WO2012077134A1 - Méthode de préparation de polymorphes d'aripiprazole - Google Patents

Méthode de préparation de polymorphes d'aripiprazole Download PDF

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WO2012077134A1
WO2012077134A1 PCT/IN2011/000830 IN2011000830W WO2012077134A1 WO 2012077134 A1 WO2012077134 A1 WO 2012077134A1 IN 2011000830 W IN2011000830 W IN 2011000830W WO 2012077134 A1 WO2012077134 A1 WO 2012077134A1
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aripiprazole
solvent
mixture
solution
process according
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PCT/IN2011/000830
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English (en)
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Bhaskar Bhirud Shekhar
Singh Sarin Gurdeep
Sivaji Aavula
Pranav Gupta
Vinodrai Naik Rajesh
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Ind-Swift Laboratories Limted
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Publication of WO2012077134A1 publication Critical patent/WO2012077134A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

Definitions

  • the present invention relates to an industrially advantageous and efficient process for the preparation of aripiprazole polymorph having particle size less than 100 ⁇ . Specifically, present invention relates to processes for the preparation of aripiprazole hydrate A, anhydrous crystal B and crystalline aripiprazole Type II.
  • Aripiprazole chemically known as 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl] butoxy]-3,4- dihydrocarbostyril, of formula
  • Schizophrenia most commonly manifests as auditory hallucinations, paranoid or playful delusions, or disorganized speech and thinking with significant social or occupational dysfunction. Onset of symptoms typically occurs in young adulthood, with around 1.5% lifetime prevalence of the population affected. Diagnosis is based on the patient's self-reported experiences and observed behavior. No laboratory test for schizophrenia currently exists. 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 has been approved by the FDA for the treatment of schizophrenia in 2, 5, 10, 15, 20 and 30 mg tablets for oral administration and is currently marketed under the brand name of Abilify ® .
  • the commercially marketed product contains the aripiprazole as the free base; i.e., not as an aripiprazole salt.
  • Aripiprazole and related compounds were first disclosed in US patent 5,006,528 (herein referred as US '528). It discloses various salts of aripiprazole and their preparation. The patent discloses double re-crystallization of crude aripiprazole from ethanol resulting in colorless crystals having a melting point 139-139.5° C.
  • aripiprazole Like any other pharmaceutical solids, aripiprazole also 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 and/or conformations of the molecules in the crystal lattice.
  • aripiprazole anhydride crystals may exist as Type-I, Type-II and Type-Ill crystals.
  • This article designate aripiprazole crystal prepared by US '528 as Type I aripiprazole and identified as an anhydrate.
  • anhydrate crystals of aripiprazole can be prepared by re-crystallization of aripiprazole from ethanol or by heating aripiprazole hydrate (Type- Ill) at a temperature of 80 °C.
  • Type-II aripiprazole crystals can be prepared by heating Type-I crystals at 130 °C to 140 °C for 15 hours. This process of heating is not easily applied to an industrial scale preparation of anhydride aripiprazole Type-II.
  • US patent application publication 2004/0058935 discloses several polymorphic forms of aripiprazole namely hydrate A, crystal B, type C, D, E, F & G and processes for their preparation. In application, it is disclosed that hydrate A is useful intermediate for preparation of anhydrate forms.
  • Aripiprazole hydrate A is prepared by milling conventional aripiprazole hydrate.
  • Aripiprazole anhydrous form B (also known as crystal B), which seems to be preferred crystalline form, is low hygroscopic and is a stable crystalline form.
  • Aripiprazole form B is prepared by heating aripiprazole hydrate A at 90-125 0 C for about 3 to 50 hours.
  • Aripiprazole form B is also prepared by heating conventional hygroscopic aripiprazole anhydrous crystals or conventional aripiprazole hydrate at 100 °C or 120 °C for 3 to 50 hours.
  • US patent 7,507,823 discloses a process for synthesis of aripiprazole hydrate A by providing a mixture of unprocessed aripiprazole in a solvent and mixture of supercritical fluid, optionally along with modifier, with water into a particle formation vessel to produces crystalline aripiprazole hydrate.
  • the process involves use of supercritical fluid which requires elevated pressure and is thus not suitable for industrial scale manufacturing.
  • US patent 7,642,353 discloses a process for preparation of aripiprazole form B by dissolving aripiprazole in a suitable solvents like 1-propanol, 2-propanol, 1-butanol, ethyl acetate, acetonitrile and mixture thereof at reflux temperature, adding seed crystals of aripiprazole form B to the solution, cooling the mixture and isolating crystals of aripiprazole form B. Process requires seeding with aripiprazole form B and silent about the mode to get seeding material.
  • a suitable solvents like 1-propanol, 2-propanol, 1-butanol, ethyl acetate, acetonitrile and mixture thereof at reflux temperature
  • US patent 7,655,798 discloses a process for preparation of aripiprazole Type II by dissolving aripiprazole in a solvent selected from 2-propanol, dimethylsulfoxide or mixture there and optionally further adding ethyl acetate.
  • Patent discloses that use of iso-propanol during crystallization of aripiprazole may results in Type I or Type II depending on conditions. Higher crystallization temperature favors Type II while lower temperature favors Type I. Process require strict condition of temperature for the formation of aripiprazole Type II, therefore not advisable to employ for industrial synthesis.
  • US patent application publication 2005/0152981 discloses a process for preparation of aripiprazole hydrate by mixing jet stream of a solution of aripiprazole in an organic solvent with a jet stream of anti-solvent to create high turbulence at their point of impact to produce slurry of crystals of aripiprazole monohydrate.
  • the process involves use of special machine for producing jet streams of two solutions and also requires special knowledge of instrument to provide sufficient linear velocity of streams to achieve high intensity micromixing prior to nucleation.
  • complex procedural requirements for operating machine and need of special machine add to the cost of final API i.e. aripiprazole, making the process unsuitable from the commercial point of view.
  • US patent application publication 2005/0277650 discloses a process for aripiprazole hydrate by dissolving aripiprazole in a aqueous, organic solvent at elevated temperature, adding seed crystals of aripiprazole hydrate to the solution, cooling the mixture, and isolating crystals of aripiprazole hydrate. Process requires seeding with aripiprazole hydrate and silent about the mode of getting seed of aripiprazole hydrate crystals.
  • US patent application publication 2006/0142299 discloses a process for preparation of aripiprazole form B by refluxing aripiprazole hemi-ethanolate or methanolate in ethyl acetate followed by cooling and isolation of flake-like crystals. Process needs isolation of aripiprazole alcoholate and then conversion to desired polymorph, thus adds an extra step to the process.
  • US patent application publication 2009/0198059 discloses a process for preparation of aripiprazole form B by basification of aripiprazole acid salt with base in a mixture of water and organic ester solvent subsequently separating the layers and concentrating organic layer followed by cooling to isolate aripiprazole form B. Process requires neutralization of aripiprazole salt and then conversion to form B, thus makes the process lengthy and unsuitable to employ for industrial synthesis.
  • US patent application publication 2009/0247542 discloses a process of preparation of aripiprazole Type II which is referred therein as form J by suspending/ dissolving aripiprazole in ketonic solvents.
  • methyl ethyl ketone and acetone have been used as solvent for preparation of Form J.
  • solvent is methyl ethyl ketone
  • recrystallization is carried out, but when solvent is acetone then aripiprazole is suspended and form J is prepared by acetone digestion.
  • PCT publication WO 2008/059518 discloses a process for preparation of crystalline anhydrous aripiprazole by refluxing aripiprazole in an organic solvent selected from alcohols, esters, acetic acid, tetrahydrofuran or mixture thereof followed by cooling to isolate wet compound. The wet solid is then heated in an organic solvent such as dichloromethane, optionally charcoalised, and seeded with crystalline anhydrous aripiprazole to give the desired product. Process requires isolation of product and then again heating in an organic solvent. Process also needs seeding with anhydrous aripiprazole to give crystalline anhydrous aripiprazole.
  • a recent PCT publication WO 2010/106551 discloses a process for preparation of anhydrous aripiprazole form B by heating aripiprazole in an alcoholic solvent till complete dissolution followed by cooling, centrifugation and drying.
  • the obtained dry material is sieved using sifter of 40 mesh size without crushing, separating out sieve tops and further drying the sieved material.
  • Process requires sieving of material to get the desired material but sieving is performed by using sifter of 40 mesh size (400 micron) which results in larger particle of aripiprazole.
  • Another disadvantage is that the amount of energy used to sieve the sample is arbitrarily determined.
  • polymorphs exhibit different physicochemical properties such as solubility, dissolution rate, bioavailability and chemical and physical stabilities.
  • polymorphism has become a topic of great interest for pharmaceutical industries as it has the potential to significantly affect the physical properties of a compound.
  • process for preparing such polymorph should be robust and efficient in producing commercial quantity of crystalline compounds. This question arises because sometimes the most suitable polymorph is difficult to produce.
  • Further particle size of the drug molecule also affects its physicochemical properties and in case of aripiprazole it is especially important for effective formulation. So, it is of greatest importance for pharmaceutical industry to ensure reliable, robust, cost effective as well as efficient process for synthesis of crystalline aripiprazole of desired particle size.
  • the present invention provides an easy, industrially advantageous and efficient process for the preparation of polymorphs of aripiprazole, mainly hydrate A, anhydrous form B and crystalline aripiprazole Type II with desired particle size which does not involve use of special equipment or milling, and avoids need for heat treatment or heat conversion or long-term exposure to high temperatures.
  • the principal and foremost objective of the present invention is to provide an industrially advantageous and efficient process for preparation of aripiprazole polymorph having particle size less than 100 ⁇ .
  • Another objective of the present invention is to provide a process for the preparation of crystalline aripiprazole mainly hydrate A, form B and Type II.
  • Another objective of the present invention is to provide a process for the preparation of aripiprazole hydrate A having particle size less than 100 ⁇ .
  • Another objective of the present invention is to provide a process for the preparation of aripiprazole form B having particle size less than 100 ⁇ .
  • Still another objective of present invention is to provide a process for the preparation of crystalline aripiprazole Type-II, which does not require long-term exposure to high temperatures.
  • Yet another objective of present invention is to provide an efficient process, which produces pure hydrate A, form B and crystalline aripiprazole Type II consistently.
  • present invention provides an improved, industrial advantageous and efficient process for the preparation of aripiprazole polymorph, specifically aripiprazole hydrate A, form B and Type II.
  • present invention provides a process for the preparation of aripiprazole hydrate A, comprising the steps of:
  • step b) mixing solution of step a) with a second solvent
  • step c) optionally, adding water to the mixture of step b);
  • present invention provides a process for preparation of aripiprazole crystal form B, comprising the steps of:
  • step b) mixing solution of step a) with a second solvent
  • present invention provides crystalline aripiprazole having particle size less than 100 ⁇ .
  • present invention provides a process for the preparation of crystalline aripiprazole Type II, comprising the steps of:
  • step c) preparing a suspension of seed crystals of crystalline aripiprazole type II in hydrocarbon solvent; d) . admixing the solution of step b) with suspension of step c);
  • present invention provides a process for the preparation of crystalline aripiprazole Type II, comprising the steps of:
  • step b) admixing the solution of step b) with a suitable hydrocarbon solvent
  • Figure 1 shows X-ray diffraction pattern of crystalline aripiprazole Type II as given in Japan-Korea Symposium on Separation Technology, p. 937 (1996)
  • Figure 2 shows X-ray diffraction pattern of crystalline aripiprazole Type II prepared according to present invention
  • the term, "dc> 0 " refers to the particle size at which 90% of the particles have the same or a smaller particle size.
  • d me an refers to average particle diameter by mass.
  • Type II of aripiprazole means a crystalline aripiprazole substance having X-ray diffraction pattern that substantially corresponds to that of Type II product as defined in an article, "73 ⁇ 4e fourth Japan-Korea Symposium on Separation Technology, p. 937 (1996) " and given as figure 1.
  • substantially corresponds means it cover differences or variations in the pattern that would not be understood by a person skilled in the art to represent a difference in crystal structure, but rather differences in techniques, sample preparation and instrument etc.
  • ambient temperature means temperature of the surrounding. It means any suitable temperature found in a laboratory or other working quarter, and is generally not below about 15 °C and not above about 30 °C. Accordingly, present invention provides an industrially advantageous and efficient process for the preparation of aripiprazole polymorph. Specifically present invention provides process for the preparation of aripiprazole hydrate A and form B having particle size less than 100 ⁇ .
  • the present invention provides a process for preparation of aripiprazole hydrate form A.
  • the process involves dissolution of aripiprazole in a suitable alcoholic solvent or mixture thereof with water at a temperature of 60 °C to reflux temperature of the solvent for 10 minutes to 8 hours, preferably till complete dissolution.
  • the solution can be optionally, filtered to remove any insoluble particles, if present, in the solution.
  • Suitable solvent can be selected amongst alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof or in mixture with water.
  • dissolution can be carried out at 60 °C to 100 °C for 10 minutes to 6 hours.
  • Second solvent includes C 3-8 nitriles such as acetonitrile, propionitrile; aliphatic ketones such as acetone, methyl ethyl ketone; aliphatic or cyclic ether such as isopropyl ether, 1,2-diethoxy ethane, 1,2-dimethoxy ethane, tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert- butyl ether, dibutyl ether, diphenyl ether and the like or mixture thereof or in mixture with water.
  • the resulting product can be isolated from the mixture by inducing precipitation.
  • a solution of aripiprazole is provided in alcoholic solvent followed by addition of second solvent to the resulting solution. Thereafter, resulting solution can be optionally cooled to a temperature of -30 to 30 °C followed by addition of water to the solution and then inducing the precipitation of hydrate A.
  • aripiprazole hydrate A crystal can be prepared by adding mixture of second solvent with water to the solution of aripiprazole in a suitable alcoholic solvent.
  • aripiprazole hydrate A crystal can be prepared by crystallizing aripiprazole from a solvent mixture containing a suitable alcoholic solvent, second solvent or mixture thereof and water.
  • the desired product can be isolated from the solution of aripiprazole, alcoholic solvent, optionally water, and second solvent, prepared by any of the method described by the present invention, by inducing precipitation of hydrate A.
  • the precipitation can be initiated by lowering the temperature to fasten the precipitation of hydrate A.
  • the temperature of solution can be lowered immediately by adding pre-cooled second solvent to the solution of aripiprazole (in alcoholic solvent or in mixture with water) or two solution can be mixed in reversed order i.e. aripiprazole solution can be added to the pre cooled second solvent to fasten the precipitation of hydrate A.
  • Second solvent can be cooled to a temperature of less than ambient temperature, preferably - 40 °C to 25 °C prior to mixing with aripiprazole solution.
  • reaction mixture after the addition of second solvent can be cooled fastly to form aripiprazole hydrate A.
  • Aripiprazole hydrate A thus formed by process of present invention can be isolated by the suitable techniques known in the art such as filtration, centrifugation, decantation and the like.
  • present invention provides a process for the preparation of aripiprazole crystal form B.
  • the process involves dissolution of aripiprazole in a suitable solvent at a temperature of 60 °C to reflux temperature of the solvent for 10 minutes to 6 hours, preferably till complete dissolution.
  • Suitable solvent can be selected amongst ketone such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; aliphatic alcohol such as methanol, ethanol, n-propanol, n- butanol, isobutanol and the like or mixture thereof.
  • the dissolution can be carried out 60 to 90 °C for 30 minutes to 2 hours.
  • aripiprazole solution thus formed is mixed with a second solvent.
  • the mixing of the two solutions can be carried out in any order, aripiprazole solution can be added to the second solvent or second solvent can be added to solution of aripiprazole in suitable solvent. Alternatively, two solutions can be mixed simultaneously.
  • Second solvent includes ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; aliphatic ether such as isopropyl ether, diethyl ether, methyl tert-butyl ether, di-n- butyl ether, diphenyl ether; aliphatic alcohols such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like or mixture thereof, provided second solvent is different from the solvent used for the dissolution of aripiprazole.
  • ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone
  • aliphatic ether such as isopropyl ether, diethyl ether, methyl tert-butyl ether, di-n- butyl ether, diphenyl ether
  • aripiprazole crystal form B can be isolated from the resulting solution by inducing precipitation by any suitable method. Precipitation can be induced from the solution by reducing the temperature of the solution or by concentrating the solution by evaporation followed by cooling.
  • aripiprazole crystal form B can be isolated from the resulting solution by reducing the temperature of solution.
  • the solution can be cooled - 40 to 60 °C and/or stirred for few minutes to several hours, preferably -5 to 10 °C for 10 to 60 minutes, preferably till complete precipitation of the product takes place.
  • pre cooled second solvent can be added to the solution of aripiprazole in suitable solvent or reverse addition can be carried out to shorten the cooling time and to fasten the precipitation, this makes the solution to cool immediately and results aripiprazole of lower particle size as compared to undisturbed cooling of the solution.
  • Second solvent can be cooled to a temperature of less than ambient temperature, preferably - 40 °C to 25 °C prior to mixing with aripiprazole solution.
  • Crystal form B of aripiprazole can be isolated from resulting mixture by suitable techniques such as filtration, centrifugation and the like.
  • aripiprazole crystal form B can be isolated from the resulting solution by concentrating the solution.
  • the solution can be concentrated by the partial or complete removal of the solvents from the solution. Thereafter, the resulting residue can be cooled to -40 to 60 °C and/or stirred for few minutes to several hours, preferably -5 to 10 °C for 10 to 60 minutes, preferably till complete precipitation of product takes place.
  • Crystal form B of aripiprazole can be isolated from resulting mixture by suitable techniques such as filtration, centrifugation and the like.
  • the rate of cooling used in processes of the present invention is not particularly limited but in general can be used to affect the particle size of the formed crystals.
  • a faster rate of cooling generally leads to smaller crystals where as gradual cooling rate; i.e., allowing the solution to cool without special cooling leads to larger crystals.
  • the final temperature after cooling may also affect particle size, yield and/or purity of the product.
  • Solution can be stirred at high speed or slow speed. It may affect the nature of the product obtained from the solution. Stirring speed of the solution can be 60 to 3000 revolution per minutes (rpm) or more; preferably more than 200 rpm. Solution can be stirred without making any special emphasis on speed of revolution of solution.
  • the order and manner of adding the solvents to aripiprazole does not affect the nature of the final product but cooling rate can make an impact on particle size.
  • the amount of solvent added to each stage may depend on several factors such as amount of aripiprazole to be crystallized and/or purity of starting aripiprazole. It is found by the present inventor that the specific solvent system used in the present invention, proved to be highly advantageous in yielding the aripiprazole hydrate A and crystal form B of particular particle size.
  • Crystalline polymorph of aripiprazole both hydrate A and crystal form B thus isolated by the processes of present invention yield aripiprazole having particle size less than 100 ⁇ .
  • a common particle size distribution of aripiprazole prepared by the present invention falls within the range 35 to 85 ⁇ . It is found that the crystalline aripiprazole particles formed by the process of present invention are in the desired size/population whereas milling to obtain a desired smaller size is not preferred because it tends to cause and/or increase hygroscopicity of aripiprazole.
  • Aripiprazole hydrate A as well as crystal form B can be incorporated into pharmaceutical composition in the form of particles having a particle size of 100 ⁇ or less.
  • aripiprazole For increasing rate of dissolution, it is normally desired that aripiprazole have an average particle size of less than 100 ⁇ , or 50 ⁇ or less. Similarly, the population of particles typically has a dci 0 of not greater than 100 ⁇ , more typically not greater than 50 ⁇ .
  • present invention provides an improved, efficient and industrially advantageous process for the preparation of crystalline aripiprazole type-II by providing a mixture of aripiprazole in a suitable solvent followed by addition of hydrocarbon solvent.
  • the process involves heating of mixture of aripiprazole in a suitable solvent at a temperature of 50 °C to reflux temperature of solvent till complete dissolution.
  • Mixture of aripiprazole in suitable solvent can be provided by various means which is not particularly limited.
  • the temperature for the dissolution also depends on volume and nature of solvent used.
  • the temperature at which aripiprazole is dissolved in a suitable solvent may range from 50 °C to reflux temperature of the solvent.
  • the dissolution can be carried out above 55 °C.
  • aripiprazole can be synthesized in a suitable solvent and reaction mixture containing aripiprazole solution can be used for further crystallization process to prepare crystalline aripiprazole Type II.
  • Solvent employed for dissolution can be selected from solvent in which aripiprazole is having more solubility.
  • solvent can be selected from ethers such as tetrahydrofuran; ketones such as acetone; nitriles such as acetonitrile and the like or mixture thereof or mixture with water.
  • the concentration of aripiprazole solution may be varied according to the solvent used, and its volume and temperature of dissolution.
  • the volume of solvent used can vary from 1 to 45 ml for 1 gm of starting aripiprazole; preferably 2 to 40 ml of solvent can be used for 1 gm of solvent. More preferably, 2 to 35 ml of solvent can be used for the dissolution of 1 gm of starting aripiprazole.
  • the solution of aripiprazole in a suitable solvent is then combined with second solvent in which aripiprazole is insoluble or is less soluble.
  • Second solvent is preferably hydrocarbon solvent such as n-hexane, n-heptane, cyclohexane and the like or mixture thereof.
  • Hydrocarbon solvent can be added to the solution of aripiprazole or solution of aripiprazole can be added to hydrocarbon solvent.
  • the amount of hydrocarbon solvent can vary depending upon the nature of solvent and it is not particularly limited. Preferably, 1 to 45 ml of hydrocarbon solvent can be added to the solution with respect to 1 gm of starting aripiprazole, more preferably 2 to 40 ml of hydrocarbon solvent is used for the process with respect to 1 gm of starting aripiprazole.
  • Hydrocarbon solvent can be optionally chilled prior to mixing with solution of aripiprazole in order to induce fast crystallization. Preferably hydrocarbon solvent can be cooled to a temperature of -10 to 15 °C, most preferably 0 to 5 °C. Use of chilled hydrocarbon solvent for the preparation of crystalline aripiprazole type II has been found to beneficial in terms of high yield of crystalline aripiprazole type II.
  • crystallization can be induced or aided by adding small amount of seed crystal of aripiprazole Type II.
  • Seeding material can be added prior to mixing with hydrocarbon solvent or after the mixing the initial solution with hydrocarbon solvent or it can be added along with hydrocarbon solvent.
  • seeding can be carried out at a temperature of 50 to 60 °C, preferably at temperature where seed crystals do not dissolve in resulting mixture.
  • seed crystals can be first suspended in hydrocarbon solvent and then resulting suspension is mixed with a solution of aripiprazole in a suitable solvent.
  • Suspension of seed crystal of aripiprazole Type II in hydrocarbon solvent can be added to solution of aripiprazole or a solution of aripiprazole can be added to the suspension of seed crystals in hydrocarbon solvent.
  • suspension of seed crystals in hydrocarbon solvent can be optionally chilled prior to mixing with solution of aripiprazole.
  • suspension can be cooled to a temperature of -10 to 15 °C, most preferably 0 to 5 °C.
  • the amount of seed crystal can vary from 0.2% to 10 % by weight of starting aripiprazole, preferably 0.4 % to 8 %, more preferably 0.5 to 5 % by weight of starting aripiprazole.
  • the mixture comprising aripiprazole, first solvent and hydrocarbon solvent with or without seeding can be stirred at a temperature of 5 °C to ambient temperature till complete formation of crystalline aripiprazole Type II take place.
  • mixture can be stirred at a temperature of 5 to 30 °C for 30 minutes to 30 hours.
  • the mixture can be first stirred at a temperature of 20-30 °C and then can be optionally cooled to temperature of 0 to 15 °C.
  • Preferably mixture can be cooled to a temperature of 0 to 5 °C.
  • Resulting product i.e. aripiprazole Type II can be isolated from the mixture using a suitable techniques known in art such as filtration, centrifugation, decantation and the like.
  • filtration of crystalline aripiprazole type II can be carried out at a temperature of 0- 10 °C, more preferably at a temperature of 0- 5 °C.
  • Isolated aripiprazole Type II can be optionally washed with suitable solvent selected from hydrocarbon solvent such as n-heptane, n-hexane, cyclohexane and the like or mixture thereof.
  • suitable solvent selected from hydrocarbon solvent such as n-heptane, n-hexane, cyclohexane and the like or mixture thereof.
  • Aripiprazole Type II thus obtained by the process of present invention can be dried using suitable techniques known in the art.
  • Starting material, aripiprazole, used for preparation of hydrate A, crystal form B and Type II of present invention can be of any polymorphic form for example an isolated or un-isolated crude product arising from the synthesis of aripiprazole or an aripiprazole product already crystallized such as the hydrate form A, Type I, Type II, Type III or Form B to G or form XII, compound 2, form C, anhydrate, hydrate, solvate and mixture thereof as made by the techniques disclosed in the art, including hydrated and solvated forms.
  • Starting material can be amorphous or crystalline or solvate of aripiprazole.
  • the main advantage of the present invention is that it provides a process for preparation of crystalline aripiprazole hydrate A, crystal form B and Type II which circumvent the adherence of aripiprazole to equipment by avoiding milling and also circumvent the need of special handling techniques to maintain the equipment and does not require thermal treatment at a temperature higher than 100 °C which can decompose the product.
  • Present invention provides a new solvent system for synthesis of aripiprazole hydrate A as well crystal form B that directly yield the product with a particle size less than 100 ⁇ ⁇ ⁇ without need of milling or special equipment such as jet stream.
  • a suspension of aripiprazole (100 g) in a mixture of ethanol (1600 ml) and water (400 ml) was heated to reflux till complete dissolution. The solution was filtered to remove suspended particles. Acetone (1500 ml) was added to resulting filtrate at 75-78 °C. The reaction mass was cooled under stirring and the temperature was brought down 0-5 °C. The reaction mass was stirred for 60 minutes at 0-5 °C. The solid thus precipitated was filtered and dried below 50 °C for 2 hours to give title compound having particle size diameter of dg 48.42 ⁇ .
  • a suspension of aripiprazole (100 g) in a mixture of ethanol (1600 ml) and water ( 400 ml) was heated to reflux till complete dissolution. The solution was filtered to remove suspended particles. Diisopropyl ether (1500 ml) was added to the resulting filtrate at 70-75 °C. The reaction mass was rapidly cooled under stirring and temperature was brought down 0-5 °C. The reaction mixture was stirred for 60 minutes. The precipitated solid was filtered and dried to give title compound having particle size diameter of d % 45 ⁇ .
  • Diisopropyl ether (1500 ml) was added to resulting filtrate at 70-75°C.
  • Reaction mixture was cooled under rapid stirring of around 200 rpm and the temperature was brought down 10-15 °C.
  • a suspension of aripiprazole (5 g) in acetone (100 ml) was heated to reflux till complete dissolution.
  • the hot reaction mixture was added into cold isopropyl ether (75 ml, 0 to -5 °C) and then cooled to 0-5 °C.
  • Reaction mixture was stirred for 1 hour followed by distillation of solvent (approximately 80 %) under vacuum at below 35 °C. Resulting reaction mixture was cooled to 0-5 °C and stirred for 1 hour.
  • a suspension of aripiprazole (100 g) in a ethanol (1500 ml) was heated to reflux till complete dissolution.
  • the solution was filtered hot through a candle filter and poured into cold particle free methyl tertiary butyl ether (3000 ml) at -50 to -30 °C.
  • the reaction mass was stirred at -30 to -15 °C for 3 hours.
  • Resulting solid was filtered and suck dried for 30 minutes.
  • Aripiprazole (5 g) was dissolved in acetonitrile (150 ml) at 80-82 °C. Chilled n-heptane (150 ml) containing seeds of Type II crystals (0.1 g) was added to the above solution and stirred for 1 hour. Mixture was further stirred at room temperature for 24 hours. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for 60 minutes. Product thus formed was filtered, washed with chilled n-heptane and dried under vacuum to give 4.4 g of title compound.
  • Aripiprazole (5 g) was dissolved in acetonitrile (150 ml) at 80-82 °C. Above solution was added to chilled suspension of seeds of Type II crystals (0.1 g) in n-heptane (150 ml) and stirred for 1 hour. Mixture was further stirred at 20-25 °C for 24 hours. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for 60 minutes. Product thus formed was filtered, washed with chilled n-heptane and dried under vacuum at 80-85 °C to give 4.1 g of title compound.
  • Aripiprazole (5 g) was dissolved in tetrahydrofuran (10 ml) at 60-65°C. Above solution was added to a chilled suspension containing seeds of Type II crystals (0.1 g) in n-heptane (10 ml) and stirred for 1 hour. Mixture was further stirred at 20-25 °C for 24 hours. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for 30 minutes. Product thus formed was filtered, washed with chilled n-heptane and dried under vacuum at 80-85 °C to give 3.8 g of title compound.
  • Aripiprazole (5 g) was dissolved in acetone (110 ml) at 50-55°C. Above solution was added to chilled n-heptane (1 10 ml) containing seeds of Type II crystals (0.1 g) and stirred for 1 hour. Mixture was further stirred at room temperature for 24 hours. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for one hour. Product thus formed was filtered, washed with chilled n-heptane and dried under vacuum at 80-85 °C to give 4.2 g of title compound.
  • Aripiprazole (5 g) was dissolved in acetonitrile (200 ml) at reflux temperature and the hot solution was poured into chilled cyclohexane (100 ml) containing seeds of aripiprazole Type II crystals (0.1 g). The reaction mass was stirred at 25-30 °C. The reaction mass was then cooled to 0-5 °C and stirred for 60 minutes. Product thus formed was filtered, washed with n- heptane (25 ml) and dried under vacuum for 12 hours to give 4.3 g of title compound.
  • Example 19 Preparation of aripiprazole Type II
  • Aripiprazole (5 g) was dissolved in acetonitrile (200 ml) at reflux temperature and n-heptane (100 ml) was added to the solution followed by seeds of aripiprazole Type II crystals. Resulting mixture was stirred at 25-30 °C. The reaction mass was then cooled to 0-5 °C and stirred for 60 minutes. Product thus formed was filtered, washed with n- heptane (25 ml) and dried under vacuum for 12 hours to give 4.4 g of title compound.
  • Aripiprazole 50 g was dissolved in acetone (1.25 L) at 50-60 °C and solution was filtered to remove suspended particles. Particle free n-heptane (175 ml) was slowly added to the above solution and was stirred then slowly cooled to 20-25 °C till complete formation of Type II crystals. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for 3 hours. Resulting product was filtered, washed with chilled n-heptane and dried under vacuum at 80-85 °C for 12 hours to give 44 g of title compound.
  • Aripiprazole (50 g) was dissolved in acetone (1.25 L) at 50-60 °C.
  • n-Heptane (1.25 L) was added to the above solution followed by addition of seeds of Type II crystals (1 g).
  • Reaction mass was cooled to 20-25 °C and stirred till complete formation of Type II crystals. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for 3 hours.
  • Product thus formed was filtered, washed with chilled n-heptane and dried under vacuum at 80-85 °C for 12 hours to give 41.5 g of title compound.
  • Example 22 Preparation of aripiprazole Type II
  • Aripiprazole 50 g was dissolved in acetone (1.25 L) at 50-60 °C. The hot resulting solution was poured into n-heptane (1.25 L) containing seeds of Type II crystals and was stirred at 20-25 °C for 24 hours. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for 3 hours. Product thus formed was filtered, washed with chilled n-heptane and dried under vacuum at 80-85 °C to give 42.2 g of title compound.
  • Aripiprazole (50 g) was dissolved in a mixture of acetone (1.0 L) and water (0.25 L) at 60-65 °C. Resulting solution was poured into n-heptane (1.0 L) containing seeds of Type II crystals and the stirred at 20-25 °C for 24 hours. Thereafter the reaction mass was cooled to 0 to 5 °C and stirred for 3 hours. Resulting solid was filtered, washed with chilled n-heptane and dried under vacuum at 80-85 °C to give 42.2 g of title compound.

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Abstract

L'invention concerne une méthode de préparation de polymorphes et d'hydrates d'aripiprazole A, de forme B et de type II. Elle concerne également une méthode de préparation de polymorphes d'aripiprazole présentant une taille moyenne des particules inférieure à 100 μm, au moyen d'un système de solvants spécifique, dans des conditions de réaction pouvant induire la précipitation.
PCT/IN2011/000830 2010-12-07 2011-12-05 Méthode de préparation de polymorphes d'aripiprazole WO2012077134A1 (fr)

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IN2905/DEL/2010 2010-12-07
IN2905DE2010 2010-12-07

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Publication number Priority date Publication date Assignee Title
CN104151237A (zh) * 2014-08-08 2014-11-19 广东东阳光药业有限公司 一种小粒径喹诺酮衍生物的制备方法
JP2016069349A (ja) * 2014-10-01 2016-05-09 株式会社パーマケム・アジア アリピプラゾール無水物ｂ形結晶の製造方法
CN105924393A (zh) * 2016-07-05 2016-09-07 陕西省食品药品检验所 一种阿立哌唑新晶型及其制备方法
JP2017526747A (ja) * 2014-08-25 2017-09-14 アルカームス ファーマ アイルランド リミテッド 統合失調症治療用の持続放出型製剤におけるアリピプラゾール誘導体の結晶化プロセス
US20180155290A1 (en) * 2015-05-08 2018-06-07 Davuluri Ramamohan Rao Improved Process for the Preparation of Aripiprazole with Reduced Particle Size

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WO2005058835A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Procedes de preparation de formes cristallines d'aripiprazole
CN1772738A (zh) * 2005-06-07 2006-05-17 上海医药工业研究院 阿立哌唑晶型及其制备方法
WO2006053781A1 (fr) * 2004-11-18 2006-05-26 Synthon B.V. Procédé de synthèse d'aripiprazole cristallin
CN101172966A (zh) * 2007-04-06 2008-05-07 重庆医药工业研究院有限责任公司 一种阿立哌唑微晶的制备方法

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Publication number Priority date Publication date Assignee Title
WO2005058835A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Procedes de preparation de formes cristallines d'aripiprazole
WO2006053781A1 (fr) * 2004-11-18 2006-05-26 Synthon B.V. Procédé de synthèse d'aripiprazole cristallin
CN1772738A (zh) * 2005-06-07 2006-05-17 上海医药工业研究院 阿立哌唑晶型及其制备方法
CN101172966A (zh) * 2007-04-06 2008-05-07 重庆医药工业研究院有限责任公司 一种阿立哌唑微晶的制备方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104151237A (zh) * 2014-08-08 2014-11-19 广东东阳光药业有限公司 一种小粒径喹诺酮衍生物的制备方法
JP2017526747A (ja) * 2014-08-25 2017-09-14 アルカームス ファーマ アイルランド リミテッド 統合失調症治療用の持続放出型製剤におけるアリピプラゾール誘導体の結晶化プロセス
JP2016069349A (ja) * 2014-10-01 2016-05-09 株式会社パーマケム・アジア アリピプラゾール無水物ｂ形結晶の製造方法
US20180155290A1 (en) * 2015-05-08 2018-06-07 Davuluri Ramamohan Rao Improved Process for the Preparation of Aripiprazole with Reduced Particle Size
CN105924393A (zh) * 2016-07-05 2016-09-07 陕西省食品药品检验所 一种阿立哌唑新晶型及其制备方法

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