WO2006077584A2

WO2006077584A2 - New crystalline forms of aripiprazole

Info

Publication number: WO2006077584A2
Application number: PCT/IL2006/000076
Authority: WO
Inventors: Itai Adin; Carmen Iustain
Original assignee: Chemagis Ltd.
Priority date: 2005-01-18
Filing date: 2006-01-18
Publication date: 2006-07-27
Also published as: WO2006077584A3

Abstract

The present invention provides novel crystalline forms of Aripiprazole and processes for their preparation.

Description

NEW CRYSTALLINE FORMS OF ARIPIPRAZOLE

FIELD OF THE INVENTION

The present invention relates to solid state chemistry and more particularly to novel crystalline forms of Aripiprazole and to processes for their preparation.

BACKGROUND OF THE INVENTION

Aripiprazole (Compound 1 below), also known by its chemical names 7-(4-(4- (2,3-dichlorophenyl)-l-piperazinyl)-butoxy)-3,4-dihydro carbostyril or 7-(4-(4-(2,3- dichlorophenyl)-l-piperazinyl)-butoxy)-3,4-dihydro-2(liϊ)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia.

1

Aripiprazole has shown efficacy in acutely relapsed and longer term schizophrenia and schizoaffective disorder. Aripiprazole is marketed in the United States as Ability™ by the Bristol-Myers Squibb Company.

The synthetic route for obtaining Aripiprazole and structurally related carbostyril derivatives, was first described in U.S. Patent No. 4,734,416 and later in

U.S. Patent No. 5,006,528. The synthetic route disclosed in U.S. Patent No. 5,006,528 includes a crystallization step from ethanol. The reported melting point of the resulting crystals was 139-139.5 ⁰C.

U.S. Patent Application No. 2004/0058935 (hereinafter the '935 application) provides new crystalline modifications of Aripiprazole, including a hydrated form, and some anhydrous modifications. It is stated in the '935 application that Aripiprazole anhydride crystals exist as type I and type II crystals; the type I can be prepared by recrystallization of Aripiprazole from an ethanol solution, or by heating Aripiprazole hydrate at 80°C; and the type II crystals of Aripiprazole anhydride can be prepared by heating the type I crystals of Aripiprazole anhydride at 130° C to 140°C for 15 hours.

The '935 application teaches that Aripiprazole is obtained as a highly hygroscopic product. Hygroscopic solids might change their physical and chemical characteristics due to the increased content of water; hence hygroscopicity should be avoided in pharmaceutical products.

Table 1 below presents the various crystalline forms of Aripiprazole, preparation procedures and some characteristic XRPD peaks thereof, as taught in the '935 application.

Table 1 - Characteristic X-ray powder diffraction peaks and preparation procedures for the Ari i razole forms accordin to the '935 a lication.

Additional forms of Aripiprazole are further described in application WO

2004/083183 (hereinafter the '183 application). Two crystalline forms of Aripiprazole and four forms of Aripiprazole hydrochloride are taught in this patent application. Table 2 below presents characteristic XRPD peaks and preparation procedures of the Aripiprazole crystalline forms taught in the '183 application. As can be seen in Tables 1 and 2, it appears that the crystalline forms I and II of the '183 application are identical to forms D and A, taught in the '935 application. Table 2 - Characteristic powder diffraction peaks and preparation procedures of the Aripi razole cr stalline forms accordin to the ' 183 a lication.

Other polymorphs of Aripiprazole (which are referred to as forms I, III and IV) are disclosed in application WO 2004/106322. Application WO 2005/058835 (hereinafter the '835 application) further discloses Aripiprazole forms I, II, VI, VIII, X, XI, XII, XrV, XIX, XX. According to the teachings of the '835 application, Aripiprazole form XII is prepared inter alia by crystallization from ethanol (see example 5 in the '835 application), affording "a dry Aripiprazole crystalline form". Noteworthy, ethanol solvates which are the object of the present invention are not mentioned in the '835 application. Application WO 2005/009990 discloses Aripiprazole forms III, IV and V, and application US 2005/0277650 discloses a crystalline hydrate of Aripiprazole and a process of preparing this hydrate form.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a novel crystalline form of Aripiprazole, referred to herein as Aripiprazole form AETl. This unique form is a stable ethanol hemi-solvate, containing about 5 ± 2 weight percents ethanol. Upon heating to about 100 ⁰C, Aripiprazole form AETl undergoes a transition to Aripiprazole form B (disclosed in the '935 application), which involves loss of ethanol.

TGA exemplary curve at 10 °C/min of Aripiprazole form AETl, presented in Figure 4, shows a sharp weight loss of 5.8 % around 100 ⁰C, which is typical of a solvated form. In accordance with the present invention, Aripiprazole form AETl is produced by crystallization from ethanol, with or without further treatment. That is, upon crystallization, the filtered crystals can be left in the open air, so as to allow residual amount of ethanol to freely evaporate, or, alternatively, can be gently dried, optionally under reduced pressure, at relatively low temperature (e.g., not exceeding 50 ⁰C).

In another aspect, the present invention provides a novel crystalline form of Aripiprazole, referred to herein as Aripiprazole form AETH. This unique form is a stable ethanol solvate containing about 2-3 % ethanol, which corresponds to an Aripiprazole: ethanol ratio of 4:1.

Aripiprazole form AETH is obtained by heating Aripiprazole form AETl to temperatures below the minimum temperature of the transition of Aripiprazole form AETl to Aripiprazole form B, e.g., lower than 100 ⁰C, more preferably lower than 90 ⁰C, and even more preferably lower than 80 ⁰C. The observed melting point of Aripiprazole form AETH is about 140 ⁰C, due to the phase transition to Aripiprazole form B during the melting point measurement procedure.

According to the present invention, the two ethanol solvates of Aripiprazole, namely Aripiprazole form AETl and Aripiprazole form AETH exhibit extended stability, as depicted in figure 9 and Table 5. The data of the experiments demonstrate that Aripiprazole form AETH has better stability, which makes this form most suitable for pharmaceutical compositions.

In yet another aspect, the present invention provides additional novel crystalline forms of Aripiprazole, referred to herein as forms AMI and AM2. Surprisingly, it was found that crystallization from methanol provides solvated forms of Aripiprazole containing either 1 or 2 mole equivalents of methanol per one mole of

Aripiprazole.

Aripiprazole form AM2 was obtained only once, using the same method of obtaining form AMI but without drying the crystals, and it was characterized by using the traditional methods. It produces unique powder diffraction pattern, and unique

DSC and TGA curves, typical of a solvated form (see, Figures 12 and 13). The spectral data shows that Aripiprazole form AM2 is significantly different from the related form AMI. Aripiprazole form AM2 is thermodynamically less stable than form AMI at room temperature, and is spontaneously transformed into Aripiprazole form AMI after few weeks. Fast transformation of Aripiprazole form AM2 to form

AMI was achieved by heating Aripiprazole form AM2 at a temperature higher than room temperature. BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying figures.

Figure 1 - Powder X-ray diffraction pattern of Aripiprazole form AETl. Figure 2 — Infra-red spectrum of Aripiprazole form AETl .

Figure 3 - DSC curve of Aripiprazole form AETl.

Figure 4 - TGA curve of Aripiprazole form AETl .

Figure 5 - Powder X-ray diffraction pattern of Aripiprazole form AETH.

Figure 6 - Infra-red spectrum of Aripiprazole form AETH. Figure 7 - DSC curve of Aripiprazole form AETH.

Figure 8 - TGA curve of Aripiprazole form AETH.

Figure 9 - Stability curves of Aripiprazole forms AETl and AETH

Figure 10 - Powder X-ray diffraction pattern of Aripiprazole form AM2.

Figure 11 - Infra-red spectrum of Aripiprazole form AM2. Figure 12 - DSC curve of Aripiprazole form AM2.

Figure 13 - TGA curve of Aripiprazole form AM2.

Figure 14 - Powder X-ray diffraction pattern of Aripiprazole form AMI.

Figure 15 - Infra-red spectrum of Aripiprazole form AMI.

Figure 16 - DSC curve of Aripiprazole form AMI . Figure 17 - TGA curve of Aripiprazole form AMI .

Figure 18 — Powder X-ray diffraction pattern of dry Aripiprazole form B (see example

5).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present inventors have now surprisingly uncovered novel crystalline forms of Aripiprazole, characterized by improved properties, and particularly minimized or no hygroscopicity, as compared with prior art crystalline Aripiprazole. According to one aspect of the present invention, there is provided an ethanol solvate of Aripiprazole, which is obtained by crystallization from ethanol, either under air or under nitrogen atmosphere. This crystalline form is referred to herein as form AETl. Aripiprazole form AETl differs from the crystalline form disclosed in the '935 application, which is a hydrate obtained by crystallization from a wateπethanol mixture containing significant amounts of water, e.g., ethanol:water ratio of 8:2.

According to the present invention, Aripiprazole form AETl produces unique powder X-ray diffraction pattern, presented in Figure 1 and in Table 3 below. The diffraction peaks at 8.7, 10.2, 12.6, 18.1, 19.6 and 24.5 ±0.2 degrees 2Θ are most characteristic of this form.

Table 3 - Aripiprazole form AETl - Powder x-ray diffraction peak positions and intensities

Aripiprazole form AETl further produces a unique infra-red spectrum, presented in Figure 2. The pattern created by the bands in the range of 1000-1200 cm¹ is most characteristic of this form.

Aripiprazole form AETl is produced by crystallization from ethanol, with or without further treatment. That is, upon crystallization, the filtered crystals can be left in the open air, so as to allow residual amount of ethanol to freely evaporate, or, alternatively, can be gently dried, optionally under reduced pressure, at relatively low temperature (e.g., not exceeding 50 ⁰C).

Aripiprazole form AETl is an ethanol hemi-solvate, containing about 5 ± 2 weight percents ethanol. Upon heating to about 100 ⁰C, Aripiprazole form AETl undergoes a transition to form B (disclosed in the '935 application), which involves dissociation of ethanol.

TGA exemplary curve at 10 °C/min of Aripiprazole form AETl, presented in Figure 4, shows a sharp weight loss of 5.8 % around 100 ⁰C, which is typical of a solvated form.

A related endothermic peak around 100 ⁰C was also observed in the DSC curve, as shown in Figure 3, followed by melting of the in-situ created Aripiprazole form B.

Further heating of the DSC sample did not result in form C (disclosed in the '935 application) and a melting point of about 150 ⁰C was not observed as reported for Aripiprazole form C.

The observed melting point of Aripiprazole form AETl is about 139-140 ⁰C, which is similar to the reported melting point of the crystals obtained from ethanol in U.S. Patent No. 5,006,528. According to the DSC and TGA curves of Aripiprazole form AETl, it may be taught that this melting occurs after a phase transition during which ethanol is emitted and a crystalline form similar to Aripiprazole form B is obtained. A similar phenomenon is observed for the hydrous form, which explains the similarity in the observed melting points, since the discharge of solvents is usually not observed during traditional melting point measurements. The dry Aripiprazole form B may be obtained by heating Aripiprazole form

AETl under vacuum to 80 ⁰C for about 24 hours, as described in example 5. The powder X-ray diffraction pattern of the dry Aripiprazole form B is depicted in Figure 18.

Aripiprazole form AETl was left for 24 hours in a desiccator at 60 ⁰C and 100 % relative humidity, with no significant record of weight change.

In another aspect, the present invention provides a novel crystalline form of Aripiprazole, referred to herein as Aripiprazole form AETH. This unique form is a stable novel ethanol solvate containing about 2-3 % ethanol, which corresponds to an Aripiprazole:ethanol ratio of 4:1. The Aripiprazole form AETH produces unique powder X-ray diffraction pattern, presented in Figure 5 and in Table 4 below. The strong diffraction peaks at 8.6, 10.1, 11.0, 16.6, 18.1, 19.3, 19.6, 20.3, 22.1, 23.1 and 24.4 ±0.2 degrees 2Θ are most characteristic of this form. Table 4 - Aripiprazole form AETH - Powder x-ray diffraction peak positions and intensities

The infra-red spectrum of Aripiprazole form AETH is presented in Figure 6.

Aripiprazole form AETH can be prepared by drying form AETl at a temperature lower than the transition temperature (about 100 ⁰C), preferably lower than 90 ⁰C, and more preferably at 80 ⁰C, during a time period longer than two hours.

Upon heating to a temperature higher than 100 ⁰C, Aripiprazole form AETH undergoes a transition to Aripiprazole form B.

A TGA curve of Aripiprazole form AETH at 10 °C/min, presented in Figure 8, shows a typical sharp weight loss around 100 ± 10 ⁰C, corresponding to discharge of ethanol.

A related endothermic peak at about 95 ± 5 ⁰C was observed in the DSC curve of this form, presented in Figure 7, followed by melting of the in-situ created Aripiprazole form B. Aripiprazole Form C was not produced by further heating the DSC sample.

Form AETH was left for 24 hours in a desiccator at 60 ⁰C and 100 % relative humidity, with no significant record of weight changes. According to the present invention, the two ethanolate forms of Aripiprazole, namely Aripiprazole form AETl and Aripiprazole form AETH exhibit extended stability, as depicted in figure 9. The data of the experiments, which were carried out at 4O⁰C, demonstrate that Aripiprazole form AETH has better stability, which makes this form most suitable for pharmaceutical compositions.

Table 5 summarizes the stability tests which were carried out with Aripiprazole forms AETl and AETH, detailing the current stability results of the two Aripiprazole solvates at the experimental temperatures of 25⁰C and 3O⁰C.

According to the data presented in Table 5, Aripiprazole form AETH has better stability at the two experimental temperatures. There are changes in the XRPD spectra of the Aripiprazole form AETl although it still contains about 4% ethanol after six months.

Table 5 - Stability tests with Aripiprazole forms AETl and AETH

According to another aspect of the present invention, there are further provided Aripiprazole forms AM2 and AMI. Aripiprazole form AM2 was obtained only once, using the same method of obtaining form AMI but without drying the crystals, hence form AM2 can be called a "disappearing polymorph", in analogy to the Ritonavir case.

Ritonavir is an anti-AIDS drug, manufactured and marketed by Abbott Laboratories, which was initially marketed as a sole polymorphic form. About two years after entering the market it was surprisingly discovered that several Ritonavir lots contained a second polymorphic material (which is now designated as form II) having reduced solubility, which forced Abbott Laboratories to withdraw the capsules from the market for almost a year and to introduce an oral solution instead. [See for example an article by S.L.Morissette et al., in Proceedings of the National Academy of Sciences of the United States of America, Vol. No. 5, 2180-2184 (2003)]. Aripiprazole form AM2 was characterized by using the traditional methods.

According to one embodiment of this aspect of the present invention, Aripiprazole form AM2 produces unique powder diffraction pattern, and unique DSC and TGA curves, typical of a solvated form (see, Figures 12 and 13). The spectral data shows that Aripiprazole form AM2 is significantly different than the related form AMI. Aripiprazole Form AM2 is thermodynamically less stable than form AMI at room temperature, and is spontaneously transformed into Aripiprazole form AMI after few weeks. Fast transformation of Aripiprazole form AM2 to form AMI was achieved by heating Aripiprazole form AM2 at a temperature higher than room temperature. According to the present invention, Aripiprazole form AM2 produces a unique powder X-ray diffraction pattern, presented in Figure 10 and in Table 6 below. The strong diffraction peaks at 4.3, 8.5, 16.9, 19.2, 20.6 and 21.7 ±0.2 degrees 2Θ are most characteristic of this form.

Table 6 - Aripiprazole form AM2 - Powder x-ray diffraction peak positions and intensities

Aripiprazole form AM2 produces a unique infra-red spectrum, presented in Figure 11. The pattern created in the range of 750-900 cm^"1 is most characteristic of this form. Aripiprazole form AM2 is a solvate, containing about 13 % by weight of methanol (2:1 ratio methanol: Aripiprazole). Upon heating to 50-90 ⁰C, Aripiprazole form AM2 undergoes a transition to form AMI, which involves dissociation of one mole equivalent of methanol from the crystalline form.

A TGA exemplary curve of Aripiprazole form AM2, presented in Figure 13, shows a weight loss of about 13.5 % in the temperature range of 80- 150 ⁰C.

The DSC curve of Aripiprazole form AM2, presented in Figure 12, shows two major peaks at the said temperature range: one sharp peak at abount 90 ⁰C and a second broad peak around 120-140 ⁰C, each related to the discharge of one mole equivalent of methanol. Aripiprazole form B was not produced during the DSC measurement thereof. A melting point of about 140 ⁰C, reported for Aripiprazole form B, was not observed in the preparation of Aripiprazole form AM2.

According to another embodiment of this aspect of the present invention, there is provided Aripiprazole form AMI, which produces unique powder diffraction pattern, presented in Figure 14 and in Table 7 below. The diffraction peaks at 9.4, 10.6, 18.2, 18.5 and 24.3 ±0.2 degrees 2Θ are most characteristic of this form.

Aripiprazole form AMI produces a unique infra-red spectrum, presented in Figure 15. The pattern created in the range of 950-1100 cm^'1 is most characteristic of this form.

Aripiprazole form AMI can be produced by crystallization from methanol. Aripiprazole form AMI is a mono-solvate containing about 6.5 ± 1% by weight of methanol (1:1 ratio methanol :Aripiprazole). Upon heating to 120-140 ⁰C₅ Aripiprazole form AMI undergoes a transition to form B, which involves dissociation of one mole equivalent of methanol therefrom.

Table 7 - Aripiprazole form AMI - Powder x-ray diffraction peak positions and intensities

A TGA curve of this form, presented in Figure 17, shows a weight loss of about 6.5 % at a temperature between 120-140 ⁰C, related to the discharge of methanol.

The DSC curve of Aripiprazole form AMI, presented in Figure 16, shows a sharp endothermic peak around 110-120 ⁰C₅ related to the discharge of methanol, followed by melting of the in-situ created Aripiprazole forms B (140 ⁰C) and Aripiprazole form C (150 ⁰C). Aripiprazole form AETl was left for 24 hours in a desiccator at 60 ⁰C and 100

% relative humidity, with no significant record of weight change.

The disclosure of the methanol solvates of the present invention contradicts the observations described in the '183 application.

Aripiprazole form AMI is stable at room temperature. Upon heating and/or vacuum drying it transforms into a crystalline modification similar to the Aripiprazole form B described above. The novel crystalline forms of Aripiprazole can be efficiently formulated in pharmaceutical compositions and used for treating medical conditions, and particularly psychotic disorders such as schizophrenia, for which treatment with aripiprazole is beneficial. Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention, as delineated hereinabove and as claimed in the claims section below, finds experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non-limiting fashion.

INSTRUMENTSAND METHODS

The novel crystalline forms of Aripiprazole, described hereinabove, have been characterized by powder X-ray diffraction, which produces a fingerprint of the particular crystalline form. Measurements of 2Θ values are typically accurate to within ± 0.2 degrees. The X-ray diffraction data were acquired using a PHILIPS X- ray diffractometer model PW1050-70. System description:

voltage 4OkV, current 28 niA, diversion slit=l°, receiving slit=0.2mm, scattering slit=l° with a graphite monochromator. Experiment parameters: pattern measured between 2Θ = 4° and 2Θ = 36° with 0.05° increments; count time was 0.5 second per increment

The novel crystalline forms of Aripiprazole described herein were further characterized by infra-red (IR) spectroscopy, run on Nicolet Furrier-transform infrared spectrometer model Avatar 360, with Omnic software version 5.2. All samples were run as KBr disks. The infra-red measurements are accurate to within 4 cm^"1. The novel crystalline forms of Aripiprazole described herein have been further characterized by differential scanning calorimetry (DSC), run on TA instruments model QlOOO, with Universal software version 3.88. Samples were analyzed inside crimped 40 μl Aluminum pans. Heating rate for all samples was 10 °C/min. The novel crystalline forms of Aripiprazole have been further characterized by thermogravimetric analysis, run on TA instruments model Q500, with universal software version 3.88. Samples were run inside platinum baskets at heating rate of 10 °C/min.

EXAMPLE l

Preparation of Aripiprazole form AETl

In a 100 ml three-necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, Aripiprazole (1.3 grams) was dissolved in 15 ml of ethanol. The solution was heated using an oil bath to reflux, and left to cool down to 25 ⁰C. The resulting crystals were left to dry inside the hood. 1.1 grams (85 % yield) of Aripiprazole form AETl were obtained.

EXAMPLE ! Preparation of Aripiprazole form AETH

Aripiprazole form AETl₅ prepared as described in Example 1, was heated to 80 ⁰C for about 30 hours.

EXAMPLE 3

Preparation of Aripiprazole form AMI

In a 1000 ml three-necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, Aripiprazole (4 grams) was dissolved in 600 ml of methanol. The solution was heated, using an oil bath, to reflux, and left to cool down to 25 ⁰C. The resulting crystals were left to dry in a hood. 3.0 grams (75 % yield) of Aripiprazole from AMI were obtained.

EXAMPLE 4 Preparation of Aripiprazole form AM2 In a 1000 ml three-necked round bottom flask equipped with a reflux condenser, a thermometer and a magnetic stirrer, Aripiprazole (4 grams) was dissolved in 600 ml of methanol. The solution was heated, using an oil bam, to reflux, and left to cool down to 25 ⁰C to obtain 3.0 grams of Aripiprazole form AM2 in 75 % yield. EXAMPLE 5 Preparation of dry Aripiprazoleform B

Aripiprazole form AETl, prepared as described in Example 1, was heated under vacuum to 80 ⁰C for about 24 hours. Aripiprazole form B was obtained, having a powder X-ray diffraction pattern, as depicted in Figure 18.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. A 7-(4-(4-(2,3-dichlorophenyl)-l-piperazinyl)-butoxy)-3,4-dihydro- 2(lH)-quinolinone (Aripiprazole) crystalline form AETl, characterized by a powder X-ray diffraction pattern, substantially as depicted in Figure 1 and Table 3, that exhibits diffraction peaks at 8.0, 8.7, 10.2, 10.6, 12.0, 12.6, 13.1, 14.1, 15.4, 17.4, 18.1, 18.7, 19.6, 20.1, 20.5, 21.5, 23.1, 24.5, 25.3, 26.3, 26.7, 27.0, 27.8, 28.5, 29.3 and 30.2 ±0.2 degrees 2Θ.

2. The crystalline Aripiprazole form AETl of claim 1, further characterized by an infra-red (IR) spectrum with a unique pattern at 1000-1200 cm^'1, substantially as depicted in Figure 2.

3. The crystalline Aripiprazole form AETl of claim 2, further characterized by a DSC curve with sharp endothermic peak around 100 ⁰C, substantially as depicted in Figure 3.

4. The crystalline Aripiprazole form AETl of claim 3, further characterized by a TGA curve, substantially as depicted in Figure 4.

5. The crystalline Aripiprazole hemi-solvate form AETl of claim 4, further characterized by diminished hygroscopicity and comprising an ethanol content of about 3-7 weight percent.

6. A process for preparing Aripiprazole crystalline form AETl, the process comprising: providing Aripiprazole; and crystallizing said Aripiprazole from an ethanol solution.

7. A stable crystalline Aripiprazole form AETH, characterized by a powder X-ray diffraction pattern, substantially as depicted in figure 5 and Table 4, that exhibits diffraction peaks at 8.6, 10.1, 11.0, 16.6, 18.1, 19.3, 19.6, 20.3, 22.1, 23.1 and 24.4 ±0.2 degrees 2Θ.

8. The stable crystalline Aripiprazole form AETH of claim 7, further characterized by an infra-red (IR) spectrum substantially as depicted in Figure 6.

9. The stable crystalline Aripiprazole form AETH of claim 8, further characterized by a DSC curve, substantially as depicted in Figure 7.

10. The stable crystalline Aripiprazole form AETH of claim 9, further characterized by a TGA curve, substantially as depicted in Figure 8.

11. The stable crystalline Aripiprazole solvate form AETH of claim 10, further characterized by diminished hygroscopicity and comprising an ethanol content of about 2-3 weight percent, which corresponds to an Aripiprazole: ethanol ratio of 4:1.

12. The crystalline Aripiprazole form AETH of claim 11, further characterized by increased stability for a period of at least 3 months, preferably for 6 months, as depicted in table 5 and in Figure 9.

13. A process for preparing the Aripiprazole crystalline form AETH, the process comprising: providing Aripiprazole form ATEl; and heating said Aripiprazole form ATEl.

14. A crystalline Aripiprazole form AM2, characterized by a powder X-ray diffraction pattern, substantially as depicted in Figure 10 and Table 6, that exhibits diffraction peaks at 4.3, 8.5, 9.9, 11.8, 12.5, 12.8, 13.4, 13.8, 14.6, 15.7, 16.2, 16.9, 18.1, 19.2, 19.9 20.6, 21.7, 21.4, 23.4, 24.4, 25.0, 25.9, 26.4, 26.9, 27.4, 29.0 and 30.0 ±0.2 degrees 2Θ.

15. The crystalline Aripiprazole form AM2 of claim 14, further characterized by an infra-red (IR) spectrum, substantially as depicted in Figure 11, with a unique pattern at 750-900 cm^"1.

16. The crystalline Aripiprazole form AM2 of claim 15, further characterized by a DSC curve with a first sharp endothermic peak at about 90 ⁰C and a second broad peak at 120-140 ⁰C, substantially as depicted in Figure 12.

17. The crystalline Aripiprazole form AM2 of claim 16, further characterized by a TGA curve indicating a weight loss of about 13 % percent between 80-160 ⁰C, substantially as depicted in Figure 13.

18. The crystalline Aripiprazole form AM2 of claim 17, further characterized by diminished hygroscopicity and comprising a methanol content of about 13 %.

19. A crystalline Aripiprazole form AMI , characterized by a powder X-ray diffraction pattern, substantially as depicted in Figure 14 and Table 7, that exhibits diffraction peaks at 9.4, 10.6, 11.4, 11.8, 12.3, 13.3, 14.3, 15.4, 17.0, 17.3, 17.7, 18.2, 18.5, 19.0, 19.4, 19.8 20.2, 21.3, 22.8, 23.1, 24.3, 24.8, 25.6, 26.4, 26.8, 27.3, 27.5, 28.0, 28.9, 29.3, 29.8 and 30.2 ±0.2 degrees 20.

20. The crystalline Aripiprazole form AMI of claim 19, further charact teerriizzeedd bbyy aann iinnffrraa--rreedd ((IIRR)) ssppeectrum with a unique pattern at 950-1100 cm^" , substantially as depicted in Figure 15.

21. The crystalline Aripiprazole form AMI of claim 20, further characterized by a DSC curve with one sharp endothermic peak at around 110 ⁰C, substantially as depicted in Figure 16.

22. The crystalline Aripiprazole form AMI of claim 21, further characterized by a TGA curve indicating a weight loss of about 6.5 % percent at 110- 120 ⁰C, substantially as depicted in Figure 17.

23. The crystalline Aripiprazole form AMI of claim 22, further characterized by diminished hygroscopicity and comprising a methanol content of about 6.5 ± 1 weight percent.

24. A process for preparing a crystalline Aripiprazole methanolate, the process comprising: providing Aripiprazole; and crystallizing said Aripiprazole from a methanol solution.

25. A process for preparing the dry Aripiprazole form B, the process comprising: providing Aripiprazole form AETl; and heating the said Aripiprazole form AETl at 8O⁰C under vacuum for about 24 hours.

26. A pharmaceutical composition comprising, as an active ingredient, at least one crystalline Aripiprazole form selected from the group consisting of Aripiprazole form AETl and Aripiprazole form AETH, preferably Aripiprazole form AETH₅ and pharmaceutically acceptable carriers.

27. Use of at least one crystalline Aripiprazole form selected from the group consisting of Aripiprazole form AETl, and Aripiprazole form AETH, preferably Aripiprazole form AETH, in the preparation of a medicament for treating a medical condition in which treatment with Aripiprazole is beneficial e.g., schizophrenia.