) of form X of aripiprazole
£;xarnpie 14
3 g anpiprazofe hydrate, obtained as described in example 22 are suspended in 80 ml isopropanol, seeded with 0,5 g aripiprazole form X and stirred at 50°C over night. The suspension is cooied to room temperature, filtered and dried at room temperature under *actium for 17 hours to give 4,61 g (85,5%) aripiprazole form X .
Example 15
Example 14 is repeated using 5 g of the ethanol hemisoivate as starting material instead of
the hydrate. The yield is 4,51 g (84,3%) of form X of aripiprazoie.

Example 16
2 g aripiprazoie methanol solvate obtained as described in example 6 are suspended in 30 ml isopropanol. seeded with 0,5 g aripiprazoie form X and stirred at 50°C over night. The suspension is coo?ea to room temperature, filtered and dried at room temperature under vacuum *or 17 hours tc grve 1 f94g (77,2%) aripiprazoie form X .

Claims:
1. Form X of ariprprazoJe charactenzed by an X-ray powder diffraction pattern with peaks at 10.0. 11.6, 15.7: 15.3, 18.5, 20.4, 21.8, 22.2 and 23.3 degrees 29.
2. Forr: X of anpspnazDie of daim 1 characterized by an X-ray powder diffraction pattern substernal* in accordance with Table 1 and Figure 4.
3. Form X or arcaprs2ote of daim 1 characterized by an infrared spectrum substantially in
accordance with Figure 1.
4. Form X of aspprH2oie of claim 1 characterized by two endothermic peaks with onset temperatLrres of about 119°C and 149°C at a heating rate of 5°K/min in in differential scanrwig calorsraeiry.
5. Arp£*razoie ethanoi hemisoivate characterized by an X-ray powder diffraction pattern with peaks at 17.4. 18.1, 19.6, 23.3 and 27.9 degrees 26.
6. Ariprprazoie ethanoi hemisoivate of claim 5 characterized by an X-ray powder diffraction pattern substantially in accordance with Table 2 and Figure 5.
7. Aripiprazofe ethanoi hemisoivate of claim 5 characterized by an infrared spectrum substanciaHy ?n accordance with Figure 2.
a. Anpiprazofe ethanoi hemisoivate of claim 5 characterized by an endothermic peak with an onset temperature of about 97°C followed by an exothermic event and two endothermic zzaaks with onset temperatures of about 139°C and 148°C at a heating rate of 5°K/min in
differential scanning caiorimetry.
9 AricwrazGle methanol solvate characterized by an X-ray powder diffraction pattern with peaks at 11.5, 17.3, 18.5, 19.8, 23.1, 24.4 and 26.9 degrees 29.
10. Aripip*a2ote methanol solvate of claim 9 charactenzed by an X-ray powder diffraction
pattern substantially in accordance with Table 3 and Figure 6.

11. Aripiprazole methanol solvate of claim 9 characterized by an infrared spectrum substandaiiy in accordance with Figure 3.
12. Aripiprazote methanol solvate of claim 9 characterized by an endothermic peak with an onset lemperaiure of about 113CC followed by an exothermic event and two endothennic peaks mfo onset lemperaiures of about 139CC and 148°C at a heating rate of 5°K/min in
m tiferasiiija£ scsarmng caJorimetry.
13. Process for preparing form X of aripiprazole, comprising the steps of:
a) dissolving mkm^szD^e m a suitable solvent by heating
b) siowfy cocwig the soiutkm to room temperature or below to effect crystallization
c) QDfcnafy teoiassng crystalline form X of aripiprazole.

14. Process acconJng to claim 13, wherein the form used in step a) is aripiprazole ethanol hemssoivate and/or aripiprazole methanol solvate and/or aripiprazole hydrate.
15. Process for preparing form X of aripiprazole according to claim 13 or claim 14, wherein the solvent rn steo a) is acetone, tetrahydrofuran or 2-propanol and/or in step b) seed crystals of iorrr X of aripiprazoie are added.
16- :>rooass according tc claim 15, wherein the solvent is 2-propanoi and the preferred anoeraiure range is about 40°C to about 70°C.
17. Process for preparing fortft-X ofaripiprazole-Gharacterizedin that a suspension of- ~--■— anptprazole in a suitable solvent is seeded with crystals of form X and the suspension is
stirred at a suitable temperature in order to effect transformation of the used form of anoiprazole into form X.
* a Process according to claim 17, wherein the solvent is selected from 2-propanol, acetone,
"-octane! or 1-propanoL
19. Process according to claim 17. wherein the solvent is 2-propanol and the preferred temoersture ranee is about 40°C to about 60°C.

20. Process for preparing aripiprazofe ethanol hemisolvate, comprising the steps of: a) dissolving aripiprazole in ethanol by heating
h) stowfy coding the solution to room temperature or below to effect crystallization c) isolating the crystalline ethanol hemisolvate cf) drying the ethanol hemisolvate at a temperature below about 60°C.
21- Process kx pRgeanog arpipcazole ethanol hemisolvate, comprising the steps of:
ai dissafemg wkme&zalB in a solvent in which aripiprazofe is soluble at room temperature
trt dttufeg the soiuson wfth ethanol
cl asoiaing #se crys&Bne ethanol hemisolvate
ri> sfcyang fie etani hemtsohrate at a temperature below about 60°C.
22 Process for pre&armg aripiprazole ethanof hemisolvate characterized in that a suspension ot an&pmzole ki ethanoj is stirred at a suitable temperature in order to effect transforrnatjon ct tine used form of aripiprazole into aripiprazole ethanol hemisolvate.
23. Process for preparing aripiprazole methanol solvate, comprising the steps of:
a) cfissolving aripiprazole in methanol by heating
b) slowty cooling the solution to room temperature or below to effect crystallization
c) isolating the crystalline methanol solvate
d^ crying the methanol solvate at a temperature below about 60DC.
2*. >~3cess for preparing aripiprazole methanol solvate, comprising the steps of:
&} cissoMog arip^azoLeJa-a-Soivent-in-whrch aripiprazole is soluble at room temperature
b) (Muting the solution with methanol
c> isolating the crystalline methanol solvate
x ±wig the methanol solvate at a temperature below about 60°C.
25.. Process according to claim 21 or claim 24, wherein the solvent is selected from rnefrryiene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide or N-rneshyipyf rolidon e.

28. Process for preparing aripiprazoie methanol solvate characterized in that a suspension of aripiprazoie in methanol is stirred at a suitable temperature in order to effect transformation of the used form of aripiprazoie into aripiprazoie methanol solvate.
27. Form X of anp&razoie or aripiprazoie ethanol hemisoivate for use as a medicament
2& Use of ferm X or anck&szoke or aripiprazoie ethanoi hemisoivate for the preparation of a
medkss&ert tor tnse treatment of schizophrenia.
2S. Ftsarmacei^3ca§ ^ornoostton comprising an effective amount of form X of aripiprazoie or
assapesaDie etesid hemisofvaie and a pharmaceuticaify acceptable carrier.

Documents:

3273-CHENP-2007 CORRESPONDENCE OTHERS 09-07-2014.pdf

3273-CHENP-2007 CORRESPONDENCE OTHERS 18-06-2014.pdf

3273-CHENP-2007 CORRESPONDENCE OTHERS 25-07-2014.pdf

3273-CHENP-2007 POWER OF ATTORNEY 18-06-2014.pdf

3273-CHENP-2007 AMENDED CLAIMS 04-06-2014.pdf

3273-CHENP-2007 AMENDED CLAIMS 18-07-2014.pdf

3273-CHENP-2007 AMENDED PAGES OF SPECIFICATION 04-06-2014.pdf

3273-CHENP-2007 CORRESPONDENCE OTHERS 24-09-2013.pdf

3273-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 18-07-2014.pdf

3273-CHENP-2007 EXAMINATION REPORT REPLY RECIEVED 04-06-2014.pdf

3273-CHENP-2007 FORM-1 04-06-2014.pdf

3273-CHENP-2007 OTHER PATENT DOCUMENT 04-06-2014.pdf

3273-CHENP-2007 OTHER PATENT DOCUMENT 1 04-06-2014.pdf

3273-CHENP-2007 OTHERS 04-06-2014.pdf

3273-CHENP-2007 (FORM 3).pdf

3273-CHENP-2007 (POR PETITION).pdf

3273-CHENP-2007 AF3 PETITION).pdf

3273-CHENP-2007 FORM-3 25-07-2014.pdf

3273-chenp-2007-abstract.pdf

3273-chenp-2007-claims.pdf

3273-chenp-2007-correspondnece-others.pdf

3273-chenp-2007-description(complete).pdf

3273-chenp-2007-drawings.pdf

3273-chenp-2007-form 1.pdf

3273-chenp-2007-form 26.pdf

3273-chenp-2007-form 3.pdf

3273-chenp-2007-form 5.pdf

3273-chenp-2007-pct.pdf

« Previous Patent

Next Patent »

Patent Number

262892

Indian Patent Application Number

3273/CHENP/2007

PG Journal Number

39/2014

Publication Date

26-Sep-2014

Grant Date

22-Sep-2014

Date of Filing

25-Jul-2007

Name of Patentee

SANDOZ AG

Applicant Address

LICHTSTRASSE 35,CH-4056 BASEL,

Inventors:

#	Inventor's Name	Inventor's Address
1	BRAUN, DORIS	KNEIPPSTRASSE 5, A-6850 DOMBIRN,
2	GRIESSER, ULRICH	AUSSERKRISTEN 11A, A-6094 AXAMS, AUSTRIA
3	TESSADRI, RICHARD	KIEBACHGASSE 14, A-6020 INNSBRUCK, AUSTRIA
4	WIESER, JOSEF	SIEGFELD 92, A-6403 POLLING, AUSTRIA
5	LENGAUER, HANNES	AHORNWEG 22, A-6250 KUNDL, AUSTRIA

PCT International Classification Number

C07D 215/22

PCT International Application Number

PCT/EP06/00725

PCT International Filing date

2006-01-27

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	05001638.5	2005-01-27	EUROPEAN UNION