Home » New drugs EU » The European Medicines Agency (EMA) Approves Otsuka’s Aripiprazole (ABILIFY®) for the Treatment of Moderate to Severe Manic Episodes in Bipolar I Disorder in Adolescents

The European Medicines Agency (EMA) Approves Otsuka’s Aripiprazole (ABILIFY®) for the Treatment of Moderate to Severe Manic Episodes in Bipolar I Disorder in Adolescents


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Aripiprazole (OPC-14597, OPC-31, BMS-337039) cas no 129722-12-9

Aripiprazole is a psychotropic drug that is available as ABILIFY® (aripiprazole) Tablets, ABILIFY DISCMELT® (aripiprazole) Orally Disintegrating Tablets, ABILIFY® (aripiprazole) Oral Solution, and ABILIFY® (aripiprazole) Injection, a solution for intramuscular injection.

Abilify 2mg tablets (US)

Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)-1- piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C23H27Cl2N3O2 and its molecular weight is 448.38.

ABILIFY® (aripiprazole)  Structural Formula Illustration

ABILIFY Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

ABILIFY DISCMELT Orally Disintegrating Tablets are available in 10 mg and 15 mg strengths. Inactive ingredients include acesulfame potassium, aspartame, calcium silicate, croscarmellose sodium, crospovidone, crème de vanilla (natural and artificial flavors), magnesium stearate, microcrystalline cellulose, silicon dioxide, tartaric acid, and xylitol. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake.

ABILIFY Oral Solution is a clear, colorless to light yellow solution available in a concentration of 1 mg/mL. The inactive ingredients for this solution include disodium edetate, fructose, glycerin, dl-lactic acid, methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose, and purified water. The oral solution is flavored with natural orange cream and other natural flavors.

ABILIFY Injection is available in single-dose vials as a ready-to-use, 9.75 mg/1.3 Ml (7.5 mg/mL) clear, colorless, sterile, aqueous solution for intramuscular use only. Inactive ingredients for this solution include 150 mg/mL of sulfobutylether β-cyclodextrin (SBECD), tartaric acid, sodium hydroxide, and water for injection.

Wednesday, February 6, 2013

Otsuka Pharmaceutical Co. Ltd. announced today that the European Medicines Agency (EMA) has approved a label extension for aripiprazole for the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 and older.

Aripiprazole was studied in a 30-week placebo controlled trial involving 296 children and adolescents, who met DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥ 20 at baseline. Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS total score.
The recommended dose for aripiprazole in this indication is 10mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2mg (using aripiprazole oral solution 1mg/ml) for 2 days, titrated to 5mg for 2 additional days to reach the recommended daily dose of 10 mg.
The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. The frequency and type of undesirable effects in adolescents with Bipolar I Disorder were similar to those in adults except for somnolence, extrapyramidal disorder, akathisia, and fatigue, abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia. Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, aripiprazole is not recommended for use in patients below 13 years of age
Aripiprazole brand names: AbilifyAripiprex) is a partial dopamine agonist of the second generation class of atypical antipsychoticswith additional antidepressant properties that is used in the treatment of schizophrenia,bipolar disorder, and clinical depression. It was approved by the U.S. Food and Drug Administration (FDA) for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007; and to treat irritability in children with autism on 20 November 2009.[1][2] Aripiprazole was developed by Otsuka in Japan, and in the United States,Otsuka America markets it jointly with Bristol-Myers Squibb.
patent expiry
United States 5006528 1994-10-20 2014-10-20
United States 7115587 2005-01-21 2025-01-21
Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amineU.S. Patent 5,006,528
Aripiprazole synth.png

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2 (1H)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia (U.S. Pat. No. 4,74,416 and U.S. Pat. No. 5,006,528). 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 (Aripiprazole) is an atypical antipsychotic, on 15 November 2002 by the U.S. FDA clearance to market, its efficacy is through the dopamine D2 receptor and serotonin 5HT1A receptor partial agonist activity and serotonin 5HT2A receptor antagonism activity mediated common. With its unique mechanism of action and safety assessment, aripiprazole known as third-generation antipsychotic drugs.

[0003] Aripiprazole is a quinolinone derivative, developed by the Japanese company Otsuka Pharmaceutical, the chemical name

Is: 7 – {4 – [4 - (2,3 - dichlorophenyl)-1_ piperazinyl] butoxy} -3,4 – dihydro-quinolone, the following structural formula:


Figure CN101538252BD00031

[0005] For the preparation of aripiprazole, Japanese OtsukaPharmaceutical’s patent EP 0367141A2, and related patents US4234585, CN89108934 preparation methods described in 5. In addition, the patent CN1450056A, CN1562973A, CN1784385A, CN1680328A, CN1576273A, etc. describe some of these five Preparation

Method is very similar way. These preparation methods are direct or indirect use of 7 – hydroxy -3,4 – dihydro – quinolin-2 – one (HCS) that the key to higher prices of raw materials, and some methods involve harsh reaction conditions, poor selectivity, low yield, but also increases the cost of industrial production of the product.

[0006] Chinese patent CN1304373C preparation method is not described in the 7 – hydroxy-3 ,4 _ dihydro-2_ (1H) – quinoline

Quinolone intermediates for their preparation of the core reaction is as follows:


Figure CN101538252BD00032

[0008] This reaction is Friedel-Crafts alkylation reaction, there is a harsh reaction conditions, the yield is low, the reaction selectivity is poor, the shortcomings of high emissions, is not conducive to industrial mass production. SUMMARY OF THE INVENTION

[0009] In order to solve the above problems, the present invention provides a simple, high selectivity, high yield, low cost, environmentally friendly, easy to prepare industrialization aripiprazole and intermediates thereof.

[0010] The technical solution of the present invention, the present invention provides in one aspect a process for preparingaripiprazole novel intermediates.

[0011] The present invention, on the other hand provides a method for the preparation of intermediates.

[0012] The present invention provides the use of the other intermediates for preparing aripiprazole two new preparation methods.

[0013] Specifically, the present invention relates to novel intermediates, compounds of formula ⑴:


Figure CN101538252BD00041

[0015] wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl and other common alkyl groups in any one, and preferably is ethyl.

[0016] Compound of formula ⑴: 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate, is the following prepared by the procedure:

[0017] Step one, the acylation reaction: with 4 – methyl – 3 – nitro-phenol (VIII) and acetic anhydride as the raw material, DMAP as catalyst, to give 4 – methyl – 3 – nitrophenyl acetate ( VII).

[0018] wherein 4 – methyl – 3 – nitro-phenol (VIII), acetic anhydride, DMAP molar ratio is preferably 1: 1.0 to 1.4: 0.05, at room temperature, the reaction time is preferably 0.5 to 3 hours.

[0019] Step two, the bromination reaction: The resulting product, 4 to Step one – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide and benzoyl peroxide as a raw material , carbon tetrachloride solvent reflux, to give 4 – bromomethyl-3 – nitrophenyl acetate (VI).

[0020] wherein 4 – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide, benzoyl peroxide molar ratio is preferably 1: 1 to 1.2: 0.05, reaction time is preferably 4-18 hours.

[0021] Step three, instead of the reaction: in an appropriate solvent, adding an alkaline agent and diethyl malonate was stirred in an ice bath, was added dropwise step two the resulting product, 4 – bromomethyl-3 – nitrophenyl yl acetate (VI) solution after completion of the addition reaction of 1 to 3 hours to obtain a brown liquid product, 2 – (4_ acetoxy-2 – nitrobenzyl) malonate (V).

[0022], wherein the alkali agent is a common organic or inorganic base selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide; the solvent is selected from tetrahydrofuran, methanol, ethanol, butanol, tert-butanol, toluene or N, N-dimethylformamide; 4 – bromomethyl-3 – nitrophenyl acetate (VI), alkaline agent and lipid diethyl molar ratio is preferably 1: 1.0 to 1.8: 1.0 to 1.4.

[0023] Step 4 Hydrolysis decarboxylation: the product obtained in Step Three 2 – (4_ acetoxy-2 – nitro-benzyl)-malonic acid diethyl ester (V) was added concentrated hydrochloric acid and a suitable solvent, heating and stirring reflux, to give a yellow solid product 3 – (4_ hydroxy-2 – nitrophenyl) propionic acid (IV).

[0024] wherein the solvent is selected from water, methanol, ethanol or acetic acid, water soluble solvent, was heated with stirring under reflux time is preferably 3 to 18 hours. [0025] Step five, the esterification reaction: the product obtained in step 4, 3 – (4 – hydroxy-2 – nitrophenyl) propionic acid (IV) was added to an appropriate solvent, the mixture was stirred in an ice bath, was added dropwise thionyl sulfone, after completion of the addition reaction of 1 to 3 hours, to give a pale brown liquid product 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III).

[0026] wherein the solvent is selected from anhydrous methanol, ethanol, propanol, isopropanol, butanol, t-butanol, benzyl alcohol, alcohol and other common solvents.

[0027] Step VI substitution reaction: 1,4 – dibromobutane was added to an appropriate solvent and an alkaline reagent, heated to 50 ~ 100 ° C, the product obtained was added dropwise Step Five 3 – (4_ hydroxy – nitrophenyl) propionate (III) solution, after the addition was complete the reaction was kept 2 to 4 hours to obtain a brown liquid product 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II).

[0028] wherein the solvent is selected from methanol, 95% ethanol, ethanol, acetonitrile and N, N-dimethylformamide, and the like; said alkaline agent is a common organic or inorganic weak base, such as triethylamine, pyridine, potassium carbonate, sodium carbonate, etc..

[0029] Step 7 condensation reaction: the product obtained in Step Six 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II) adding a suitable solvent, (2,3 – dichlorophenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, to obtain

The intermediate product 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl)-piperazin-1 – yl) butoxy)-2 – nitrophenyl) propionate ⑴.

[0030] Among them, 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate (I), (2, 3 – dichloro-phenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, the four molar ratio is preferably 1: 0.9 to 1.0: 2.0 to 2.2: 0.05 to 0.5. The solvent is selected from methanol, ethanol and N, N-dimethylformamide, acetonitrile and the like. Step six of the alkaline reagent and alkaline reagent used in the same, said catalyst is a common low-iodine salts, such as sodium iodide, potassium iodide.

[0031] The present invention provides two other hand, the use of a compound of formula ⑴ preparing aripiprazole new method.

[0032] Method one: ⑴ intermediate compound of formula in an appropriate solvent in the acid or salt or a base in the presence of a reducing agent under the action of restoring ring closure reaction to obtain aripiprazole.

[0033] Method one reductive cyclization of the reducing agent used is iron, zinc, sodium sulfide, stannous chloride, and preferably iron; reaction solvent is selected from water, methanol, ethanol, ethyl acetate or in one or more of the mixed solvent; said acid is a common organic or inorganic acid, preferably acetic acid or hydrochloric acid; said salt is a common inorganic or organic salts selected from chloride, ferrous chloride, , ammonium sulfate, calcium chloride, zinc chloride, sodium chloride, sodium bromide or sodium acetate and the like; common said base is an inorganic base selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate; the reduction ring-closing reaction temperature range of 30 ~ 140 ° C, preferably about 80 ° C; reaction time ranges from about 0.5 to 8 hours, preferably 2 hours.

[0034] Method two: ⑴ intermediate compound of formula in an appropriate solvent in the first catalyst, the reduction reaction, and then carried out in a suitable solvent can be prepared by cyclization of aripiprazole.

[0035] The reduction reaction of the second approach, the reducing agent is hydrogen or a carboxylic acid; the catalyst is selected from molybdenum, molybdenum dioxide or Raney nickel, preferably Raney nickel; the solvent is selected from methanol, ethanol, ethyl acetate or acetic acid, preferably ethanol; said ring-closing reaction of the solvent is selected from N, N-dimethylformamide, trichlorobenzene or xylene; reaction temperature range of 50 ~ 180 ° C, preferably about 70 ~ 150 ° C; reaction time the range of about 1 to 8 hours.

[0036] In summary, the present invention is described for preparing aripiprazole method in 4– methyl – 3 – nitro-phenol (VIII) as a starting material, by acetylation protected hydroxy, radical instead of 4 – bromomethyl-3 – nitrophenyl acetate (VI), the diethyl malonate and a nucleophilic substitution reaction to obtain 2 – (4_ acetoxy-2 – nitrobenzyl ) malonic acid diethyl ester (V), which is decarboxylated by hydrolysis, esterification, to give 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III), the reaction product with dibromobutane an ether compounds, and with (2,3 – dichlorophenyl)-piperazine hydrochloride 1_ condensation, to give 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl) piperazine -1 – yl) butoxy) -2 – nitrophenyl) propionate (I), and then by reductive cyclization step, or first reduced and then ring-closing reaction of aripiprazole. The synthetic route of the present invention is as follows: [0037]

Figure CN101538252BD00061

According to Example 1 of Japanese Unexamined Patent Publication No. 191256/1990, anhydrous aripiprazole crystals are manufactured for example by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with 1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting raw anhydrousaripiprazole with ethanol. Also, according to the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996), anhydrousaripiprazole crystals are manufactured by heating aripiprazole hydrate at 80° C. However, the anhydrous aripiprazole crystals obtained by the aforementioned methods have the disadvantage of being significantly hygroscopic.

The hygroscopicity of these crystals makes them difficult to handle since costly and burdensome measures must be taken in order ensure they are not exposed to moisture during process and formulation. Exposed to moisture, the anhydrous form can take on water and convert to a hydrous form. This presents several disadvantages. First, the hydrous forms of aripiprazole have the disadvantage of being less bioavailable and less dissoluble than the anhydrous forms ofaripiprazole. Second, the variation in the amount of hydrous versus anhydrousaripiprazole drug substance from batch to batch could fail to meet specifications set by drug regulatory agencies. Third, the milling may cause the drug substance, Conventional Anhydrous Aripiprazole, to adhere so manufacturing equipment which may further result in processing delay, increased operator involvement, increased cost, increased maintenance, and lower production yield. Fourth, in addition to problems caused by introduction of moisture during the processing of these hygroscopic crystals, the potential for absorbance of moisture during storage and handling would adversely affect the dissolubility of aripiprazole drug substance. Thus shelf-life of the product could be significantly decreased and/or packaging costs could be significantly increased. It would be highly desirable to discover a form of aripiprazole that possessed low hygroscopicity thereby facilitating pharmaceutical processing and formulation operations required for producing dosage units of an aripiprazole medicinal product having improved shelf-life, suitable dissolubility and suitable bioavailability.

Also, Proceedings of the 4 the Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) state that, anhydrous aripiprazole crystals exist as type-I crystals and type-II crystals; the type-I crystals of anhydrous aripiprazolecan be prepared by recrystallizing from an ethanol solution of aripiprazole, or by heating aripiprazole hydrate at 80° C.; and the type-II crystals of anhydrousaripiprazole can be prepared by heating the type-I crystals of anhydrousaripiprazole at 130 to 140° C. for 15 hours.

By the aforementioned methods, anhydrous aripiprazole type-II crystals having high purity can not be easily prepared in an industrial scale with good repeatability.

Chemical Synthesis of Aripiprazole (active ingredient for Abilify)

Chemical Synthesis of Abilify-Aripirazole-Atypical Antipsychotics-Otsuka-BMS-aripiprazole - Ann re ピ have suitable plastic AKZO

Experimental Procedures for the preparation of Aripiprazole (Abilify, aripiprazole)

US 5,006,528 discloses process for the preparation of Aripiprazole in two steps The first step comprises synthesis of 7 -. (4-bromobutoxy) -3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3, 4 -dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield The resulting 7-BBQ is further reacted with 1 -. (2,3 – dichlorophenyl)-piperazine to obtain Aripiprazole.

Preparation of 7 – (4-Bromobutoxy) 3 ,4-dihydro-2 (1H) quinolinon ( 7 – (4-Bromobutoxy) 3 ,4-dihydrocarbostyril; 7-BBQ)

7-Hydroxy-3 ,4-dihydro-2 (1H)-quinolinone (aka 7-Hydroxy-3 ,4-dihydrocarbostyril, 60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40 – 45 ° C for 24 hours Reaction mass was cooled upto room temperature and was filtered off The resulting filtrate was distilled off.. under vacuum. The resultant mass was cooled to 25-30 ° C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The . solid was filtered and dried under vacuum at 55-60 ° C for 20 hours to obtain title compound mp 110.5-111 ° C; 1H NMR (DMSO-d6) ä 1.81 (2H, m,-CH2-), 1.95 (2H , m,-CH2-), 2.41 (2H, t, J) 7 Hz,-CH2CO-), 2.78 (2H, t, J) 7 Hz,-CH2-C-CO-), 3.60 (2H, t, J) 6 Hz,-CH2Br), 3.93 (2H, t, J) 6 Hz, O-CH2-), 6.43 (1H, d, J) 2.5 Hz), 6.49 (1H, dd, J) 2.5, 8 Hz ), 7.04 (1H, d, J) 8 Hz), 9.98 (1H, s, NHCO). Anal. (C13H16NO2Br) C, H, N.

Yield: 73-75%; Purity: 93-95%

Preparation of Aripiprazole (7 – {4 – [4 - (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One)

7 – (4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30 ° C. To this potassium carbonate (67.2 gm) and l – (2,3 – dichlorophenyl). piperazine hydrochloride (44.9gm) were added under stirring The reaction mixture was refluxed at 80-85 ° C for 8 hours The reaction mass was cooled to room temperature, filtered and the resulting solid was washed. with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80 ° C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to . obtain title compound Yield: 75-80%; Dimer Impurity: <0.1% 1H NMR:. DMSO-d6 d 9.96 [1H, s, NH]; 7.29 [2H, m, Ar]; 7.13 [1H, q, Ar ]; 7.04 [1H, d, Ar]; 6.49 [1H, dd, Ar]; 6.45 [1H, d, Ar]; 3.92 [2H, t,-CH2-O-]; 2.97 [4H, bb, 2 ( -CH2-)]; 2.78 [2H, t,-CH2-N2-)]; 2.39 [4H, m, 2 (-CH2-)]; 1.73 [2H, m, - CH2-]; 1.58 [2H, m .,-CH2-] IR: cm-1 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588 .

Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water
Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85 ° C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30 ° C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 6 hours to obtain title compound.
Yield: 87-89% HPLC Purity: 99.89
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 15.83 m, d 50 = 60.12 m, d 90 = 144.99 m
Preparation of aripiprazole anhydrous Type I using ethanol and water
Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85 ° C for 1-2 hours. The resulting mixture was cooled to 25-30 ° C within 4 hours and . stirred for 3 hours The resulting solid was filtered and dried under suction for 1 hour The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 3 hours to obtain title compound Yield:.. 90% HPLC Purity: 99.9 %
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 22.01 m, d 50 = 105.10 m, d 90 = 232.97 m

For the Process of references Aripiprazole (Abilify, Japanese: Oh, Bldg re phi, Ann reピplastic AKZO have suitable; Chinese: Ann-law who, aripiprazole)

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi, Tatsuyoshi Tanaka, Tetsuro Kikuchi, Katsura Tottori, Yasufumi Uwahodo, and Takao Nishi; Novel Antipsychotic Agents with Dopamine autoreceptor Agonist Properties: Synthesis and Pharmacology of 7 – [4 - (4-Phenyl-1- piperazinyl) butoxy] – 3,4-dihydro-2 (1H)-quinolinone Derivatives ; J. Med Chem. 1998, 41, 658-667.

Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi; Carbostyril Derivatives , Otsuka Pharmaceutical Co., Ltd.;. U.S. Patent 5006528 ; Issue Date: Apr 9, 1991

BANDO, Takuji, YANO, Katsuhiko, FUKANA, Makoto, AOKI, Satoshi; Method for producing fine particles of aripiprazole anhydride crystals b; OTSUKA PHARMACEUTICAL CO, LTD, WO 2013002420 A1..

Yuanqiu Hui, Chen Hongwen, Qian Wen, firewood rain column, Xu Dan, Yang Zhimin, Tian Zhoushan; method for preparing high purity of aripiprazole; NJCTT Pharmaceutical Co., Ltd.; application number: 201210292382.0; Publication Number: CN102863377A; Publication date: 2013.01.09 After (The invention relates to the field of medicine and chemical industry, in particular to a method for preparing high purity of aripiprazole would join aripiprazole A solvent is heated, filtered, and the filtrate was added to a solvent B, low temperature mixing, filtration, the filter cake is suspended in water, adjusted to alkaline pH of the aqueous solution, filtration, high temperature vacuum dried to obtain a high-purity refined product Aripiprazole This method is simple, high purity, suitable for the industrial the large-scale application)


Zheng Si Ji, Liu Xiaoyi, Fulin Yong, Tan Bo, Zhou Min: A aripiprazole pharmaceutical formulation and preparation method; Shanghai Pharmaceutical Co., Ltd. and Western; Publication date: 2013.01.02: Application Number: CN 201210235157.3; Publication Number: CN102846543A (the invention provides a method for preparing aripiprazole pharmaceutical formulation, comprising the steps of: an acidic solution containing aripiprazole is dissolved in the acidulant, to obtain an acidic solution containing the drug; Thereafter, the resulting drug-containing acidic solution alkalizing agents and materials prepared by wet granulation or suspension to give aripiprazole pharmaceutical formulation; said excipients include antioxidants)

Zheng Si Ji; Tan wave; Fulin Yong; Liu Xiaoyi; Yuanshao Qing; Cao Zhihui; aripiprazole Ⅰ type microcrystalline, aripiprazole solid preparation and preparation methods; application number: 201110180032.0; Publication Number: CN102850268A; Publication Date: 2013.01.02

Cai Fu Bo, Qin Xinrong, Du Xiaochun, Li Ling; kind of aripiprazole improved method of synthesis; Chengdu Nakasone Pharmaceutical Group Co., Ltd.; Application Number: 200910058148.X; Publication Number: CN101781246A; Publication date: 2010.07.21 (the invention provides a method of synthesis of aripiprazole improved method according to the modified method of the present invention, aripiprazole into the etherification reaction and condensation reaction of two-step synthesis, by an etherification reaction in the quinolone compound and at least 6-fold molar equivalents of 1,4 – dihalo-butane reacted with a non-polar solvent ether aripiprazole precipitate, and recovering 1,4 – dihalo-butane recycling; azeotropic condensation reaction of a ketone to be / water mixture as solvent, aripiprazole etherified with a piperazine compound or a salt thereof in the presence of a base under reflux and alkaline metal iodide compound conditions, the amount of water added to the end of the reaction, cooling crystallization, filtration, and dried to give aripiprazole. improved high yield synthesis of high purity, step simple, low cost, suitable for industrial production.)

GUPTA, Vijay Shankar, KUMAR, Pramod, VIR, Dharam; Process for producing aripiprazole in anhydrous type i crystals; JUBILANT LIFE SCIENCES LIMITED; WO 2012131451 A1

SRIVASTAVA JAYANT GUPTA Vijay Shankar;. Improved process for the preparation of 7 (4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole; wo2011030213 A1

No Generic Abilify in the US until April 2015

On May 7, 2012, The US Court of Appeals for the Federal Circuit ruled in favor of Otsuka Pharmaceutical Co., Ltd. In its patent litigation against several companies including Israel-based Teva and Weston, Ontario-based Apotex seeking FDA approval to market generic copies of Abilify ®.. The Federal Circuit Affirmed a Decision of the U.S. District Court for the District of New Jersey Holding that the asserted claims ofU.S. Patent No. 5,006,528 Covering aripiprazole, the active Ingredient in Abilify ®, are Valid, THUS Maintaining Patent and Regulatory Protection for Abilify ® in the U.S. until at least April 20, 2015 . The Case is Otsuka Pharma Co.. V. sand Inc.., 2011-1126 and 2011-1127, US Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, US District Court for the District of New Jersey (Trenton).

Chemical Name for Aripiprazole (Abilify for active Ingredient): 7 – {4 – [4 - (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One
CAS Number 129722 -12-9
aripiprazole chemical name 7 – [4 - [4 - (2,3 - dichlorophenyl) -1 - piperazinyl] butoxy] -3,4 – dihydro-2 ( 1H) – quinolinone

Aripiprazole (, Aripiprazole, Abilify) is an atypical antipsychotic medication for the quinoline derivatives, aripiprazole is a dopamine system stabilizer first, positive and schizophrenia negative symptoms have a significant effect. For the treatment of schizophrenia, the development of Otsuka Pharmaceutical Co., Ltd., in November 15, 2002 by the U.S. Food and Drug Administration (FDA) approval in the U.S., domestic aripiprazole has (Booz clear (brisking, manufacturers : Chengdu Nakasone Pharmaceutical), Austrian (Manufacturer: Shanghai Pharmaceutical Co., Ltd. and Western)) have been approved by the listing in China. On sale in the United States where the law by Bristol-Myers Squibb is responsible. An law where the main patent protection in the United States, and more than three-quarters of its sales from the U.S., patent will expire in April 2015.

Aripiprazole synthetic route

7 – hydroxy-3 ,4. Dihydro -2 (1H) – quinolinone as a starting material, 1,4. Dibromobutane ether to give 7 – (4 – Bromo-butoxy) -3,4 – dihydro – 2 (1H) quinolinone, and then with 1 – (2,3 – dichlorophenyl) piperazine acid condensation aripiprazole (7 – [4 - [4 - (2,3 - dichlorophenyl) -1 - piperazinyl] butoxy] -3,4 – dihydro -2 (1H) – quinolinone)

Aripiprazole preparation method

7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone
A reaction flask was added 7 – hydroxy – 3,4 – dihydro -2 (1H) – quinolone 32.6 g (0.2mol), 1,4 – dibromo butane 129.5g (0.6mol), 11.2% KOH solution 250ml (0.5mol) and DMF975ml, was heated to 60 º C for 2h diluted with 1L water, the aqueous layer with ethyl acetate. acetate (300ml × 2) and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover the solvent, the residue was recrystallized from isopropanol, to give 7 – (4 – Bromo-butoxy) – 3,4 – dihydro -2 (1H) – quinolone 38.7g, yield 68%, mp108 ~ 110 º C.

Synthesis of aripiprazole
in the reaction flask was added 7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone, 29.8g (0.1mol), KI25g (0.15mol) 95% Ethanol 596ml, stirred and heated to 60 º C, was added N-2 30min after 3 – dichlorophenyl piperazine 23.1g (0.1mol) and triethylamine 20ml (0.15mol), stirred for 8h at 60 º C the mixture is filtered. crystallization filtrate was cooled, filtered and the filter cake was recrystallized twice from ethanol and dried to obtain aripiprazole 25.6g, yield 57%, mp138.9 ~ 139.6 º C.


Aripiprazole is a new antipsychotic belonging to the class of atypical antipsychotic drugs. It has been proposed that aripiprazole antipsychotic action could be mediated through a combination of partial agonist action at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors

Aripiprazole is a quinolinone derivative with the chemical name 7-[4-[4-(2,3-dichlorophenyl)-1- piperazinyl]butoxy]- 3,4-dihydro-2(1H)-quinolinone.
The active substance does not contain any chiral centres and does not exhibit any optical isomerism.
Aripiprazole active substance is a white crystalline powder and is practically insoluble in water and its solubility is pH dependent. Therefore, a particle size effect on dissolution of the tablets can be expected. In order to ensure batch-to-batch consistency of the product, and to ensure adequate bioavailability, aripiprazole is subject to milling.
Aripiprazole can exist in several crystalline forms, Form I was chosen for the development and commercialisation.. Aripiprazole is synthesised by a 2-step process. In the first step, 7-hydroxy-3,4-dihydro-2(H)- quinolinone is transformed into an intermediate, which is reacted with 1-(2,3-dichlorophenyl) piperazine hydrochloride to obtain aripiprazole. The process, specifications and control methods are adequately described in the restricted section of the EDMF.

Schizophrenia is a major psychotic disorder. Its essential features consist of a mixture of characteristic
signs and symptoms that have been present for a significant length of time during a 1-month period (or
for a shorter time if successfully treated), with some signs of the disorder persisting for at least 6
The characteristic symptoms of schizophrenia have often been conceptualized as falling into two
broad categories positive and negative (or deficit) symptoms with a third category, disorganized,
recently added because statistical analyses have revealed that it is a dimension independent of the
positive symptom category, where it was previously included. The positive symptoms include
delusions and hallucinations. Disorganized symptoms include disorganized speech (thought disorder)
and disorganized behaviour and poor attention. Negative symptoms include restricted range and
intensity of emotional expression (affective flattening), reduced thought and speech productivity
(alogia), anhedonia, and decreased initiation of goal-directed behaviour (avolition).
The onset of schizophrenia typically occurs during adolescence or early adulthood. It affects men and
women with equal frequency. The peak age at onset for males, however, is the early 20s, and for
women it is the late 20s and early 30s. The majority of patients alternate between acute psychotic
episodes and stable phases with full or partial remission. Inter-episode residual symptoms are
common. This often-chronic illness can be characterized by three phases that merge into one another
without absolute, clear boundaries between them. These phases, which form the structure for
integrating treatment approaches, are described below:
Acute phase. During this florid psychotic phase, patients exhibit severe psychotic symptoms, such as
delusions and/or hallucinations and severely disorganized thinking, and are usually unable to care for
themselves appropriately. Negative symptoms often become more severe as well.
Stabilization phase. During this phase, acute psychotic symptoms decrease in severity. This phase may
last for 6 or more months after the onset of an acute episode.
Stable phase. Symptoms are relatively stable and, if present at all, are almost always less severe than
in the acute phase. Patients can be asymptomatic; others may manifest non-psychotic symptoms, such
as tension, anxiety, depression, or insomnia. When negative (deficit) symptoms and/or positive
symptoms, such as delusions, hallucinations, or thought disorder, persist, they are often present in
attenuated, non-psychotic forms (e.g., circumstantiality rather than looseness, illusions rather than  hallucinations, overvalued ideas rather than delusions).
There are a number of antipsychotics in use but none is ideal in particular because their safety profile  is complex. The in vitro affinity profile of aripiprazole for dopamine and serotonin receptors is similar  to the one of so-called atypical antipsychotics. It is postulated that aripiprazole’s mechanism of action  is novel as it involves a combination of partial agonist action (agonist/antagonism) at dopamine D2  and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors.

Aripiprazole is a new antipsychotic belonging to the class of atypical antipsychotic drugs. It has been
proposed that aripiprazole antipsychotic action could be mediated through a combination of partial
agonist at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors.
The non-clinical characterization of aripiprazole as a dopamine D2 receptor partial agonist at pituitary
lactotrophs predicts a low potential to induce hyperprolactinemia in humans but it may be dose related.
Studies on the sedative liability of aripiprazole suggest a reduced sedative potential compared to
typical antipsychotics. The safety pharmacology profile of aripiprazole r


  1. […] REFERENCES: 1. Kane, JM et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2012;73(5):617-62 2. Fleischhacker WW, Sanchez R, Perry PP, et al. Aripiprazole once-monthly for the treatment of schizophrenia: a double-blind, randomized, non-inferiority study vs. oral aripiprazole. Annual Meeting of the American Psychiatric Association, 18–22 May, 2013 (poster). 3. Sanchez R, et al. Patient-reported Outcomes with Aripiprazole-Intramuscular-Depot for Long-term Maintenance Treatment in Schiziphrenia. NR6-42 2012 (poster) 4. Carson WH, Perry P, Sanchez R, et al. Effects of a Once-Monthly Formulation of Aripiprazole on Secondary Efficacy Outcomes in Maintenance Treatment of Schizophrenia. Institute on Psychiatric Services meeting, October 4–7, 2012 (Poster) 5. Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention. Agid O, et al. Expert Opin. Pharmacother. (2010) 11(14):2301-2317 6. Ayuso-Gutierrez JL, del Rio Vega JM. Factors influencing relapse in the long-term course of schizophrenia. Schizophr Res. 1997; 28(2-3): 199-206 7. Baloush-Kleinman V, et al. Adherence to antipsychotic drug treatment in early-episode schizophrenia: a six-month naturalistic follow-up study. Schizophr Res. 2011;130(1-3):176-81. 8. National Institute of Mental Health (NIMH). Health Topics: Statistics. Available at http://www.nimh.nih.gov/statistics/1SCHIZ.shtml. Accessed October 22, 2013 9. World Health Organization (WHO). Schizophrenia Fact Sheet. 2010. Available at: http://www.who.int/mental_health/management/schizophrenia/en/. Accessed October 22, 2013. 10. World Health Organization (WHO) The global burden of disease:2004 update (2008) 11. National Institute of Mental Health (NIMH). The Numbers Count: Mental Disorders in America. 2010. Available at http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorde rs-in-America/index.shtml#Schizophrenia. Accessed October 22, 2013 12. Regier DA, et al. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry. 1993;50(2):85-94. 13. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. Second edition. 2004. Available at http://psychiatryonline.org/content.aspx?bookid=28&sectionid=1665359. Accessed October 28, 2013 14. Robinson D, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3):241-247 read my earlier blog post http://newdrugapprovals.wordpress.com/2013/02/07/the-european-medicines-agency-ema-approves-otsukas-&#8230; […]

  2. If you are taking Abilify and cannot afford it, please feel free to visit http://www.medicationcoupons.com and get your Free Abilify Coupons today!

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DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

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