Field of the invention
The present invention relates to process for preparation of Aripiprazole form B having purity at least 99.5% and substantially free from dimer impurity of formula (II).

Background of the invention
The chemical name of Aripiprazole is 7-[4[-(2, 3-dichlorophenyl)-l-piperazinyl] butoxy] 3, 4-dihydro-2-(lH) quinolinone and molecular formula is C23H27CI2N3O2 and molecular weight is 448.39. Aripiprazole is represented by structural formula
(D

Aripiprazole is marketed by Bristol Myers Squibb under tradename Abilify and is indicated for the treatment of Alzheimer's dementia, antipsychotic disorders and bipolar disorders.
7-[4-[4-(2,3-dichlorophenyl)piperazin- 1 .yl]butoxy]-1,2,3,4-tetrahydroquinolin-2-one exhibits high affinity for dopamine D2 and D3, serotonin 5-HT]A and 5- HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1-adrenergic and histamine H1 receptors. Aripiprazole functions as a partial

agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.
7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one is disclosed in US patent no. 4,734,416 and also disclosed in US patent no. 5,006,528. The process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)piperazin-1 -yl]butoxy]-1,2,3,4-tetrahydroquinolin-2-one is well disclosed in US patent no. 5,006,528 which resulting color flake crystals having melting point of 139 -139.5°C. This process involves the formation of high level of dimer impurity, which causes low yield and also affects the purity the final product. However, no polymorphic details are reported in these patents. Moreover, the purification process involves two crystallization steps from ethanol to obtain the pure Aripiprazole which results in reduction in yields. Furthermore, it increases operational cost of the process.
In an article of Aoki (Study on Crystal Transformation of Aripiprazole, The Fourth Japan- Korea Symposium on Separation Technology, p.937 ff (1996)), this solid state form was designated as Type I aripiprazole and identified as an anhydrate. Aoki also teaches that the Type I aripiprazole may be converted into a Type II aripiprazole by heating at 130-140°C for 15 hours. This product is an anhydrate as well with a melting point of 150°C. When both Type I and Type II aripiprazole were recrystallized from an alcoholic solvent containing water up to 20%, the product is an aripiprazole hydrate labeled as Type III by Aoki. Type III aripiprazole can be converted into Type I by heating at 80°C.
US patent application no. 2004/0058935 discloses low hygroscopic forms of Aripiprazole and the process for their preparation from the Aripiprazole hydrate Form 'A'. It further states that the anhydrous Aripiprazole made by the Japanese patent publication No. 191256/1990, yields the Aripiprazole, which is significantly hygroscopic. As per US patent application no. 2004/0058935 anhydrous crystals of Aripiprazole exist as type-I crystals and type-II crystals.
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Further discloses that the type-I crystals are prepared -by recrystallization from ethanol or by heating Aripiprazole hydrate at 80°C and type-II crystals by heating type-I crystals at 130 to 140°C for 15 hrs.
US patent application no. 2004/0058935 discloses various polymorphic forms of 7_[4-[4-(2}3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one (Aripiprazole) such as anhydrous Form B, Form C, Form D, Form E and Form G and hydrated Form A. It discloses process for the Aripiprazole polymorphic form-B by heating the Aripiprazole hydrate 'A' at 90 - 125°C for about 3- 50 hrs. The process for Polymorphic Form-C is by heating the Aripiprazole anhydrous to a temperature of 140-150°C. The process for Form-D is recrystallization from toluene; process for Form-E is heating with acetonitrile or by recrystallization from acetonitrile and the process for Form-F is by heating the suspension of anhydrous Aripiprazole in acetone. The polymorphic Form-G is by heating to 170°C for at least 2 weeks in a sealed tube, which is a glassy mass. It further discloses the characterization data X-ray diffraction pattern; IR absorption and DSC of Form B, Form C, Form-D, Form-E, Form-F and Form-G. It further reported the melting point of Aripiprazole anhydrous Form B as 139.7°C. A drawback of the disclosed process is that it produces a mixture of polymorphic forms. Moreover, the process suffers with operational difficulty at industrial scale.
WO 2004/106322 discloses the polymorphic forms of 7-[4-[4-(2;3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3;4-tetrahydroquinolin-2-one namely Form II. Form III and Form IV. All the forms are characterized by their DSC and XRD pattern.
WO 2004/083183 discloses the polymorphic forms of 7-[4-[4-(2,3-dichlorophenyl)piperazin-1 -yl]butoxy]-1,2,3;4-tetrahydroquinolin-2-one hydrochloride salt namely Form A, form B, Form C and Form D. Ail the polymorphs are characterized by their XRD pattern.

WO 2006/012237 discloses the crystal form of anhydrous aripiprazole. It is prepared by dissolving aripiprazole in an appropriate solvent by heating, and then rapidly cooling with agitation of high speed, to cause the anhydrous aripiprazole crystal to swiftly and uniformly precipitate.
WO 2006/053780 Al discloses aripiprazole hemi-ethanolate and aripiprazole methanolate. It also discloses a process for the preparation of aripiprazole form B by heating aripiprazole alcoholate.
WO 2006/053781 Al discloses the process for the preparation of crystalline aripiprazole form B by crystallizing from a solvent selected from 1-propanol, 2-propanoi, I-butanol, ethyl acetate, acetonirirle or combination thereof
WO 2006/077584 A2 discloses aripiprazole form AET1, form AETH, form AMI and form AM2. Aripiprazole form AET1 is stable ethanol hemi-solvate, containing about 5 ± 2 weight of ethanol and it is prepared by crystallization from ethanol. Moreover, dry aripiprazole form B is prepared by heating aripiprazole form AET1 under vacuum to 80°C for about 24 hrs, Form AMI and form AM2 is prepared by crystallization from methanol containing either 1 or 2 mole equivalents of methanol per one mole of Aripiprazole.
The solvents traditionally used for the preparation of a drug substance are sometimes difficult to remove completely by practical manufacturing techniques, which are in actuality employed during the production. Therefore, in the preparation of drug substance wherein plural steps are serially carried out till the final step, each solvent used in each step may possibly residue in drug substance. Further the residual solvents in drug substances may alter it biological activity.
Since a solvent may play an important role in increasing the yield rate or in determination of physical properties of drug substance such as crystal form, purity, solubility, etc., even if such a solvent is known to be toxic, there may be

many cases that the use thereof in the preparation of drug substance cannot be avoided in terms of risk-benefits. In such cases, this guideline (ICH guidelines Q3C(R3)) decrees that a concentration of a residual solvent in drug substance should be not more than a specified value, which is toxicologically acceptable.
Moreover, the content of undesired impurity in the final product is always a cause of concern with respect to Food and Drug Authorities (FDA) requirement. Therefore, it is required to have the undesired impurity content well below the level specified in the International Conference on Harmonization (ICH) guideline as per regulatory authority. Particularly with respect to the known impurity the acceptable limit 0.15%. Therefore it is extremely important to control the level of dimer impurity to comply with the regulatory requirement.
Therefore, it is desirable to have a process which is devoid of the drawback of prior art and operational friendly, simple and economical.
Unexpectedly, the present inventors have found that even by single crystallizing and sequentially followed steps as mentioned hereinbelow leads to Aripiprazole form B having purity at least 99.5% and substantially free from dimer impurity of formula (II).

Surprisingly, the process of the present invention provides aripiprazole form B with good purity, high yield and it also reduces dimer impurity of the final product.

Object of the invention
The object of the present invention is to provide a process for the preparation of aripiprazole form B having purity at least 99.5% and substantially free from dimer impurity.
Another object of the present invention is to provide a process for the preparation aripiprazole form B having yield more than 85%.
A further object of the present invention is to provide a process for the preparation aripiprazole form B having organic volatile impurities (OVI) content less than 1000 ppm.
A furthermore object of the present invention is to provide a process for the preparation of aripiprazole form B by single crystallization.
Yet another object of the present invention is to provide a process for the preparation of aripiprazole form B, which controls the dimer impurity in final product.
Brief description of the drawings
Figure 1 represents the powder X-ray diffraction (XRD) pattern of Aripiprazole Form B having purity at least 99.5% and substantially free from dimer impurity.
Detailed description of the invention
Accordingly, the present invention relates to a process for the preparation of Aripiprazole form B having purity at least 99.5% and substantially free from dimer impurity of formula (II).

V
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According to one aspect of the present invention, the Aripiprazole form B is characterized by powder X-ray diffraction peaks at about 11.09, 12.11, 14.42, 15.00, 16.65, 19.39, 20.43 and 22.12 ±0.2 degree two-theta.
The process for the preparation of Aripiprazole form B having purity at least
99.5% and substantially free from dimer impurity, comprises the steps of
i) dissolving aripiprazole in 25 volume of ethanol along with 10%
activated charcoal ii) heating the reaction mixture obtained in step (i) to reflux for 5 hrs iii) filtering the reaction mixture obtain in step (ii) iv) stirring the solution obtained in step (iii) for 2-3 hrs at temperature 20-
35°C v) cooling the solution 0°C to -5°C for 1 hr vi) suspending the resulting product obtained in step (v) in water vii) filtrating the resulting product obtained in step (vi) viii) drying at 80°C for 10-12 hrs in hot air to obtain form B having purity at least 99.5%
In the present invention, the process for the preparation of Aripiprazole form B having purity more than 99.5% comprises the steps of dissolving aripiprazole in 25 volume of ethanol with 10% activated charcoal, heating the reaction mixture to reflux for 5 hrs and filtered. Filtrate is stirred for 2-3 hrs at temperature 20-35°C and cooled to 0 to -5°C for 1 hr. The resulting product is suspended in water and filtered. After filtration drying the product at 80°C for 10-12 hrs in hot air to

obtain form B having purity at least 99.5% and substantially free from dimer impurity.
Yet another aspect of the present invention is to provide a process which significantly reduces the organic volatile impurities (OVI) content of the Aripiprazole form B i.e. less than 1000 ppm.
Advantages of the present invention over prior art:
i) The present invention provides easy process for drying,
ii) It also avoids the use of vacuum drying technique for 80 hrs. iii) The present invention reduces the OVI content i.e. below 1000 ppm. iv) The final product i.e. form B is obtained by single crystallization, v) The present invention provides final product substantially free from dimer impurity.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example
Preparation of Aripiprazole form B
100g of aripiprazole was dissolved under reflux in 2500ml of ethanol with 10g of Activated Charcoal. The solution was refluxed for 5 hrs and filtered through hyflo bed. The filtrated solution was slowly allowed to 25-35°C during a period of 2-3 hrs while being under stirred. The suspension was further cooled to 0 to -5°C and maintained for 1 hr. The solid was collected by filtration and wet cake is taken in 2000ml of water and stirred it for 2 hrs at ambient temperature. The resultant suspension was filtered washed with water. Unload wet cake and dry in

hot air oven for 6-S hrs up to moisture content with in limit to obtain Aripiprazole formB.
HPLC :- >99.5% Moisture content:- <0.5% OV] content :- <1000 ppm
10

We claim
1. A process for the preparation of Aripiprazole form B having purity at least 99.5% and substantially free from dimer impurity, comprises the steps of i) dissolving aripiprazole in ethanol along with 10% activated charcoal ii) heating the reaction mixture obtained in step (i) to reflux iii) filtering the reaction mixture obtain in step (ii) iv) stirring the solution obtained in step (iii) v) cooling the solution 0°C to -5°C for 1 hr vi) suspending the resulting product obtained in step (v) in water vii) filtrating the resulting product obtained in step (vi) viii) drying to obtain form B having purity at least 99.5%
2. A process as claimed in claim 1, wherein said step (i) aripiprazole is dissolved in 20-30 volume of ethanol.
3. A process as claimed in claim 2, wherein aripiprazole is dissolved in 25 volume of ethanol.
4. A process as claimed in claim 1, wherein said step (ii) time period of heating the reaction mixture to reflux is 5 hrs.
5. A process as claimed in claim 1, wherein said step (iv) stirring the solution for 1-4 hrs at temperature 20-35°C.
6. A process as claimed in claim 5, wherein said step (iv) stirring the solution for 2-3 hrs at temperature 25-35°C.
7. A process as claimed in claim 1, wherein said step (v) cooling temperature is 5°C to-10°C.
8. A process as claimed in claim 7, wherein said step (v) cooling temperature is 0°C to -5°C.
9. A process as claimed in claim 1, wherein said step (viii) drying is carried out at 60-90°C for 5-15 hrs in hot air.
10. A process as claimed in claim 9, wherein said step (viii) drying is carried out at 80°C for 10-12 hrs in hot air.

11. A process as claimed in claim 1, wherein said aripiprazole form B is
having OVI content less than 1000 ppm.
12. A process for the preparation of Aripiprazole form B having purity at least
99.5% and substantially free from dimer impurity, comprises the steps of
i) dissolving aripiprazole in 25 volume of ethanol along with 10%
activated charcoal ii) heating the reaction mixture obtained in step (i) to reflux for 5 hrs iii) filtering the reaction mixture obtain in step (ii) iv) stirring the solution obtained in step (iii) for 2-3 hrs at temperature 20-
35°C v) cooling the solution 0°C to -5°C for 1 hr vi) suspending the resulting product obtained in step (v) in water vii) filtrating the resulting product obtained in step (vi) viii) drying at 80°C for 10-12 hrs in hot air to obtain form B having having purity at least 99.5%