DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF ARPIPRAZOLE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of sterile Aripiprazole Hydrate A having a mean particle size less than about 50 µm.

BACKGROUND OF THE INVENTION

Aripiprazole is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril, of Formula – I.
.

Aripiprazole Hydrate A is approved under the brand name Abilify Maintena®, a typical antipsychotic indicated for the treatment of schizophrenia.

US 5006528 discloses Aripiprazole (Formula-I). This patent also discloses a process for the preparation of Aripiprazole by reacting 7-(4-bromobutoxy)-3,4-dihyro-2(1H)-quinolinone of Formula–II with 1-(2,3-dichlorophenyl)piperazine hydrochloride of Formula–III. The process is depicted in the below as scheme-I:

Scheme-I

Aripiprazole exist in different polymorphic forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements of the molecules in the crystal lattice.

Polymorphism of Aripiprazole was disclosed in Study on Crystal Transformation of Aripiprazole, presented at the Fourth Japan-Korea Symposium on Separation Technology, 1996. According to this reference, Aripiprazole exists as Type–I, Type–II and Type –III crystals. This journal disclosed that Aripiprazole recrystallized from ethanol solution was anhydrous crystal Type–I. The Type–I crystals were converted to Type–II crystals by heating at 130– 140 °C for 15 hours. When these polymorphs were crystallized from alcoholic solvent containing water up to 20% (v/v) solution, were converted to Type –III hydrous crystals.

Aripiprazole Hydrate A is disclosed in US patent 8399469. This patent discloses a process for the preparation of Aripiprazole Hydrate A comprises dissolving anhydrous Aripiprazole in hydrous ethanol followed by dried at 50 °C for 2 hours to obtain conventional Aripiprazole Hydrate which is then milled to obtain Aripiprazole Hydrate A.

A PCT application WO 2012077134, discloses the preparation of Aripiprazole Hydrate A comprises the suspension of Aripiprazole in ethanol followed by filtration, adding acetone to the filtrate followed by the addition of demineralized water.

US patent 7807680 discloses the process for the preparation of sterile bulk Aripiprazole Hydrate A comprises suspending Aripiprazole in 95% ethanol followed by impinging jet crystallization technique.

US patent 9457026 discloses the preparation of Aripiprazole Hydrate A suspension by using pulverization method. US ‘026 also disclosed that the method for sterilizing bulk Aripiprazole Hydrate A can be selected from a number of methods such as aseptic crystallization, autoclave sterilization, gas sterilization, and radiation sterilization.

Another US patent 9066848 discloses the preparation of sterile Aripiprazole Hydrate A with small particle size and narrow particle size distribution without milling by using impinging jet crystallization in the presence of an organic solvent.

The major disadvantages associated with the above processes is the use of tedious and costly instrumental technologies such as milling, pulverization, impinging jet crystallization, aseptic crystallization, autoclave sterilization, gas sterilization, and radiation sterilization, which are difficult to manage at industrial scale, which makes the process commercially not viable.

The inventors of the present invention found an improved process to prepare sterile Aripiprazole Hydrate A, which is industrially feasible, can avoid the use of above known tedious instrumental technologies.

The present invention directed towards an improved process for the preparation of sterile Aripiprazole Hydrate A with smaller particles having mean particle size less than about 50 µm.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide an improved process for the preparation of sterile Aripiprazole Hydrate A with mean particle size less than about 50 µm.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides an improved process for the preparation of sterile Aripiprazole Hydrate A with smaller particles comprises:
a) providing a solution of Aripiprazole in a solvent mixture;
b) optionally heating the above solution to a temperature of about 30 – 100 °C to get clear solution;
c) passing the solution through 0.22 µm filter;
d) adding the above Aripiprazole filtrate to an anti-solvent;
e) isolating Aripiprazole Hydrate A crystals.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of sterile Aripiprazole Hydrate A with smaller particles having mean particle size less than about 50 µm.

Step a) of the aforementioned process comprises providing a solution of Aripiprazole in a solvent mixture.

The solvent used in above reaction system comprises water, alcohols, ketones, nitriles, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers and mixtures thereof. The alcohols comprises C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol; ketones selected from acetone, methyl ethyl ketone, methyl isopropyl ketone; nitrile solvent selected from acetonitrile, propionitrile; halogenated hydrocarbons selected from methylene chloride, ethylene chloride, chloroform; hydrocarbons selected from hexane, cyclohexane, toluene, xylene; amides selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone; sulfoxides selected from but are not limited to dimethyl sulfoxide; nitriles selected from acetonitrile, propionitrile; esters comprises, ethyl acetate and butyl acetate; ethers selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran; and mixtures thereof.

The above dissolution is carried out at a temperature ranging from about 10 – 50 °C.

Step b) of the aforementioned process comprises the heating of the Aripiprazole solution of step a) for 15 – 60 mins until the clear solution is obtained.

Step c) of the aforementioned process comprises passing the solution of step b) through the filter with 0.22 µm diameter nozzles.

The above filtrate is collected and is heated to a temperature ranging from about 30 – 100 °C to dissolve any precipitated aripiprazole.

Step d) of the aforementioned process comprises adding the above Aripiprazole filtrate to an anti-solvent which is capable of initiating precipitation of aripiprazole from solution at a temperature ranging from about 0 – 20 °C.

The anti-solvent used herein comprises water.

The above solution is maintained at 0 – 15 °C for 30 – 120 minutes to complete the crystallization.

Step e) of the aforementioned process comprises the isolation of Aripiprazole Hydrate A crystals, wherein the isolation comprises filtering the product, washing the obtained filtrate by using a solvent or mixture thereof, drying the filtrate to a temperature of about 20 – 50 °C .

The solvent system used in the above step is as defined above.

The mean particle size of the sterile Aripiprazole Hydrate A obtained by the above process is less than about 50 µm.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE-1:

Preparation of sterile Aripiprazole Hydrate A:

Aripiprazole (100 g) was added to the solvent mixture of ethanol (absolute alcohol, 1500 ml), acetone (1000 ml) and water for injection (150 ml) at 20-30 °C under nitrogen atmosphere. The reaction mixture was heated to 50-60 °C for 25 – 30 minutes to obtain a clear solution. The obtained clear solution was passed thorough 0.22 µm filter at 50-60 °C and washed with preheated 1:1 solution mixture of ethanol and acetone (100 ml) at 50 – 55 °C. The filtrate was collected and heated to 50 – 60 °C to dissolve any precipitated material to obtain the pre heated Aripiprazole solution. Water for injection (300 ml) was cooled separately to 2 – 10 °C to obtain pre cooled water.

The above pre heated Aripiprazole solution was slowly added to the above pre cooled water at 2 – 10 °C. The temperature of the reaction mass was maintained 2 °C to 10 °C for 60 minutes to complete the crystallization. The solution was filtered and the filtrate was washed with precooled 1:1 solvent mixture of ethanol and acetone (100 ml, 5±2°C). The product was kept under suction for approximately 30 minutes in nitrogen atmosphere to squeeze most of the filtrate. The obtained Aripiprazole was dried at 20 – 25 °C under reduced pressure (approximately 20 mmHg) till water content is in-between 4.0 % w/w-4.5 % w/w (by KF) to obtain the sterile Aripiprazole Hydrate A crystals with a mean particle size of 11.970 µm. ,CLAIMS:CLAIMS
We claim,
1. A process for the preparation of sterile Aripiprazole hydrate A with smaller particle size comprises:
a) providing a solution of Aripiprazole in a solvent mixture;
b) optionally heating the above solution to a temperature of about 30 – 100 °C to get clear solution;
c) passing the solution through 0.22 µm filter;
d) adding the above Aripiprazole filtrate to an anti-solvent;
e) isolating Aripiprazole Hydrate A crystals.

2. The process according to claim 1, wherein the solvent mixture of step (a) comprises water, alcohols, ketones, nitriles, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers and mixtures thereof.

3. The process according to claim 1, wherein the anti-solvent of step (d) comprises water.

4. The process according to claim 1, wherein the particle size of the sterile Aripiprazole Hydrate A comprises a mean particle size of less than about 50 µm.