DESC:RELATED APPLICATIONS
This application is related to Indian Provisional Application 2693/MUM/2015 filed 16th Jul, 2015 and is incorporated herein in its entirety.
FIELD OF THE INVENTION
The present invention relates to an improved and commercial viable process for the preparation of type I crystals of aripiprazole and aripiprazole conventional hydrate.
BACKGROUND OF THE INVENTION
Aripiprazole, is an atypical antipsychotic, useful for the treatment of schizophrenia and is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4 dihydrocarbostyril, represented by compound of formula I.

Formula I
Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. Onset of schizophrenia typically occurs between the age of 16 and 25 and affects 1 in 100, individuals worldwide. It is more prevalent than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome. Moreover, early therapeutic intervention can avert costly hospitalization.
Aripiprazole is currently marketed in United States under the trade name Abilify® as oral tablets and indicated for the treatment of schizophrenia. Aripiprazole is also present in ABILIFY MAINTENA® as its monohydrate. ABILIFY MAINTENA® is an extended-release injectable suspension available in 400-mg or 300-mg strength pre-filled dual chamber syringes and 400-mg or 300-mg strength vials.
United States Pat. No. 5006528 discloses recrystallization of aripiprazole from ethanol resulting in colorless flake crystals.
‘Study on Crystals Transformation of Aripiprazole, The Fourth Japan-Korea Symposium on Separation Technology, p.937-940 (1996)’ discloses that aripiprazole recrystallized from ethanol solution was anhydrous crystal type 1. Type 1 crystals were converted to type 2 crystals by heating at 130-140°C for 15 hours.
The present invention provides a process for preparation of type I crystals and aripiprazole conventional hydrate by using non-alcoholic solvents; more preferably by using ketonic solvent. Present process is commercially viable and does not require seeding.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of type I crystals of aripiprazole comprising:
a) heating aripiprazole in a non-alcoholic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole.
The present invention provides a process for aripiprazole conventional hydrate comprising:
a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) optionally drying the precipitated solid at a temperature not exceeding 55°C to get aripiprazole conventional hydrate
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: XRPD pattern of type I crystals of aripiprazole according to example 2, batch 1.
Figure 2: Differential Scanning colorimetry (DSC) curve of type I crystals of aripiprazole according to example 2, batch 1.
Figure 3: XRPD pattern of aripiprazole conventional hydrate according to example 3.
Figure 4: DSC curve of aripiprazole conventional hydrate according to example 3.
Figure 5: XRPD pattern of aripiprazole Hydrate A according to example 4.
Figure 6: DSC curve of aripiprazole Hydrate A according to example 4.
DETAILED DESCRIPTION OF THE INVENTION
The term “crude aripiprazole” as used herein refers to aripiprazole isolated from the reaction mixture without any further purification. For e.g. by removal of reaction solvent from the reaction mixture by filtration, centrifugation, concentration, evaporation etc.; or cooling of reaction mixture to a temperature lower than the ambient conditions; or liquid-liquid extraction and the like.
The term “pure aripiprazole” as used herein refers to aripiprazole obtained by purification of crude aripiprazole by well-known methods in the art such as liquid-liquid extraction, column chromatography, crystallization, recrystallization, slurrying in a suitable solvent, washing with a suitable solvent, acid-base purification and the like. “Pure aripiprazole” may be either crystalline or amorphous. It also includes various crystalline forms of aripiprazole.
The term “type I crystals of aripiprazole” as used herein refers to type 1 crystals of aripiprazole as disclosed in ‘Study on Crystals Transformation of Aripiprazole, The Fourth Japan-Korea Symposium on Separation Technology, p.937-940 (1996)’. Type I crystals of aripiprazole are characterized by X-ray powder diffraction (XRPD) having peak reflections at about 11.0, 16.6, 19.3, 20.3 and 22.1 ±0.2 degrees 2 theta and shows hygroscopicity greater than 0.4 % when left for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C.
Hygroscopicity of the aripiprazole sample was determined as a moisture content obtained after placing the sample for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C. Moisture content can be determined by well-known methods in the art such as Karl-Fischer method.
The term “type II crystals of aripiprazole” as used herein refers to type 2 crystals of aripiprazole as disclosed in ‘Study on Crystals Transformation of Aripiprazole, The Fourth Japan-Korea Symposium on Separation Technology, p.937-940 (1996)’.
The term “aripiprazole conventional hydrate” as used herein refers to aripiprazole conventional hydrate as disclosed in US8399469 and characterized by X-ray powder diffraction (XRPD) having peak reflections at about 12.6, 15.1, 17.4, 18.2, 18.7, 24.8 and 27.5 ±0.2 degrees 2 theta.
The term “anhydrous aripiprazole crystals B” as used herein refers to anhydrous aripiprazole type B crystals as disclosed in US8399469 and characterized by X-ray powder diffraction (XRPD) having peak reflections at about 11.0, 16.6, 19.3, 20.3 and 22.1±0.2 degrees 2 theta.
The term “anhydrous aripiprazole crystals C” as used herein refers to anhydrous aripiprazole type C crystals as disclosed in US8399469 and characterized by X-ray powder diffraction (XRPD) having peak reflections at about 12.6, 13.7, 15.4, 18.1, 19.0, 20.6, 23.5 and 26.4 ± 0.2 degrees 2 theta.
The term “Aripiprazole Hydrate A” as used herein refers to hydrate A crystals of aripiprazole as disclosed in US8399469 and characterized by X-ray powder diffraction (XRPD) having peak reflections at about 12.6, 15.4, 17.3, 18.0, 18.6, 22.5 and 24.8 ± 0.2 degrees 2 theta.
The term “mean particle size” as used herein refers to volume mean diameter. Volume mean diameter can be measured by laser-light scattering (LLS) methods.
In one embodiment present invention provides a process for the preparation of type I crystals of aripiprazole comprising:
a) heating aripiprazole in a non-alcoholic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole.
In one embodiment, in step a) of above process, aripiprazole used is selected from the group consisting of crude aripiprazole, pure aripiprazole, type II crystals of aripiprazole, aripiprazole conventional hydrate, anhydrous aripiprazole crystals B, anhydrous aripiprazole crystals C or mixture thereof.
In one embodiment, in step a) of above process, aripiprazole used may be obtained by the reaction of l-(2,3-dichlorophenyl)piperazine or its salt with 7-(4-halobutoxy)-3,4-dihydrocarbostyril or salt thereof, in presence of diisopropylamine as a base and alkali metal iodide.
In one aspect of above embodiment, alkali metal iodide may be selected from the group consisting of sodium iodide, potassium iodide, caesium iodide, lithium iodide, rubidium iodide and the like; more preferably alkali metal iodide is sodium iodide.
In one embodiment, in step a) of above process, aripiprazole used may be obtained by the reaction of l-(2,3-dichlorophenyl)piperazine or its HCl salt with 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril or 7-(4-bromobutoxy)-3,4-dihydrocarbostyril or salt thereof, in presence of diisopropylamine as a base and sodium iodide in a suitable solvent.
In one embodiment, in step a) of above process, formed solution may be in the form of monophasic system or biphasic system or multiphasic system; more preferably monophasic system.
In another embodiment, in step a) of above process, non-alcoholic solvent used may be a single solvent or mixture of two or more solvents.
Non-alcoholic solvent is selected from the group consisting of ketonic solvent, chlorinated solvent, ester solvent, ether solvent, nitrile solvent, hydrocarbon solvent, amide solvent, sulfoxides or mixture thereof; more preferably ketonic solvent.
Ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, or mixture thereof; more preferably methyl ethyl ketone.
Chlorinated solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride and the like.
Ether solvent is selected from the group consisting of diethyl ether, methyl tertiary butyl ether, di-isopropyl ether, tetrahydrofuran, 1-4-dioxan, 2-methyl tetrahydrofuran and the like.
Ester solvent is selected from the group consisting of ethyl acetate, butyl acetate, isopropyl acetate and the like.
Nitrile solvent is selected from the group consisting of acetonitrile, propionitrile and the like.
Hydrocarbon solvent is selected from the group consisting of cyclohexane, toluene, xylene, hexane and the like.
Amide solvent is selected from the group consisting of dimethyl formamide, dimethyl acetamide and the like and sulfoxide solvent such as dimethyl sulfoxide.
In another embodiment in step a) of above process, aripiprazole may be heated in a mixture of non-alcoholic solvent and water to form a solution.
In one embodiment, present invention provides a process for the preparation of type I crystals of aripiprazole comprising:
a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole.
In one embodiment, in step a) of above process, aripiprazole used is selected from the group consisting of crude aripiprazole, pure aripiprazole, type II crystals of aripiprazole, aripiprazole conventional hydrate, anhydrous aripiprazole crystals B, anhydrous aripiprazole crystals C or mixture thereof.
In one embodiment, in step a) of above process, aripiprazole used may be obtained by the reaction of l-(2,3-dichlorophenyl)piperazine or its salt with 7-(4-halobutoxy)-3,4-dihydrocarbostyril or salt thereof, in presence of diisopropylamine as a base and alkali metal iodide.
In one aspect of above embodiment, alkali metal iodide may be selected from the group consisting of sodium iodide, potassium iodide, caesium iodide, lithium iodide, rubidium iodide and the like; more preferably alkali metal iodide is sodium iodide.
In one embodiment, in step a) of above process, aripiprazole used may be obtained by the reaction of l-(2,3-dichlorophenyl)piperazine or its HCl salt with 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril or 7-(4-bromobutoxy)-3,4-dihydrocarbostyril or salt thereof, in presence of diisopropylamine as a base and sodium iodide in a suitable solvent.
In one embodiment, in step a) of above process, ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, or mixture thereof; more preferably methyl ethyl ketone.
In one embodiment, in step a) of above process, aripiprazole may be heated in a mixture of ketonic solvent and water; more preferably in a mixture of methyl ethyl ketone and water.
In one aspect of above embodiment, aripiprazole may be suspended in a ketonic solvent or mixture of ketonic solvents, to which water is added followed by heating to form a solution.
In another aspect, first a mixture of ketonic solvent and water is prepared, followed by addition of aripiprazole, which is then heated to form a solution.
In another aspect, first aripiprazole may be suspended in a ketonic solvent or mixture of ketonic solvents, followed by heating to form a solution, to which water may be added.
The mixture of ketonic solvent and water may have 5-40% (v/v) of water, preferably 10-30% (v/v) of water; more preferably 10% (v/v) of water.

In one embodiment, in step a) of above process, heating may be carried out at a temperature in the range of 50-85°C; preferably at reflux temperature of solvent; more preferably at a temperature of 75-80°C.
In one embodiment, in step b) of above process, the hot solution may be cooled to room temperature or below room temperature with optional stirring to precipitate aripiprazole wet solid.
Cooling may be carried out slowly or fast.
In one aspect, the hot solution may be cooled to a temperature of 20-50°C within 1-5 hours, more preferably to a temperature of 25-30°C within 1-2 hours.
In another aspect, it may be further cooled to a temperature of 0-5°C and maintained at this temperature for at least 30 minutes to effect the precipitation with optional stirring.
In one embodiment, in step c) of above process, the precipitated solid may be isolated by filtration, centrifugation; more preferably by filtration.
In another embodiment, the isolated precipitated solid may be further washed with the solvent used in step a).
In one embodiment, in step d) of above process, drying of the precipitated solid may be carried out at a temperature of 60-85°C, preferably at 70-80°C; more preferably at 80° C.
Drying may be carried out for a period of 10-50 hours, preferably for 20-50 hours; more preferably for 30 hours. Preferably drying may be carried out at a temperature of 80°C for a period of 10-50 hours; more preferably for 30 hours to obtain type I crystals of aripiprazole.
Preferably drying may be carried until the isolated precipitated solid contain less than about 0.5 % (w/w) of water to get type I crystals of aripiprazole.
In one embodiment, present invention provides type I crystals of aripiprazole, which is substantially free from contamination from type II crystals of aripiprazole.
In one embodiment, present invention provides type I crystals of aripiprazole having less than 10 % w/w of type II crystals of aripiprazole; more preferably having less than 5% w/w of type II crystals of aripiprazole; more preferably having less than 1% w/w of type II crystals of aripiprazole. The content of type II crystals of aripiprazole may be measured by XRPD or DSC, more preferably by DSC.
In a preferred embodiment, present invention provides a process for the preparation of type I crystals of aripiprazole comprising:
a) heating aripiprazole in a mixture of methyl ethyl ketone and water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole.
In one embodiment, present invention provides a process for the preparation of type I crystals of aripiprazole comprising:
a) heating aripiprazole in a mixture of acetone and water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole.
In one embodiment, present invention provides a process for the preparation of type I crystals of aripiprazole comprising:
a) heating aripiprazole in a mixture of methyl isobutyl ketone and water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole.

In one embodiment, the obtained type I crystals of aripiprazole can be micronized or milled to get desired particle size.
Micronization or milling can be carried out by using atomizer, pin mill, jet mill or ball mill; more preferably jet mill.
In one embodiment, the present invention provides type I crystals of aripiprazole with a mean particle size in the range of 10-150 µm; more preferably in the range of 30-70 µm.
In one embodiment, the obtained type I crystals of aripiprazole is subjected to milling to obtain type I crystals of aripiprazole with a mean particle size in the range of 1-10 µm.
In one aspect of above embodiment, the obtained type I crystals of aripiprazole is subjected to milling by using jet mill at 1.0 kg/cm2 nitrogen pressure to obtain type I crystals of aripiprazole with a mean particle size in the range of 1-10 µm.
In one embodiment, the obtained type I crystals of aripiprazole is subjected to milling to obtain type I crystals of aripiprazole with a mean particle size in the range of 11-30 µm; more preferably 11-20 µm.
In one aspect of above embodiment, the obtained type I crystals of aripiprazole is subjected to milling by using jet mill at 0.5 kg/cm2 nitrogen pressure to obtain type I crystals of aripiprazole with a mean particle size in the range of 11-30 µm; more preferably 11-20 µm.
In one embodiment, present invention provides a process for the preparation of type I crystals of aripiprazole with a mean particle size in the range of 11-30 µm; more preferably in the range of 11-20 µm comprising:
a) heating aripiprazole in a ketonic solvent to form a solution;
b) adding water to the solution formed in step a);
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole with a mean particle size of 11-30 µm; more preferably 11-20 µm.
In one embodiment, present invention provides a process for the preparation of sterile type I crystals of aripiprazole comprising: obtaining the type I crystals of aripiprazole by the process as described herein; and subjecting the type I crystals for terminal sterilization.
Terminal sterilization may be carried out by using dry heat sterilization, moist heat sterilization, gaseous sterilization or by radiation.
In a preferred embodiment, present invention provides a process for the preparation of sterile type I crystals of aripiprazole which comprises:
a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) filtering the solution over a sterile filter;
b) cooling the solution and optionally stirring to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85°C to get type I crystals of aripiprazole, wherein one or more steps being performed in an aseptic/sterile environment.
The ketonic solvent may be selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, or mixture thereof; more preferably methyl ethyl ketone.
In one embodiment, aripiprazole is heated in a mixture of methyl ethyl ketone and water.
The hot solution of aripiprazole in solvent is filtered over a sterile filter having pore size of 0.22 µm or less and cooled to room temperature or below to precipitate aripiprazole wet solid which is isolated from the solvent by filtration or centrifugation. The precipitated aripiprazole wet solid thus obtained is dried at a temperature of 80°C for 10-50 hours, more preferably for 30 hours.
In one embodiment, present invention provides sterile type I crystals of aripiprazole having mean particle size in the range of 10-150 µm; more preferably in the range of 30-70 µm.
In one embodiment, the obtained sterile type I crystals of aripiprazole can be micronized or milled aseptically to get desired particle size.
Micronization or milling can be carried out by using atomizer, pin mill, jet mill or ball mill; more preferably jet mill.
In one embodiment, the obtained sterile type I crystals of aripiprazole is aseptically milled to get sterile type I crystals of aripiprazole with a mean particle size of 1-10 µm.
In one aspect of above embodiment, the obtained type I crystals of aripiprazole is aseptically milled by using jet mill at 1.0 kg/cm2 nitrogen pressure to get sterile type I crystals of aripiprazole with a mean particle size in the range of 1-10 µm.
In one embodiment, the obtained sterile type I crystals of aripiprazole is aseptically milled to get sterile type I crystals of aripiprazole with a mean particle size of 11-30 µm; more preferably 11-20 µm.
In one aspect of above embodiment, the obtained type I crystals of aripiprazole is aseptically milled by using jet mill at 0.5 kg/cm2 nitrogen pressure to get sterile type I crystals of aripiprazole with a mean particle size in the range of 11-30 µm; more preferably 11-20 µm.
In one embodiment, present invention provides a process for the preparation of sterile type I crystals of aripiprazole with a mean particle size in the range of 11-30 µm; more preferably in the range of 11-20 µm comprising:
a) heating aripiprazole in a ketonic solvent to form a solution;
b) adding water to the solution formed in step a);
c) filtering the solution over a sterile filter;
d) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
e) isolating the precipitated solid; and
f) drying the precipitated solid at a temperature in the range of 60-85°C to get sterile type I crystals of aripiprazole with a mean particle size of 11-30 µm; more preferably 11-20 µm;
wherein one or more steps being performed in an aseptic/sterile environment.

The sterile type I crystals of aripiprazole obtained by the process of the present invention may be used for formulating injectable solution or extended-release injectable suspension.
In one embodiment, the obtained type I crystals of aripiprazole is subjected to milling to obtain a mixture of type I and type II crystals of aripiprazole.
In one aspect of above embodiment, the obtained type I crystals of aripiprazole is subjected to milling by using jet mill at 5.0 kg/cm2 nitrogen pressure to obtain a mixture of type I and type II crystals of aripiprazole.
In one embodiment, present invention provides a process for the preparation of aripiprazole conventional hydrate comprising:
a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) optionally drying the precipitated solid at a temperature not exceeding 55ºC to get aripiprazole conventional hydrate.
Step a), step b) and step c) of above process may be carried out as described in different embodiments for the process for type I crystals of aripiprazole.
Aripiprazole and ketonic solvent as used in step a) of above process may be selected from the group as discussed above.
In one embodiment, in step d) of above process, drying of the precipitated solid may be carried out at a temperature not exceeding 55°C for a period of 1-10 hours; more preferably the precipitated solid may be dried at a temperature of 50°C for 2 hours to obtain aripiprazole conventional hydrate.
In one embodiment, the aripiprazole conventional hydrate obtained by the process as described above, may be converted to Aripiprazole Hydrate A by milling conventional hydrate.
In one embodiment, aripiprazole conventional hydrate is milled to a mean particle size of 50 µm or less to obtain Aripiprazole Hydrate A. Milling can be achieved by using atomizer, pin mill, jet mill or ball mill.
In one embodiment, present invention provides Aripiprazole Hydrate A with a mean particle size 1-10 µm.
In one embodiment, present invention provides Aripiprazole Hydrate A with a mean particle size 11-30 µm.
In one embodiment, present invention provides a process for the preparation of Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm; comprising:
a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) optionally drying the precipitated solid at a temperature not exceeding 55ºC to get aripiprazole conventional hydrate.
e) subjecting the aripiprazole conventional hydrate obtained in step d), to milling to get Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm.
In step e) of above process, milling can be achieved by using atomizer, pin mill, jet mill or ball mill; more preferably jet mill.
In one embodiment, in step e) of above process, Aripiprazole Hydrate A obtained may be again subjected to milling to obtain Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm.
In one embodiment, in step e) of above process, aripiprazole conventional hydrate is subjected to milling by using jet mill at 1.5 kg/cm2 nitrogen pressure, to get Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm.
In one embodiment, present invention provides a process for the preparation of sterile Aripiprazole Hydrate A comprising:
a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) filtering the solution over a sterile filter;
c) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) optionally drying the precipitated solid at a temperature not exceeding 55ºC to get aripiprazole conventional hydrate;
e) milling the aripiprazole conventional hydrate to get sterile Aripiprazole Hydrate A; wherein one or more steps being performed in an aseptic/sterile environment.
Step a), step b) and step c) of above process may be carried out as described in different embodiments for the process for sterile type I crystals of aripiprazole.
In one embodiment, in step d) of above process, drying of the precipitated solid may be carried out aseptically at a temperature not exceeding 55°C for a period of 1-10 hours; more preferably the precipitated solid may be dried at a temperature of 50°C for 2 hours to obtain aripiprazole conventional hydrate.
In one embodiment, in step e) of above process, conventional hydrate is milled aseptically to a mean particle size of 50 µm or less. Milling can be achieved by using atomizer, pin mill, jet mill or ball mill.
In one embodiment, present invention provides sterile Aripiprazole Hydrate A with a mean particle size in the range of 1-10.
In one embodiment, present invention provides sterile Aripiprazole Hydrate A with a mean particle size in the range of 11-30 µm.
In one embodiment, present invention provides a process for the preparation of sterile Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm; comprising:
a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) filtering the solution over a sterile filter;
c) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) optionally drying the precipitated solid at a temperature not exceeding 55ºC to get aripiprazole conventional hydrate;
e) subjecting the aripiprazole conventional hydrate obtained in step d), to milling to get Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm;
wherein one or more steps being performed in an aseptic/sterile environment.
In step e) of above process, milling can be achieved by using atomizer, pin mill, jet mill or ball mill; more preferably jet mill.
In one embodiment, in step e) of above process, Aripiprazole Hydrate A obtained may be again subjected to aseptic milling to obtain Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm.
In one embodiment, in step e) of above process, aripiprazole conventional hydrate is subjected to aseptic milling by using jet mill at 1.5 kg/cm2 nitrogen pressure, to get Aripiprazole Hydrate A with mean particle size in the range of 1-10 µm.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
Hygroscopicity test method:
1.0 g of the test sample was accurately weighed in a weighing bottle (diameter 5 cm). Test sample was evenly distributed in the weighing bottle by sidewise shaking and the weighing bottle was placed uncovered in 60°C/100 % RH environment (20x25 cm, desiccator with 500 mL water) for 24 hours. 24 hours later, the weighing bottle was removed, immediately covered with stopper and allowed it to cool to room temperature. Moisture content of the sample was measured by Karl Fischer method.
Example 1: Preparation of Aripiprazole
Diisopropylamine (94.35g, 0.9342 mmol) was slowly added to a stirred solution l-(2,3-dichlorophenyl)piperazine hydrochloride (100 g, 0.3737 mmol) in acetonitrile (1000.0 mL) at 25°C and the resultant reaction mixture was stirred for 30.0 min. To this suspension was added 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril (104.3 g, 0.4110 mmol) and sodium iodide (56.0 g, 0.3737 mmol) at 25-30°C. The whole reaction mixture was refluxed for 24 hours. After completion of reaction, the reaction mixture was cooled to 25-30°C and concentrated to remove acetonitrile. Subsequently water (1000.0 mL) was added and product was extracted with methylene dichloride (2× 2.0 litres). Methylene dichloride layer was washed with water (1×1.0 litre) followed by saturated brine solution (1×1.0 litre) wash. Methylene dichloride layer was separated, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain solid. To this solid was added 1.7 litres of ethanol and reaction mixture was heated to 75-80°C to get a clear solution and maintained for 30.0 min. The clear reaction mass was slowly cooled to 25-30°C within 2 to 3 hours. Further the reaction mass was cooled to 0°C and maintained for 30.0 min. Product was filtered, washed with ethanol (100.0 mL) and wet solid was dried at 80°C for 40.0 hours to obtain 140.0 g of aripiprazole.
Example 2: Preparation of type I crystals of aripiprazole by using methyl ethyl ketone and water
Batch 1: 125.0 g of aripiprazole was added to a stirred solution of 1125 mL methyl ethyl ketone and 125 mL water. The resultant reaction mixture was heated to 75-80°C to get a clear solution and maintained it for 30 min at this temperature. Subsequently reaction mass slowly cooled to 25-30°C within 1-2 hours followed by further cooling to 0-5°C. Reaction mass was maintained at this temperature for 30 min to precipitate product. The precipitated product was filtered, washed with 62.5 mL of methyl ethyl ketone to obtain the wet solid. The wet solid was dried at 80°C for 24 hours to obtain 105 g of type I crystals of aripiprazole.
Purity: 99.7% (by HPLC), Particle size: D (0.1): 6.5 µm, D (0.5): 33.9 µm, D (4, 3): 37.91 µm, D (0.9):74.0 µm.
XRPD peaks of type I crystals obtained as per example 2, batch 1
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
4.72 18.70 0.42 16.58 5.35 18.00 28.26 3.15 10.27
8.26 10.71 1.55 16.94 5.23 5.33 28.79 3.10 4.98
8.73 10.13 2.26 17.69 5.01 5.50 29.78 3.00 1.28
9.53 9.28 1.45 19.32 4.60 11.35 30.16 2.96 0.95
10.43 8.48 1.35 19.50 4.55 14.72 30.87 2.90 0.69
10.79 8.20 3.59 20.36 4.36 100.00 31.53 2.84 2.65
11.01 8.03 12.80 22.05 4.03 58.04 32.49 2.76 1.90
12.06 7.34 5.23 22.74 3.91 3.60 36.02 2.49 1.62
12.58 7.04 1.49 22.99 3.87 3.84 37.08 2.42 0.83
12.99 6.82 1.45 23.72 3.75 1.75 39.62 2.28 1.66
13.73 6.45 1.32 24.28 3.67 2.30 40.93 2.20 0.97
14.35 6.17 10.36 24.81 3.59 2.27 43.74 2.07 1.00
14.93 5.93 5.07 26.06 3.42 3.24 44.88 2.02 0.62
15.46 5.73 1.64 26.61 3.35 9.05 46.08 1.97 0.63
15.69 5.65 3.42 27.06 3.30 4.27
16.34 5.42 4.67 27.39 3.26 4.80
DSC of obtained type I crystals of aripiprazole as per example 2, batch 1, is shown in figure 2.
The same procedure was repeated to prepare Batch 2 and Batch 3 of type I crystals of aripiprazole.
When these obtained type I crystals of aripiprazole were left for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C, the crystals exhibited hygroscopicity higher than 0.4 % (see, table 1).
Table 1
Sample Initial moisture content (%) Moisture content after 24 hrs (%)
Example 2, Batch 1 0.26 1.76
Example 2, Batch 2 0.22 1.62
Example 2, Batch 3 0.30 1.50

Example 3: Preparation of aripiprazole conventional hydrate by using methyl ethyl ketone and water
10.0 g of aripiprazole was added to a stirred solution of 90 mL methyl ethyl ketone and 10 mL water. The resultant reaction mixture was heated to 75-80°C to get a clear solution and maintained it for 30 min at this temperature. Subsequently reaction mass was slowly cooled to 25-30°C within 2 hours followed by further cooling to 0-5°C. Reaction mass was maintained at this temperature for 30 min. The precipitated product was filtered, washed with 2.0 mL of methyl ethyl ketone to obtain the wet solid. The wet solid was dried at 50°C for 2.0 hours under vacuum to obtain 9.0 g of aripiprazole conventional hydrate.
XRPD peaks of aripiprazole conventional hydrate as per example 3
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.20 14.25 3.90 22.54 3.94 82.19 33.96 2.64 2.18
10.50 8.42 0.43 23.24 3.83 20.63 34.14 2.63 1.98
12.45 7.11 6.33 23.77 3.74 3.67 34.46 2.60 1.37
12.66 6.99 41.80 24.10 3.69 6.15 34.83 2.58 1.20
13.13 6.75 1.18 24.82 3.59 62.65 35.60 2.52 3.95
14.87 5.96 5.31 25.11 3.55 8.10 35.84 2.51 17.49
15.12 5.86 49.50 25.44 3.50 1.98 36.30 2.47 3.97
15.48 5.72 8.86 26.02 3.42 1.90 37.01 2.43 1.95
16.19 5.47 3.68 26.59 3.35 9.43 38.23 2.35 1.45
17.02 5.21 4.79 26.96 3.31 2.89 38.55 2.34 1.23
17.41 5.09 45.42 27.53 3.24 20.19 39.04 2.31 3.40
17.56 5.05 13.23 28.10 3.18 1.84 40.11 2.25 1.31
17.79 4.99 4.22 28.78 3.10 2.22 40.49 2.23 0.92
18.09 4.90 26.13 29.83 2.99 4.48 41.57 2.17 3.01
18.25 4.86 36.89 30.03 2.98 7.68 42.22 2.14 2.46
18.73 4.74 100.00 30.32 2.95 5.40 43.80 2.07 1.86
18.91 4.69 16.55 30.53 2.93 11.58 44.68 2.03 3.68
19.44 4.57 12.84 30.95 2.89 2.69 45.03 2.01 1.35
19.55 4.54 18.09 31.59 2.83 5.66 45.60 1.99 1.60
20.46 4.34 9.96 31.90 2.81 3.81 46.08 1.97 4.49
20.62 4.31 15.42 32.12 2.79 4.99 47.93 1.90 0.90
21.24 4.18 11.30 32.71 2.74 0.96 49.43 1.84 0.46
21.80 4.08 7.25 33.08 2.71 1.28
DSC of obtained aripiprazole conventional hydrate as per example 3 is shown in figure 4.
Example 4: Preparation of Aripiprazole Hydrate A
The aripiprazole conventional hydrate obtained in example 3, was milled at 1.5 kg/cm2 nitrogen pressure using jet mill to obtain Aripiprazole Hydrate A.
Purity: 98.9% (by HPLC), Particle size: D (0.1): 1.2 µm, D (0.5): 5.6 µm, D (4, 3): 8.28 µm, D (0.9): 18.3 µm.
XRPD peaks of Aripiprazole Hydrate A as per example 4
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.21 14.23 3.08 21.26 4.18 10.00 31.93 2.80 5.32
8.74 10.11 1.85 21.83 4.07 20.26 32.16 2.78 4.40
12.34 7.17 4.82 22.57 3.94 96.47 32.76 2.73 1.56
12.47 7.10 5.24 23.26 3.82 12.26 33.10 2.71 3.70
12.67 6.98 36.17 23.80 3.74 4.92 33.97 2.64 3.17
13.15 6.73 3.43 24.12 3.69 10.49 34.49 2.60 2.24
13.83 6.41 1.76 24.88 3.58 100.00 35.62 2.52 5.62
14.89 5.95 8.87 25.13 3.54 11.42 35.86 2.50 9.73
15.13 5.85 39.85 25.65 3.47 2.85 36.33 2.47 4.67
15.51 5.71 22.86 26.02 3.42 2.38 37.11 2.42 1.68
16.21 5.47 7.82 26.60 3.35 7.33 38.26 2.35 2.67
17.04 5.20 10.16 26.97 3.31 5.08 39.03 2.31 2.17
17.43 5.09 52.28 27.54 3.24 18.45 39.75 2.27 1.48
17.58 5.04 33.87 28.41 3.14 2.41 41.56 2.17 2.92
18.13 4.89 42.12 28.75 3.11 1.50 42.28 2.14 2.97
18.27 4.86 27.54 29.86 2.99 7.01 42.54 2.13 2.66
18.74 4.73 79.16 30.07 2.97 11.70 43.88 2.06 1.73
18.93 4.69 22.32 30.55 2.93 10.79 44.70 2.03 2.30
19.46 4.56 25.31 30.97 2.89 3.00 46.08 1.97 3.63
20.50 4.33 19.54 31.31 2.86 3.08 47.82 1.90 1.42
20.65 4.30 11.74 31.63 2.83 8.74 49.46 1.84 0.51

DSC of obtained Aripiprazole Hydrate A as per example 4 is shown in figure 6.
Example 5: Preparation of type I crystals of aripiprazole by using methyl ethyl ketone and water
7.0 g of aripiprazole was added to 61.6 mL of methyl ethyl ketone and the resultant reaction mixture was heated to 75-80°C to get a clear solution. Water (8.4 mL) was added to this solution at this temperature and whole reaction mixture was maintained for 15 min at this temperature. Subsequently reaction mass was slowly cooled to 25-30°C within 30-40 min and further maintained at this temperature for 60 min. The precipitated product was filtered, washed with 3.5 mL of methyl ethyl ketone to obtain the wet solid. The wet solid was dried at 80°C for 24 hours to obtain 6.2 g of type I crystals of aripiprazole.
Particle size: D (0.1): 2.03 µm, D (0.5): 14.19 µm, D (0.9): 31.51 µm, D (4, 3): 15.81 µm.
When these obtained type I crystals of aripiprazole were left for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C, the crystals exhibited hygroscopicity higher than 0.4 % (see, table 2).
Table 2
Sample Initial moisture content (%) Moisture content after 24 hrs (%)
Example 5 0.13 4.2
Example 6: Preparation of type I crystals of aripiprazole by using acetone and water
7.0 g of aripiprazole was added to a stirred solution of 189 mL acetone and 21 mL water. The resultant reaction mixture was heated to 55-60°C to get a clear solution and maintained it for 30 min at this temperature. Subsequently reaction mass slowly cooled to 25-30°C within 60 min and maintained at this temperature for 60 min. The precipitated product was filtered, washed with 3.5 mL of acetone to obtain the wet solid. The wet solid was dried at 80°C for 24 hours to obtain 5.2 g of type I crystals of aripiprazole.
Particle size: D (0.1): 4.12, D (0.5): 18.02, D (0.9): 38.28, D (4, 3): 20.03
When these obtained type I crystals of aripiprazole were left for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C, the crystals exhibited hygroscopicity higher than 0.4 % (see, table 3).
Table 3
Sample Initial moisture content (%) Moisture content after 24 hrs (%)
Example 6 0.12 3.7
Example 7: Preparation of type I crystals of aripiprazole by using methyl isobutyl ketone and water
7.0 g of aripiprazole was added to a stirred solution of 63 mL methyl isobutyl ketone and 7 mL water. The resultant reaction mixture was heated to 75-80°C to get a clear solution and maintained it for 30 min at this temperature. Subsequently reaction mass slowly cooled to 25-30°C within 60 min and maintained at this temperature for 60 min. The precipitated product was filtered, washed with 3.5 mL of methyl isobutyl ketone to obtain the wet solid. The wet solid was dried at 80°C for 24 hours to obtain 5.1 g of type I crystals of aripiprazole.
Particle size: D (0.1): 2.19, D (0.5): 17.21, D (0.9): 37.33, D (4, 3): 18.98.
When these obtained type I crystals of aripiprazole were left for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C, the crystals exhibited hygroscopicity higher than 0.4 % (see, table 4).
Table 4
Sample Initial moisture content (%) Moisture content after 24 hrs (%)
Example 7 0.25 3.9

Comparative Example 1: Preparation of aripiprazole by using ethanol crystallization
10.0 g of aripiprazole was added to a stirred solution of 150 mL ethanol and the resultant reaction mixture was heated to 75-80°C to get a clear solution and maintained it for 30.0 min. Subsequently the reaction mass was cooled to 25-30°C within 2.0 hours and further cooled to 0-5°C and maintained for 30.0 min. The product was filtered, washed with 5.0 mL of ethanol. The wet solid was dried at 80°C for 40.0 hours to obtain 9.1 g of aripiprazole crystals.
When these obtained aripiprazole crystals (using ethanol crystallization) were left for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C., the crystals did not exhibit hygroscopicity higher than 0.4 % (see, table 5).
Table 5
Sample Initial moisture content (%) Moisture content after 24 hrs (%)
Comparative Example 1 0.31 0.38

Above data indicates that the preparation of aripiprazole by using ethanol crystallization failed to give type I crystals of aripiprazole, as indicated by hygroscopicity test results wherein moisture content after 24 hrs under specified test conditions is not more than 0.4%.
Comparative Example 2: Preparation of aripiprazole by using ethanol and water
Batch 1: 70.0 g of aripiprazole was added to a stirred solution of 1400 mL of 20% water in ethanol and the resultant reaction mixture was heated to 80-85°C to get a clear solution and maintained it for 30.0 min. Then the reaction mass was slowly cooled to 25-30°C within 2 to 3 hours and again further cooled to 0-5°C. Reaction mass was maintained at this temperature for 30.0 min. The product was filtered, washed with 50.0 mL ethanol. The wet solid was dried at 80°C for 30.0 hours to obtain 69.0g of aripiprazole crystals.
Batch 2: above process was repeated by taking 72.0 g of aripiprazole to obtain 61.0 g of aripiprazole crystals.
When these obtained aripiprazole crystals were left for 24 hours in a dessicator where the conditions were set at humidity 100%, and temperature 60°C., the crystals did not exhibit hygroscopicity higher than 0.4 % (see, table 6).
Table 6
Sample Initial moisture content (%) Moisture content after 24 hrs (%)
Comparative Example 2, Batch 1 0.1 0.32
Comparative Example 2, Batch 2 0.23 0.37
Above data indicates that the preparation of aripiprazole by using ethanol and water failed to give type I crystals of aripiprazole, as indicated by hygroscopicity test results wherein moisture content after 24 hrs under specified test conditions is not more than 0.4%.
,CLAIMS:We claim:
1. A process for the preparation of type I crystals of aripiprazole comprising

a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) drying the precipitated solid at a temperature in the range of 60-85ºC to get type I crystals of aripiprazole.

2. The process as claimed in claim 1, wherein ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl butyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, or mixture thereof.

3. The process as claimed in claim 2, wherein ketonic solvent is methyl ethyl ketone.

4. The process as claimed in claim 1, wherein the obtained type I crystals of aripiprazole has less than 5% w/w of type II crystals of aripiprazole.

5. A process for the preparation of aripiprazole conventional hydrate comprising:

a) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
b) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
c) isolating the precipitated solid; and
d) optionally drying the precipitated solid at a temperature not exceeding 55ºC to get aripiprazole conventional hydrate.

6. The process as claimed in claim 5, wherein the aripiprazole conventional hydrate is milled to get aripiprazole hydrate A.

7. Use of ketonic solvent in the preparation of type I crystals of aripiprazole or aripiprazole conventional hydrates

8. A process for the preparation of type I crystals of aripiprazole comprising
a) reacting l-(2,3-dichlorophenyl)piperazine or its salt with 7-(4-halobutoxy)-3,4-dihydrocarbostyril or salt thereof, in presence of diisopropylamine as a base and alkali metal iodide to obtain aripiprazole;
b) heating aripiprazole in a ketonic solvent optionally containing water to form a solution;
c) cooling the solution and optionally stirring the solution to obtain a precipitated solid;
d) isolating the precipitated solid; and
e) drying the precipitated solid at a temperature in the range of 60-85ºC to get type I crystals of aripiprazole.

9. The process as claimed in claim 9, wherein the alkali metal salt is selected from the group consisting of sodium iodide, potassium iodide, caesium iodide, lithium iodide, rubidium iodide and the like; more preferably alkali metal iodide is sodium iodide.

10. The process as claimed in claim 9, wherein the alkali metal iodide is sodium iodide.