WO2010107329A2 - Aripiprazole salts - Google Patents
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- WO2010107329A2 WO2010107329A2 PCT/PL2010/000031 PL2010000031W WO2010107329A2 WO 2010107329 A2 WO2010107329 A2 WO 2010107329A2 PL 2010000031 W PL2010000031 W PL 2010000031W WO 2010107329 A2 WO2010107329 A2 WO 2010107329A2
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- aripiprazole
- salt
- acid
- monoester
- maleic acid
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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
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Abstract
Aripiprazole salts, consisting of aripiprazole and tricarboxylic acid derivative, wherein one carboxyl group of an acid forms ester with C1-C4-aliphatic alcohol, represented by formula (1), wherein is double bond and R is H, or is single bond and R is -O (C=O) R2, R2 is C1-C4-aliphatic group or phenyl, optionally substituted by -CH3 or - OCH3 group in position 4 of the phenyl ring, n = 1 - 2, are new derivatives of antipsychotic effect. Aripiprazole salts are prepared in the reaction of aripiprazole free base and bicarboxylic acid anhydride in C1-C4 aliphatic alcohol as a solvent.
Description
Aripiprazole salts
Field of the invention
The invention relates to the new salts of aripiprazole, which may be useful in a treatment of psychotic disorders, and to the process for preparation thereof.
Aripiprazole is a second generation antipsychotic agent used in the treatment of schizophrenia, acute manic and mixed episodes, type I bipolar affective disorders and depression. Aripiprazole beneficial pharmacological profile results from partial agonist activity at the D2 dopamine and 5-HT1 serotonin receptors, as well as antagonism at 5-HT2 serotonin receptors.
New salts, showing the same pharmacological activity as aripiprazole, may be used as active ingredients of antipsychotic agents. They may also serve as intermediates in manufacturing process of high pharmaceutical purity aripiprazole.
Background of the invention
Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)- 1 -piperazinyl]butoxy]-3,4-dihydro- 2(lH)-quinolinon was disclosed in European Patent Application EP 367141 Al.
The method for preparation of aripiprazole described in EP 367141 Al was based on the reaction of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyryl and l-(2,3- dichlorophenyl)piperazine and/or its salt, in a presence of sodium iodide and organic base, such as triethylamine. According to this procedure, resulting intermediate 7-(4-chlorobutoxy)-3,4-dihydrocarbostyryl needs to be purified by silica gel chromatography, followed by double crystallization of the final product from ethanol. This is the main drawback to implement this method in a plant technology scale. In the International patent publication WO 03/026659 altered synthetic approach was described, in this modified procedure inorganic base, such as potassium carbonate was used and the reaction was carried out in water.
In a publication coming from IVth Japan-Korean Symposium on Separation Technology (Tokio, 1996), three polymorphic forms of aripiprazole were revealed. Recrystallization from ethanol and drying at temperature 8O0C, results in formation of aripiprazole crystalline form, named anhydrous crystalline form I, which is nowadays called Conventional anhydrous form". Upon heating at temp. 130-1400C, form I transforms into form II, which is characterized by melting point 15O0C. These forms, when subject to recrystallization from ethanol containing up to 20% amount of water, transform into hydrous form (,,Conventional hydrate"), which in turn may be converted into anhydrous form I, while drying at temperature 8O0C. Polymorphic and pseudopolymorphic forms of aripiprazole were also disclosed, among others, in
some other International patent applications, eg. WO 03/026659 (anhydrous forms B, C, D, E, F, G, Hydrate A), WO 2004/083183, WO 2004/ 106322, WO 2005/009990 (polymorphic forms I, II, III, IV), and WO 2005/058835.
Propensity of aripiprazole to form salts with acids and solvates, including hydrates, results from its molecular structure, especially the presence of basic nitrogen atoms in the molecule.
This phenomenon was, among others, the subject-matter of European Patent EP 367141 Bl, in which formation of aripiprazole salts with pharmaceutically acceptable acids in ethanol was described. The particular salts revealed in said patent were hydrochloride, sulphate, fumarate and maleate.
Many examples illustrating the use of aripiprazole salts as the intermediates yielding aripiprazole of pharmaceutical purity were found. Usually, these salts were initially purified by crystallization and then transformed into aripiprazole free base.
In WO 2006/030446 p-toluenesulfonate, benzenesulfonate, citrate, salicylate and hydrobromide salts as well as methanol and acetic acid solvates were used to obtain different polymorphic forms of aripiprazole. Transformation of crude aripiprazole into its salt yielded the compound of purity higher than 98%, and it enabled to get rid of dimer, the impurity formed during the reaction of 7-hydroxy- 3,4-dihydrocarbostyryl and 1,4-dibromobutan.
In WO 2006/079549 aripiprazole acid addition salts were described, wherein acids were selected from a group consisted of hydroiodic, oxalic, mesitylenesulfonic, tetrafluoroboronic, phosphoric, phenylphosphoric acid, comprising 1 to 3 molecules of acid per 1 molecule of aripiprazole, and solvates thereof. Process for preparing aripiprazole free of impurities was also disclosed, wherein pure aripiprazole was obtained due to acid addition salt formation with one of the above mentioned acids, followed by separation and liberation of free base from the salt.
In WO 2007/007132 aripiprazole salts with bicarboxylic acids of formula ARIn HmX were disclosed, wherein X represents acidic counterpart of given acid, n = 1 or 2 and m =1 or 2. The particular salts mentioned in the specification were aripiprazole oxalate in a molar ratio 1: 1, aripiprazole tartrate 1: 1 and aripiprazole succinate 2: 1.
EP 1837331 A2 discloses further crystalline salts of aripiprazole, obtained in the reaction with carboxylic acids, such as succinate, benzoate in polimorphic form I and II, maleate, malonate, fumarate, L-tartrate, L-malate, citrate, as well as their use in preparation process of aripiprazole.
In medical treatment tablets containing 2, 5, 10, 15, 20 and 30 mg of aripiprazole are used as well as 10 and 15 mg orally disintegrating tablets. Thus, aripiprazole has been proved to be the active substance of high efficacy, which can be administered to a patient in low therapeutic doses. For this reason, the uniform distribution of the active substance in tablets is an important factor. Following the standard pharmaceutical procedures, homogeneous tablet mixtures and uniform single dosage forms are to be prepared. It may be achieved due to extensive grinding of active substance to small particle diameter, so called micronization process.
However, it is well known that particle size of active substances, especially these characterized by low solubility, is strictly related to their physico-chemical as well as biological and pharmacological properties. Particle size has significant influence on solubilization rate of a compound, which in turn effects bioavailability of a medicament, in particular.
In WO 03/026659, the effect of particle size and hygroscopicity of crystalline forms of aripiprazole on release rate of active substance and its stability upon storage are discussed. The authors suggest that thermodynamically stable, Anhydrous Form B of aripiprazole, characterized by particle size below 50 μm is most suitable for pharmaceutical application. This non-hygroscopic aripiprazole form was obtained due to drying of ground Hydrate A. Upon drying of Conventional Hydrate, which was not subject to prior grinding, Conventional anhydrous form of high hygroscopic properties was obtained. These results show that particle size of aripiprazole is an important factor effecting complex physico-chemical transformations of this compound. According to the presentation of IVth Japanese- Korean Symposium on Separation Technology, thermodynamic transformation of aripiprazole Conventional Form I takes place upon grinding followed by heating above melting point. It results in Form III enrichment of the starting sample, far more then upon heating only. There is a possibility, that during micronization - the process based on standard grinding technique, formation of polymorph or polymorphs mixtures of different than expected physico-chemical properties may occur. This process may be also destructive to the compound and shorten the shelf- life of the drug product prepared of micronized active substance. In consequence, lack of reproducibility of crystalline aripiprazole batches may adversely affect physical and mechanical properties of solid pharmaceutical dosage form of the drug.
Description of the invention
Unexpectedly, we found out this goal may be achieved, when aripiprazole free base is subject to reaction with carboxylic acids anhydrides in some alcoholic solvents. Under these conditions aripiprazole salts with monoesters of carboxylic acids are formed, while concomitant esteryfication of one out of two carboxylic groups proceeds.
The present invention relates to aripiprazole salt, consisting of aripiprazole and bicarboxylic acid derivative, wherein one carboxyl group of an acid forms ester with Ci-C4-aliphatic alcohol, represented by formula (1), wherein is double bond and R is H, or is single bond and R is -0(C=O)R2,
R2 is Ci-C4-aliphatic group or phenyl, optionally substituted by -CH3 or - OCH3 group in position 4 of the phenyl ring, n = 1 - 2.
Preferably, bicarboxylic acid is selected from a group comprising unsaturated bicarboxylic acids, consisting of 2 to 4 carbon atoms, especially maleic acid, and O- acyl derivatives of L- or D-tartaric acid.
In the r preferred embodiment of the invention, aripiprazole salt is monoester derivative of dibenzoyl-L-tartaric, dibenzoyl-D-tartaric, di-p-anizoyl-L- tartaric, di-p- anizoyl-D-tartaric, di-p-tolyl-L-tartaric, dipivaloyl-L-tartaric, and diacetyl-L-tartaric acids.
Preferably, aripiprazole salt is the salt with monoester of maleic acid.
New salts of the present invention, depending on the molar ratio of aripiprazole free base and bicarboxylic acid anhydride used for the reaction, may consist of 1 to 2 moles of monoester to 1 mole of aripiprazole.
Preferably, new salts consist of aripiprazole and monoester molecules at 1 : 1 molar ratio.
More preferably, aripiprazole salts of the present invention consist of aripiprazole and methyl or ethyl monoester of maleic acid at 1: 1 molar ratio.
As it was mentioned above, new aripiprazole salts according to the present invention are obtained in simple technological process, which comprises aripiprazole free base reacting with bicarboxylic acid anhydride in appropriate molar ratio, in Ci-C4 aliphatic alcohol.
Aripiprazole free base used for aripiprazole salts synthesis may be prepared by any method known in the art, for example by condensing 7-(4-bromobutoxy)- 3,4,-dihydroquinolin-2-one of formula (2) and 4-(2,3-dichlorophenyl)piperazine of formula (3) or the salt thereof, according to the procedure described in EP 367141 Al or WO 03/026659.
Preferably, new aripiprazole salts are obtained according to the process comprising: a) condensing 7-(4-bromobutoxy)-3,4,-dihydroquinolin-2-one of formula (2) and 4- (2,3-dichlorophenyl)piperazine hydrochloride of formula (3) in the presence of inorganic base, eg. potassium carbonate, in a solvent selected from a group of organic solvents, water and their mixtures, to obtain aripiprazole free base, b) optionally, isolating and purifying aripiprazole free base obtained in step a), c) reacting aripiprazole free base and bicarboxylic acid anhydride of formula (4) in Ci-C4 aliphatic alcohol, d) isolating the reaction product from the post-reaction mixture.
Solvent in step a) may be water or the mixture of water and organic solvent miscible or non-miscible with water, preferably C1-4 aliphatic alcohol, eg. isopropyl alcohol.
Aripiprazole free base may be isolated from the post-reaction mixture, according to the standard procedure, including, eg., extraction, precipitation out of the post-reaction mixture, filtration or decantation, depending on the solvent used. Aripiprazole free base may be isolated from the reaction mixture in crystalline or amorphous form or in a solvated form, eg. hydrate. The solid product may be further purified by crystallization or maceration, dried and recrystallized.
It was unexpectedly discovered that preparation of new aripiprazole salts of pharmaceutical purity can be accomplished without additional purification step, like crystallization, of aripiprazole free base. In the preferred embodiment of the present invention aripiprazole salt is obtained in the process wherein condensation product of 7-(4-bromobutoxy)-3,4,-dihydroquinolin-2-one and 4-(2,3- dichlorophenyl) piperazine hydrochloride is used in situ, without its isolation from the solvent used in the reaction, or as a crude product without any w ork-up procedure.
Reaction of aripiprazole free base and bicarboxylic acid anhydride in C1-C4 aliphatic alcohol, in step d), is performed at temperature range from 00C to reflux.
Product is isolated from the post-reaction mixture either by filtration of the formed crystals or precipitation due to antisolvent, eg., tert-butyl methyl ether, addition and subsequent drying of the solid to the constant weight.
New aripiprazole salts according to present invention are isolated as solids of homogenous crystalline form, and are characterized by small particle diameter and narrow particle size distribution. Thus, the obtained crystalline substance meets the requirements to be processed into solid dosage form without any additional physic-chemical work-up, such as micronization process.
The preferred new derivative of the present invention - aripiprazole salt with methyl monoester of maleic acid (1: 1), is characterized by X-ray powder diffraction (XRPD) pattern, substantially as depicted in Fig.1, having the following Bragg reflections represented by inter-planar distances d [A], reflection angles 2Θ [°] and relative intensities I/Io [%]:
Aripiprazole salts prepared according to the present invention are generally characterized by mean particle size ranging 1-20 μm, preferably 5-10 μm. Their median particle size is within 1-30 μm range and the ratio of mean particle size and median is within 1.1-1.3.
Particularly, 90% of particles of aripiprazole salt with ethyl monoester of maleic acid is characterized by dso<5.6 μm, while 90% of particles of aripiprazole salt with methyl monoester of maleic acid is characterized by dso<27.8 μm.
New aripiprazole salts of the present invention are characterized by chemical purity that is more than 99.9% (according to HPLC method) and hence may be used for the preparation of aripiprazole free base of pharmaceutical purity, ie. purity higher than 99.5%, especially higher than 99.5%.
These unexpected advantageous physico-chemical properties of the new aripiprazole salts of the present invention, renders them useful for the direct processing into solid dosage forms.
Aripiprazole salts of the present invention are bioequivalent to aripiprazole itself due to the similar solubility of aripiprazole free base and its salts.
Aripiprazole salts according to the invention may be administered to the patients per se or they may be formulated into pharmaceutical compositions comprising therapeutic amount of active substance together with pharmaceutically acceptable carrier and /or excipients.
Pharmaceutical composition of the invention may be administered in suitable pharmaceutical dosage form, by any convenient route, eg. orally or parenterally, depending on the pharmaceutical dosage form used.
The selection of active substance dose as well as the dosage scheme applied is connected with nature and severity of condition being treated, age and body mass of the patient, and may be defined by the skilled person according to the standard treatment procedures and prophylactics in that kind of diseases.
Therapeutic daily dose of aripiprazole derivative of the present invention may vary from 1 to 30 mg, calculated on aripiprazole free base.
In monotherapy or combination therapy with other active substances, daily dose may be administered on once-a-day basis or it can be divided into several small portion doses. The combined active substances may be administered as a fixed unit dosage form, concomitantly as two different drugs or within a certain period of time, in accordance with the prescription.
Pharmaceutical composition according to the invention may be formulated in any suitable pharmaceutical form, by any method known in the art, such as the one described, eg., in Remington's Pharmaceutical Sciences, ed. XVI, Mack Publ. Co., 1980.
Pharmaceutical dosage forms for oral administration include solid pharmaceutical dosage forms, such as tablets, dragees, powders, granules, pellets
and capsules. The liquid dosage forms comprise, for example, suspensions and syrups. Except for active substance, pharmaceutically accepted diluents and/or excipients are also present. Pharmaceutically accepted diluents and excipients are any pharmacologically inert substances or their mixtures known in pharmaceutical practice.
Suitable diluents for conventional release solid dosage forms include corn starch, lactose, microcrystalline cellulose, saccharose, sorbitol, talc, mannitol, mono- or dibasic calcium phosphate, pregelatinized starch, glycine and other.
Solid pharmaceutical compositions, which are compacted into solid dosage form, such as tablet, may include other excipients to facilitate manufacturing process and to obtain drug of desired physico-chemical properties. Disintegrants, increasing dissolution rate of a compacted solid pharmaceutical composition in patient's gastrointestinal tract, comprise, for example, starch and its derivatives, croscarmellose sodium, microcrystalline cellulose, crosslinked polyvinylpyrolidon, sodium starch glycolate or other ingredients based on crosslinked polymers. Binders for solid form compositions include polyvinylpyrolidon, gelatin, guar gum, cellulose derivatives, hydroxypropylmethylcellulose (HPMC), hydroxycellulose, hydroxypropylcellulose, for instance. Lubricants contain, for example, sodium lauryl sulfate, magnesium stearate, talc, fumaric acid and other.
The surface of the tablets may be protected with a coating as it is described, for example, in Pharmaceutical Dosage Forms and Drug Delivery Systems, H.C.Ansel, L.V.Allen, N.G.Popovich, ed. VII (1999), Lippincott Williams & Wilkins. For the preparation of coating, different substances of high molecular weight and film-forming properties are used, to enable dissolution of solid composition in appropriate part of gastro-intestinal tract. These substances are carefully selected and used together with excipients, such as plasticizers, diluents, colorants, dispersing and opacifying agents.
There is also a possibility of preparing liquid pharmaceutical composition of new aripiprazole derivatives. They may include compositions for intravenous, subcutaneous or intramuscular injections, for instance. These liquid pharmaceutical compositions comprise sterile aqueous, aqueous-organic and anhydrous solutions, suspensions, dry substances as well as tablets for making solutions. For the preparation of suspensions, some excipients are used to disperse active substance uniformly through the composition in the liquid carrier. Such emulsifying agents include, for example, polysorbates, lecitin, polyoxyethylene and polyoxypropylene copolymers, peptizers, such as phosphates, polyphosphates and
citrates, water soluble polymers, such as carboxymethylcellulose, methylcellulose, polyvinylpyrolidon, gums and gelatin. Injection compositions contain, for example, pharmaceutically accepted excipients, such as pH-regulators, buffers, preservatives. Dry substances are designed for the preparation of solutions or suspensions ex tempore, due to dilution of the substance with suitable solvent.
The present invention provides new aripiprazole derivatives, characterized by advantageous physico-chemical properties, such as: particle size median in 1 - 20 μm size range, narrow particle size distribution, low hygroscopicity and homogenous polymorphic form. These properties make new aripiprazole derivatives suitable for solid dosage forms preparation, characterized by homogenous composition. In addition, the invention provides new method for the preparation of aripiprazole base of high pharmaceutical purity via new aripiprazole derivatives.
The invention is illustrated by the following examples, which should not be constructed to limit its scope in any way.
Examples
Analytical methods
Nuclear magnetic resonance spectra were recorded on Bruker Avarice spectrometer type DRX 500 MHz.
The composition of obtained salts was determined by nuclear magnetic resonance method (1H-NMR - DMSO-dβ). The molar ratio of acid and base of aripiprazole salt was determined on the basis of signals integrations of the corresponding protons assigned to base and acid moieties, respectively. In the Table below chemical shifts of protons of aripiprazole salts anionic groups are presented.
X-Ray powder diffractogram data were collected using X-ray powder diffractometer by Rigaku type MiniFlex, equipped with scintillating counter detector, with CuKa radiation, wavelength λ= 1,54056 A, the scanning range 2Θ 3° to 40°, rate of scanning Δω 0.5°/min, step size 0.02° at room temperature. Obtained diffractograms data were worked-up and analyzed using DHN_PDS program.
Particle size distribution analysis was performed by laser diffraction technique using COULTER LS analyzer.
Example I. Aripiprazole base (comparative example)
100 g of 7-(4-bromobutoxy)-3,4-dihydroquinolin-2-one, 98 g of 4-(2,3- dichlorophenyl)piperazine hydrochloride and 100 g of potassium carbonate were added to 1000 ml of water. The resulting mixture was refluxed for 6 h. After surcease of heating stirring was continued for additional 18 h. The crude product was filtered off, washed with water and dried for 20 h. Dried product was suspended in 1500 ml of isopropyl alcohol, the solution was heated to reflux and filtered while it was hot. The mixture was stirred for 18 h at ambient temperature, and the crystalline product was subsequently filtered off and washed with isopropyl alcohol. The solid was dried under the vacuum at 600C for 24 h. Aripiprazole base was obtained in 142 g yield, of purity > 99.9%. M.p. 139-1400C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSO-de δ 9.96 [IH, s, NH]; 7.29 [2H, m, Ar]; 7.13 [IH, q, Ar]; 7.04 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.45 [IH, d, Ar]; 3.92 [2H, t, -CH2-O-]; 2.97 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.53 [4H, bb, 2(-CH2-)]; 2.39 [4H, m, 2(-CH2-)]; 1.73 [2H, m, - CH2-]; 1.58 [2H, m, -CH2-]. IR: cm-i 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588.
Example II. Aripiprazole base (comparative example)
100 g of 7-(4-bromobutoxy)-3,4-dihydroquinolin-2-one, 98 g of 4-(2,3- dichlorophenyl)piperazine hydrochloride and 100 g of potassium carbonate were added to 1000 ml of isopropanol / water (9/ 1) mixture. The resulting mixture was refluxed for 6 h. After surcease of heating stirring was continued for additional 18 h. Crude product was filtered off and macerated in 1000 ml of water for 2 h. It was filtered off again and dried for 20 h. The obtained solid was placed in 1500 ml of acetone, which was heated to reflux and filtered. After cooling the product
precipitated out from the solution, than it was filtered off and washed with acetone. The crystalline solid was dried under the vacuum at 600C for 24 h. Aripiprazole base was obtained in 120 g yield, of purity > 99.9%. M.p. 139- 1400C (uncorrected). Thus obtained product was characterized as polymorphic form IV, described in WO 2004/ 106322.
Example III. Aripiprazole base
100 g of 7-(4-bromobutoxy)-3,4-dihydroquinolin-2-one, 98 g of 4-(2,3- dichlorophenyl)piperazine hydrochloride and 200 g of saturated aqueous solution of potassium carbonate were added to 900 ml of isopropanol. The resulting mixture was refluxed for 6 h. After surcease of heating stirring was continued for 18 h. The crude product was filtered off and macerated in 1000 ml of water for 2 h, it was filtered off again and dried for 20 h. The product was placed in 700 ml of isopropanol, the solution was heated to reflux than filtered while it was hot. The mixture was stirred for 18 h at ambient temperature, precipitated crystalline product was filtered off and washed with isopropanol. The crystalline solid was dried under the vacuum at 600C for 24 h. Aripiprazole base was obtained in 124 g yield, of purity > 99.9%. M.p. 139-1400C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H-NMR: DMSO-dβ δ 9.95 [IH, s, NH]; 7.30 [2H, m, Ar]; 7.13 [IH, q, Ar]; 7.04 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.44 [IH, d, Ar]; 3.92 [2H, t, -CH2-O-]; 2.98 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.53 [4H, bb, 2(-CH2-)]; 2.39 [4H, m, 2(-CH2-)]; 1.73 [2H, m, -CH2-]; 1.58 [2H, m, -CH2-]. IR: cm 1 2946; 2823; 1681; 1627; 1594; 1577; 1522; 1447; 1376; 1273; 1241; 1196; 1175; 1139; 1128; 960; 862; 776; 711; 594; 532; 467.
Example IV. Aripiprazole salt with methyl monoester of maleic acid
To aripiprazole base (20 g; 0.045 mol) in 80 ml of methanol, 80 ml of maleic acid anhydride solution in methanol (4.37 g; 0.045 mol) was added dropwise at room temperature. The resulting mixture was stirred for 18 h at ambient temperature. To this clear solution 100 ml of MTBE was added. Precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 5O0C for 24 h. Aripiprazole salt with methyl monoester of maleic acid (1: 1) was obtained in 22.5 g yield. M.p. 137-1390C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSO-de δ 9.97 [IH, s, NH]; 7.30 [2H, m, Ar]; 7.15 [IH, q, Ar]; 7.03 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.46 [IH, d, Ar]; 6.38 [IH, d, =CH-COO ]; 6.28 [IH, d, =CH-
COO-]; 3.93 [2H, t, -CH2-O-]; 3.66 [3H, s, -OCH3]; 3.02 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.64 [4H, bb, 2(-CH2-)]; 2.49 [2H, m, -CH2-]; 2.41 [2H, m, -CH2-], 1.73 [2H, m, -CH2-]; 1.62 [2H, m, -CH2-]. IR: cm-i 2950; 1731; 1688; 1628; 1577; 1522; 1485; 1452; 1366; 12725; 1211; 1167; 956; 824; 779; 713; 627; 589.
Example V. Aripiprazole salt with methyl monoester of maleic acid
100 g of 7-(4-bromobutoxy)-3,4-dihydroquinolin-2-one, 98 g of 4-(2,3- (ϋchlorophenyl)piperazine hydrochloride and 200 g of potassium carbonate saturated aqueous solution were added to 900 ml of methanol. The resulting mixture was refluxed for 18 h. After 1000 ml of ethyl acetate addition stirring was continued without heating for 1 h. Next phases were separated. The dilution of organic layer with 500 ml of methanol was followed by subsequent addition of maleic anhydride (21.85 g; 0.225 mol) at room temperature. The mixture was stirred at ambient temperature for 18 h. The clear solution was diluted with 500 ml of MTBE. The precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 500C for 24 h. Aripiprazole salt with methyl monoester of maleic acid (1: 1) was obtained in 112.5 g yield. M.p. 137-1390C (uncorrected) .
Exaple VI. Aripiprazole salt with methyl monoester of maleic acid
100 g of 7-(4-bromobutoxy)-3,4-dihydroquinolin-2-one, 98 g of 4-(2,3- dichlorophenyl)piperazine hydrochloride and 200 g of potassium carbonate saturated aqueous solution were added to 900 ml of methanol. The resulting mixture was refluxed for 18 h, than it was filtered and cooled. The precipitated solid was filtered off, washed with water and added into a solution of maleic acid anhydride (21.85 g; 0.225 mol) in 600 ml of methanol. The mixture was heated to reflux while stirring. After surcease of heating, the clear solution was diluted with 500 ml of MTBE. The precipitated crystalline product was filtered off , washed with MTBE and dried under the vacuum at 40 - 50°C for 24 h. Aripiprazole salt with methyl monoester of maleic acid (1: 1) was obtained in 112.5 g yield M.p. 137-139°C (uncorrected) .
Example VII. Aripiprazole salt with ethyl monoester of maleic acid
To the solution of aripiprazole base 20 g (0.045 mol) in 80 ml of 99% ethanol, 80 ml of maleic acid anhydride (4.37 g; 0.045 mol) solution in ethanol was added dropwise at room temperature. The resulting mixture was stirred for 18 h, than it was diluted with 100 ml of MTBE. The precipitated product was filtered off, washed
with MTBE and dried under the vacuum at 40 - 500C for 24 h. Aripiprazole salt with ethyl monoester of maleic acid (1: 1) was obtained in 23.8 g yield. M. p. 129- 1310C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSO-de δ 9.97 [IH, s, >NH]; 7.30 [2H, m, Ar]; 7.16 [IH, m, Ar]; 7.03 [IH, d, Ar]; 6.50 [IH, dd, Ar]; 6.45 [IH, d, Ar]; 6.36 [IH, d, =CH-COO ]; 6.31 [IH, d, =CH- COO ]; 4.14 [2H, q, -CH2-O-] 3.93 [2H, t, -CH2-O-]; 3.04 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.71 [4H, bb, 2(-CH2-)]; 2.56 [2H, m, -CH2-]; 2.42 [2H, m, -CH2-], 1.74 [2H, m, -CH2-]; 1.64 [2H, m, -CH2-]; 1.21 [3H, t, -CH3]. IR: cm 1 1723; 1692; 1624; 1579; 1520; 1454; 1365; 1273; 1210; 1174; 1034; 953; 829; 780; 618; 587.
Example VIII. Aripiprazole salt with ethyl monoester of maleic acid
To the solution of aripiprazole base 20 g (0.045 mol) in 80 ml of ethanol maleic acid anhydride was added (4.37 g; 0.045 mol) at room temperature. The resulting mixture was heated at 700C for 2 h. After surcease of heating, the clear solution was diluted with 100 ml of MTBE and stirred for 16 h. The precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 5O0C for 24 h. Aripiprazole salt with ethyl monoester of maleic acid (1: 1) was obtained in 23.3 g yield. M.p. 130-1310C (uncorrected).
Example IX. Aripiprazole salt with methyl monoester of diacetyl-L-tartaric acid
To the solution of aripiprazole base 20 g (0.045 mol) in 80 ml of methanol, 80 ml of diacetyl-L-tartaric acid anhydride (9.73 g; 0.045 mol) solution in methanol was added at room temperature. The resulting mixture was stirred for 18 h, the solution was condensed to 50 ml volume and it was diluted with 100 ml of hexane. The precipitated product was filtered off, washed with hexane and dried under the vacuum at 40 - 5O0C for 24 h. Aripiprazole salt with methyl monoester of diacetyl- L-tartaric acid (1: 1) was obtained in 26.8 g yield. M.p. 123-125°C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSO-d6 δ 9.97 [IH, s, >NH]; 7.32 [2H, m, Ar]; 7.15 [IH, m, Ar]; 7.04 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.45 [IH, d, Ar]; 5.61 [IH, d, >CH-]; 5.41 [IH, d, -CH<]; 3.93 [2H, t, -CH2-O-]; 3.68 [3H, s, -OCH3] 3.11 [4H, bb, 2(-CH2-)]; 2.93 [4H, bb, 2(-CH2-)]; 2.78 [2H+2H , m, -CH2-N< + -CH2-]; 2.41 [2H, m, -CH2-], 2.04 [6H, s, 2(CH3-COO-)]; 1.72 [4H, m, (-CH2-J2].
Example X. Aripiprazole salt with ethyl monoester of diacetyl-L-tartaric acid
To the solution of εiripiprazole base 20 g (0.045 mol) in 80 ml of ethanol, 80 ml of diacetyl- L- tartaric acid anhydride (9.73 g; 0.045 mol) solution in ethanol was added at room temperature. The resulting mixture was stirred for 18 h, the solution was condensed to 50 ml volume and it was diluted with 100 ml of hexane. The precipitated product was filtered off, washed with hexane and dried under the vacuum at 40 - 500C for 24 h. Aripiprazole salt with ethyl monoester of diacetyl-L- tartaric acid (1: 1) was obtained in 26.8 g yield. M. p. 118-1200C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR (DMSOd6 δ 9.97 [IH, s, >NH]; 7.32 [2H, m, Ar]; 7.15 [IH, m, Ar]; 7.04 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.45 [IH, d, Ar]; 5.59 [IH, d, >CH-]; 5.43 [IH, d, -CH<]; 4.15 [2H, dq, -CH2-O-]; 3.93 [2H, t, -CH2-O-]; 3, [4H, bb, 2(-CH2-)]; 2.91 [4H, bb, 2(-CH2- )]; 2.78 [2H+2H , m, -CH2-N< + -CH2-]; 2.41 [2H, m, -CH2-], 2.05 [6H, s, 2(CH3-COO- )]; 1.72 [4H, m, (-CH2-J2]; 1.15 [3H, t, -CH3]).
Example XI. Aripiprazole salt with methyl monoester of maleic acid (2:1)
To the solution of aripiprazole base 20 g (0.045 mol) in 60 ml of methanol, 20 ml of maleic acid anhydride (8.74 g; 0.090 mol) solution in methanol was added at ambient temperature. The resulting mixture was refluxed for 2 h. After surcease of heating, the clear solution was diluted with 100 ml of MTBE and stirred for 16 h The precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 500C for 24 h. Aripiprazole salt with methyl monoester of maleic acid in 2: 1 molar ratio, was obtained in 27.9 g yield. M. p. 133-135°C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSO-d6 δ 9.97 [IH, s, >NH]; 7.30 [2H, m, Ar]; 7.16 [IH, q, Ar]; 7.03 [IH, d, Ar]; 6.50 [IH, dd, Ar]; 6.46 [IH, d, Ar]; 6.38 [2H, d, 2(=CH-COO )]; 6.30 [2H, d, 2(=CH-COO )]; 3.93 [2H, t, -CH2-O-]; 3.66 [6H, s, 2(-OCH3)]; 3.05 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.72 [4H, bb, 2(-CH2-)]; 2.57 [2H, m, -CH2-]; 2.42 [2H, m, - CH2-], 1.73 [2H, m, -CH2-]; 1.65 [2H, m, -CH2-].
Example XII. Aripiprazole salt with methyl monoester of maleic acid (1.5:1)
To the solution of aripiprazole base 20 g (0.045 mol) in 60 ml of methanol, 20 ml of maleic acid anhydride (6.56 g; 0.068 mol) solution in methanol was added at ambient temperature. The resulting mixture was refluxed for 2 h. After surcease of heating, the clear solution was diluted with 100 ml of MTBE and stirred for 16 h The precipitated product was filtered off, washed with MTBE and dried under the
vacuum at 40 - 500C for 24 h. Aripiprazole salt with methyl monoester of maleic acid in 1.5: 1 molar ratio, was obtained in 25.9 g yield. M. p. 132-1340C (uncorrected).
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSOd6 δ 9.97 [IH, s, >NH]; 7.30 [2H, m, Ar]; 7.16 [IH, q, Ar]; 7.03 [IH, d, Ar]; 6.50 [IH, dd, Ar]; 6.46 [IH, d, Ar]; 6.38 [1,5H, d, 1,5(=CH-COO )]; 6.30 [1,5H, d, 1,5(=CH-COO-)]; 3.93 [2H, t, -CH2-O-]; 3.66 [4,5H, s, 1,5(-OCH3)]; 3.05 [4H, bb, 2(- CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.72 [4H, bb, 2(-CH2-)]; 2.57 [2H, m, -CH2-]; 2.42 [2H, m, -CH2-], 1.73 [2H, m, -CH2-]; 1.65 [2H, m, -CH2-].
Example XIII. Aripiprazole salt with ethyl monoester of maleic acid (2:1)
To the solution of aripiprazole base 20 g (0.045 mol) in 60 ml of ethanol, 20 ml of maleic acid anhydride (8.74 g; 0,090 mol) solution in ethanol was added at ambient temperature. The resulting mixture was heated at 700C for 2 h. After surcease of heating, the clear solution was diluted with 100 ml of MTBE and stirred for 16 h. The precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 500C for 24 h. Aripiprazole salt with ethyl monoester of maleic acid in 2: 1 molar ratio, was obtained in 28.3 g yield. M. p. 123-125°C (uncorrected)
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSO-de δ 9.95 [IH, s, >NH]; 7.30 [2H, m, Ar]; 7.16 [IH, m, Ar]; 7.03 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.44 [IH, d, Ar]; 6.35 [4H, dd, 2(=CH-COO )2]; 4.13 [4H, q, 2(- CH2-O-)] 3.93 [2H, t, -CH2-O-]; 3.01 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.64 [4H, bb, 2(-CH2-)]; 2.48 [2H, m, -CH2-]; 2.41 [2H, m, -CH2-], 1.73 [2H, m, -CH2-]; 1.62 [2H, m, -CH2-]; 1.21 [6H, t, 2(-CH3)].
Example XIV. Aripiprazole salt with ethyl monoester of maleic acid (1.5:1)
To the solution of aripiprazole base 20 g (0.045 mol) in 60 ml of ethanol, 20 ml of maleic acid anhydride (6.56 g; 0.068 mol) solution in ethanol was added at ambient temperature. The resulting mixture was heated at 700C for 2 h. After surcease of heating, the clear solution was diluted with 100 ml of MTBE and stirred for 16 h The precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 5O0C for 24 h. Aripiprazole salt with ethyl monoester of maleic acid in 1.5: 1 molar ratio, was obtained in 26.4 g yield. M. p. 123-1250C (uncorrected) .
Identity of the substance was confirmed by spectroscopic data analysis. 1H- NMR: DMSOd6 δ 9.95 [IH, s, >NH]; 7.30 [2H, m, Ar]; 7.16 [IH, m, Ar]; 7.03 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.44 [IH, d, Ar]; 6.35 [3H, dd, 1,5(=CH-COO )2]; 4.13 [4H, q, 2(-CH2-O-)] 3.93 [2H, t, -CH2-O-]; 3.01 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.64 [4H, bb, 2(-CH2-)]; 2.48 [2H, m, -CH2-]; 2.41 [2H, m, -CH2-], 1.73 [2H, m, -CH2-]; 1.62 [2H, m, -CH2-]; 1.21 [4,5H, t, 1,5(-CH3)].
Example XV. Aripiprazole base
The aripiprazole salt of example IV 10 g was placed in 50 ml of 4% sodium hydroxide aqueous solution. The mixture was heated at 5O0C for 2 h. After cooling to room temperature, the solid was filtered off, washed with water and dried for 24 h. The crystalline product was placed in isopropyl alcohol and the mixture was heated to reflux, than it was filtered and cooled. The crystalline solid was filtered off, washed with isopropyl alcohol and dried under the vacuum at 600C for 24 h. Aripiprazole base was obtained in 6 g yield of purity > 99.9%. M. p. 139-1400C (uncorrected) .
Identity of the substance was confirmed by spectroscopic data analysis. iHNMR: DMSO-d6 δ 9.96 [IH, s, NH]; 7.29 [2H, m, Ar]; 7.13 [IH, q, Ar]; 7.04 [IH, d, Ar]; 6.49 [IH, dd, Ar]; 6.45 [IH, d, Ar]; 3.92 [2H, t, -CH2-O-]; 2.97 [4H, bb, 2(-CH2-)]; 2.78 [2H, t, -CH2-N<]; 2.53 [4H, bb, 2(-CH2-)]; 2.39 [4H, m, 2(-CH2-)]; 1.73 [2H, m, - CH2-]; 1.58 [2H, m, -CH2-].
Example XVI. Aripiprazole salt with methyl monoester of maleic acid
The crude aripiprazole base 28.5 g (0.045 mol) of example III (after crystallization and filtration - the contents of i-PrOH was ca. 30%) to 80 ml of maleic acid anhydride (4.37 g; 0.045 mol) in methanol solution was added. The resulting mixture was refluxed for 2 h. After surcease of heating, the clear solution was diluted with 100 ml of MTBE and stirred for 16 h The precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 5O0C for 24 h. Aripiprazole salt with methyl monoester of maleic acid in 1: 1 molar ratio, was obtained in 21.9 g yield. M.p. 138-139°C (uncorrected). The particle size distribution is depicted in Fig. 2. XRPD diffractogram is depicted in Fig. 3.
Example XVII. Aripiprazole salt with ethyl monoester of maleic acid
The crude aripiprazole base 28.5 g (0.045 mol) of example III (after crystallization and filtration - the contents of i-PrOH was ca. 30%) to 80 ml of maleic acid anhydride (4.37 g; 0.045 mol) solution in ethanol was added at 20cC. The resulting mixture was heated at 700C for 2 h. After surcease of heating, the clear solution was diluted with 100 ml of MTBE and stirred for 16 h. The precipitated product was filtered off, washed with MTBE and dried under the vacuum at 40 - 500C for 24 h. Aripiprazole salt with ethyl monoester of maleic acid in 1: 1 molar ratio, was obtained in 22.6 g yield. M. p. 130-1310C (uncorrected). The particle size distribution is depicted in Fig. 1.
Example XVIII. Coated tablets containing aripiprazole salt with methyl monoester of maleic acid (1:1)
Active substance 5 mg (calculated on free base) Corn starch 50 mg Lactose monohydrate 66 mg Sodium starch glycolate 6 mg Microcrystalline cellulose 60 mg Hydroxypropylmethylcellulose 10 mg Magnesium stearate 2 mg Opadry II 3% calculated on core mass.
The ingredients listed above were compressed into round, double biconvex tablet cores of 200.00 mg ± 2% weight each. Cores were coated in a perforated pan with Opadry® II. Coated tablets of 206 mg overall weight each were obtained, containing 5 mg of active substance, calculated on aripiprazole free base.
Claims
1. Aripiprazole salt, consisting of aripiprazole and tricarboxylic acid derivative, wherein one carboxyl group of an acid forms ester with Ci-C4-aliphatic alcohol, represented by formula (1)
0) wherein is double bond and R is H, or is single bond and R is -Q(C=O)R 2,
R2 is Ci-C4-aliphatic group or phenyl, optionally substituted by -CH3 or - OCH3 group in position 4 of the phenyl ring, n = 1 - 2.
2. Aripiprazole salt according to claim 1, wherein bicarboxylic acid is chosen from a group comprising maleic acid and O-acylated derivatives of L- or D-tartaric acid.
3. Aripiprazole salt according to claim 1 or 2, wherein bicarboxylic acid is dibenzoyl- L- tartaric acid, dibenzoyl-D-tartaric acid, di-p-anizoyl-L-tartaric acid, di- p-anizoyl-D-tartaric acid, di-p-tolyl-L-tartaric acid, dipivaloyl-L-tartaric acid and diacetyl-L-tartaric acid.
4. Aripiprazole salt according to claim 1, wherein monoester and aripiprazole are present at the molar ratio 1 : 1 (n=l).
5. Aripiprazole salt according to claim 1, wherein Ci-C4-aliphatic alcohol is methanol or ethanol.
6. Aripiprazole salt according to claim 1, which is aripiprazole and ethyl monoester of maleic acid salt or aripiprazole and methyl monoester of maleic acid salt, wherein monoester and aripiprazole are present at the molar ratio 1 : 1.
7. Aripiprazole salt according to claim 6, wherein aripiprazole and methyl monoester of maleic acid salt is characterized by a powder X- Ray diffraction pattern having interplanar distances d [A], diffraction angles 2Θ [°] and relative intensities
I/Io [%]:
8. Aripiprazole salt according to claim 1, characterized by mean particle size 1-20 μm.
9. Aripiprazole salt according to claim 1, characterized by median particle size 1-30 μm and the ratio of mean particle size and median 1.1 - 1.3.
10. A process for preparation of aripiprazole salt of claim 1, comprising: a) condensation of 7-(4-bromobutoxy)-3,4-dihydroquinolin-2-on and 4-(2,3- dichlorophenyl)piperazine hydrochloride in a presence of inorganic salt, in a solvent selected from a group consisting of organic solvents, water or the mixture thereof, to yield aripiprazole free base, b) optionally, isolation and purification of aripiprazole free base obtained in step a), c) reaction of aripiprazole free base and bicarboxylic acid anhydride in Ci-C4 aliphatic alcohol, d) isolation of the reaction product from the post-reaction mixture.
11. The process according to claim 10, wherein step a) is carried out in a solvent selected from the group consisting of C 1-4 aliphatic alcohols, water or the mixtures thereof.
12. The process according to claim 10, wherein aripiprazole free base obtained in step a) is used in the next steps in situ, without isolation from the post- reaction mixture or without purification.
13. Aripiprazole salt of claim 1 for the use in a treatment of psychotic disorders.
14. A pharmaceutical composition comprising aripiprazole salt of claim 1 as an active ingredient, together with pharmaceutically acceptable carriers and/ or excipients.
15. Use of aripiprazole salt of claim 1 for the process for the preparation of aripiprazole free base of purity higher than 99.9% (according to HPLC method).
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Non-Patent Citations (1)
Title |
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H. J. LUCAS, W. BAUMGARTEN: "The reduction of Tartaric Acid" J. AM. CHEM. SOC., vol. 63, no. 60, 1941, pages 1653-1657, XP002600601 * |
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