SI22544A - Aripiprazole hemifumarate, its crystal form and procedures for its preparation - Google Patents

Abstract

The submitted invention relates to aripiprazole fumarate, a new stable polymorph of aripiprazole hemifumarate, to procedures for its preparation and pharmaceutical forms which contain it.

Description

The present invention relates to aripiprazole hemifumarate, a novel stable aripiprazole hemifumarate polymorph, to processes for its preparation and to the pharmaceutical forms containing it.

BACKGROUND OF THE INVENTION

Aripiprazole or 7- [4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy] -3,4-dihydro-2 (1H) quinolinone and its salts are useful for the treatment of schizophrenia and the indications described in EP 367141 .

Processes for the preparation of aripiprazole and some of its salts (hydrochloride, sulfate, fumarate and maleate) have been described in EP 367141. We have found a new aripiprazole salt, aripiprazole hemifumarate, which is different from aripiprazole fumarate described in EP 367141, gives the ratio of aripiprazole to fumarate 2: 1. The various crystalline forms of aripiprazole and its hydrates have been described in WO 03026659, in the Japanese untested patent application with publication no. 191256/1990 and at the 4th Japanese-Korean Symposium on Separation Technology (6-8 October 1996). New polymorphs and salts have also been described in WO 2004083183, WO 2004106322, WO 2005009990, WO 2005016261, WO 2005058835, WO 2006012237 and WO 200630446. EP 1145711, EP 1566174 and WO 03030868 describe rapidly fusible dosage forms containing superabsorbable drug-containing supernatant and an anti-caking agent, with CaSiO3 being the preferred dispersing agent.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an x-ray powder diffractogram of aripiprazole hemifumarate.

Figure 2 is a DSC thermogram of aripiprazole hemifumarate.

Figure 3 is an HPLC chromatogram of aripiprazole hemifumarate.

Figure 4 is an image of aripiprazole hemifumarate particles.

Figure 5 is a particle size distribution diagram of aripiprazole hemifumarate.

Figure 6 is an X-ray powder diffractogram of amorphous aripiprazole hemifumarate. Figure 7 is a DSC thermogram of amorphous aripiprazole hemifumarate.

8 is an X-ray powder diffractogram of aripiprazole fumarate type I prepared according to EP 367141.

Figure 9 is an X-ray powder diffractogram of aripiprazole fumarate (1: 1) type II

Figure 10 is the dissolution profile of aripiprazole from the tablets of Example 23 in 900 mL of O, 1M HCl and in 900 mL of acetate buffer at pH 4.5.

Figure 11 is an HPLC chromatogram of aripiprazole in solution for determining the dissolution profile of aripiprazole from tablets according to Example 23.

X-ray powder diffraction patterns were obtained with a Philips PW3040 / 60 X'PertPRO powder diffractometer; CuKa irradiation 1.541874. IO ^'10 m.

DSC images were recorded on a DSC 822e Mettler Toledo dynamic calorimeter. Samples of approximately 3 mg were recorded at a heating rate of 10 ° C / min under a nitrogen atmosphere.

The HPLC chromatogram of aripiprazole hemifumarate salt was obtained with a Waters Alliance 2690 chromatograph with a PDA 996 detector. Chromatographic separation was achieved using an Inertsil ODS-3 analytical column, 250x4.6 mm 5 pm. The chromatographic conditions used were: sample concentration 1 mg / ml, detection at 250 nm, flow rate 1.5 ml / min, injection volume 20 pL. Gradient elution using mobile phase A (0, 1M KH ₂ PO ₄ : CH ₃ CN = 81:19 (V / V)) and mobile phase B (0, 1M

KH ₂ PO ₄ : CH ₃ CN = 50:50 (V / V)) was used according to the following gradient program (0 min 10% B, 40 min 90% B, 45 min 90% B).

HPLC dissolution evaluation was performed using a Gemini 08 110A analytical column, 100 x 4.6 mm id, 5 pm. The chromatographic conditions used were: detection at 250 nm, mobile phase 0.05M KH ₂ PO ₄ : CH ₃ CN = 40:60 (V / V), flow rate 1.0 ml / min, injection volume 5 pL, column temperature 30 ° C ..

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a novel salt of aripiprazole and a novel stable crystalline form of aripiprazole hemifumarate and the processes for its preparation and the pharmaceutical forms containing it. The new salt is stable, reproducible and suitable for pharmaceutical form.

The aripiprazole hemifumarate of the present invention is characterized by an X-ray powder diffraction pattern having peaks at about 12.1, 15.8, 17.9, 19.7, 21.8 ± 0.2 degrees two-theta. Aripiprazole hemifumarate can be further characterized by X-ray powder diffraction peaks at about 6.7, 8.9, 11.1, 12.1, 15.8, 17.9, 19.7, 21.8, 24.6 ± 0, 2 degrees two-theta. It may either be up to 100% polymorphic purity or may include another polymorph or amorphous form.

In another aspect, the present invention relates to an amorphous aripiprazole hemifumarate, preferably an amorphous aripiprazole hemifumarate characterized by an X-ray powder diffractogram, as shown essentially in Figure 6.

The aripiprazole hemifumarate of the present invention is also characterized in that the DSC has an endothermic peak at about 187-192 ° C.

It is also an object of the present invention to provide a method of preparing aripiprazole hemifumarate. The process for the preparation of aripiprazole hemifumarate is characterized in that it comprises:

a) dissolving aripiprazole in the solvent at a temperature between 15 ° C and the reflux temperature of the solvent used;

b) adding fumamic acid in a molar ratio of 0.5-0.7 relative to aripiprazole and heating the mixture to a temperature between 15 ° C and the reflux temperature of the solvent used;

c) optional solution cooling; and

d) Optional filtering of the precipitated solid.

The fumamic acid added can be in solution or solid form.

In another aspect of the process described for the preparation of aripiprazole hemifumarate, the order of addition of aripiprazole and fumic acid may also be reversed and aripiprazole added to the fumamic acid solution. The aripiprazole added may be in solution or in solid form.

The aripiprazole base can be prepared by the procedures described in EP 367141 and may further be recrystallized and / or purified to a level of 99.9%. Aripiprazole used in the preparation of hemifumarate salt may be either pure or crude. If aripiprazole hemifumarate prepared by the present invention is not sufficiently pure, it can be recrystallized to a purity of 99.9%.

Solvents suitable for crystallization of aripiprazole hemifumarate are organic solvents such as hydrocarbons (eg pentane, hexane, heptane), halogenated hydrocarbons (eg methylene chloride), nitriles (eg acetonitrile), ketones, ethers (eg THF). ), esters and alcohols (e.g. methanol, ethanol, isopropanol, propanol, butanol).

The hemifumarate salt can be isolated in solvated form and then the solvent is removed by drying. As used herein, the term drying generally refers to solvent removal as long as aripiprazole hemifumarate does not contain less than about 6000 ppm slices of dual solvents. Drying can be achieved e.g. using heat, preferably carried out under normal pressure or reduced pressure, or by contacting aripiprazole hemifumarate in contact with humid or dry air in a fluid bed dryer, the atmosphere in the air bed dryer having a humidity of at least 15%.

The term reduced pressure refers to a pressure below 101,325 kPa, more preferably below about 13,332 kPa.

The particle size of aripiprazole hemifumarate prepared according to the present invention may be in the range of 0.1-250 micrometers. The size of the prepared aripiprazole hemifumarate particles also depends on the cooling rate of the solution. If smaller particles are required, they can be ground or micronized, optionally with other excipients. In this process, the mechanical force on the particle surface leads to a reduction in particle size, but it can also relax the structural changes of the material. For this purpose, we usually use an air jet mill, a ball mill or an impact mill as a grinding equipment.

The basic principle of machining in an air jet mill is the collision and wear between particles suspended inside the high-velocity air stream that introduces power to the grinding chamber. In a ball mill, particles are crushed by the impact of grinding media (balls, cubes, cylinders, etc.), which can occupy up to half the volume of the grinding chamber.

The grinding media falls from a raised position due to the rotation of the chamber. Friction is present among all the elements, which contributes significantly to the wear and, consequently, to the amorphous nature of the milled material. One of the most widely used mills in the pharmaceutical industry is the hammer mill. In such equipment, the particles are exposed to the impact of rapidly rotating hammers. During grinding, the material is additionally impacted by a perforated sieve placed above the outlet of the chamber.

Figure 4 shows tiny particles of aripiprazole hemifumarate irregularly shaped, which aggregate into agglomerates. Very fine particles of the active substance can spontaneously agglomerate due to van der Waals and electrostatic forces. Our industrial process produces clusters of particles perfect for formulation. The distribution of such treated particles is shown in Figure 5.

The formation of agglomerates strongly affects the physicochemical properties of the tablets. Due to the particle pooling, the content of the active substance in the tablets may be uneven and the release of the active substance from the tablets may be slowed. Therefore, particle pooling should be prevented or prevented. the resulting agglomerates are broken down by appropriate process. The problem is solved by sifting the active ingredient together with a part of the filler (such as cornstarch) through a sieve with a mesh size of 0.6 mm before breaking the granulation process, thereby breaking up the agglomerates of the active ingredient. The aripiprazole hemifumarate agglomerates can also be broken down by other methods such as ultrasound and grinding. The average particle size of aripiprazole hemifumarate according to the present invention is below 70 micrometers, preferably below 50 micrometers and more preferably below 30 micrometers. Most preferably, the particle size of aripiprazole hemifumarate is below 20 micrometers.

According to another aspect of the present invention, pharmaceutical formulations comprising aripiprazole hemifumarate of the present invention are provided in admixture with one or more carriers or excipients (s) conventionally used in the pharmaceutical industry.

A still further aspect of the present invention provides a process for the preparation of pharmaceutical forms containing aripiprazole hemifumarate as an active ingredient comprising the mixing of said active ingredient with at least one carrier (s) or excipient (s) commonly used in the pharmaceutical industry and which brings the mixture into galenic form.

The pharmaceutical forms of the present invention typically contain 1-90 wt. %, preferably 2-50 wt. %, most preferably 3-30 wt. % of active ingredient. Further, the pharmaceutical forms contain an amount of aripiprazole hemifumarate equivalent to 150 mg aripiprazole per dosage unit. Most preferably, the pharmaceutical forms of the present invention contain an amount of aripiprazole hemifumarate corresponding to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg of aripiprazole per dosage unit.

The pharmaceutical forms of the present invention may be suitable for oral administration (e.g. powders, tablets, coated tablets, capsules, orodispersible, chewable tablets, solutions, suspensions or emulsions), parenterally (e.g., injectable solutions for intravenous, intramuscular, subcutaneous or intraperitoneal administration). use), rectal (suppositories), transdermal (patches) or topical (ointments or patches) use or for implant-based administration. The solid, semi-solid or liquid pharmaceutical forms of the present invention may be manufactured by methods conventionally used in the pharmaceutical industry.

Solid dosage forms containing aripiprazole hemifumarate further comprise at least one or more excipients selected from the group of fillers or carriers, binders, decomposers, lubricants, glidants, surfactants, sweeteners, flavorings, stabilizers, etc.

Fillers can be selected (but not limited to) from lactose in various forms (anhydrous, monohydrate, spray-dried lactose, etc.), microcrystalline cellulose (such as commercially available Avicel PH 101, Avicel PH 102 or Avicel PH 112), powdered pulp , silicified microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, sucrose, glucose, fructose, dextrates, maltodextrins, other sugars such as mannitol, lactitol, xylitol, sorbitol, calcium lactate or calcium lactate. Starch, such as pregelatinized starch, can also be used as a filler.

The pharmaceutical form of the invention may also include binders such as povidone, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose (comprising from 5 to 16% by weight hydroxypropyl groups), hydroxypropylmethyl cellulose or other cellulose or other cellulose or other cellulose cellulose or other cellulose , pregelatinised starch, gelatin, polymethacrylate or a mixture of bonds.

In addition, degraders and / or super-degraders such as starches (eg maize starch, potato starch), modified starches (sodium starch glycolate), modified cellulose (croscarmellose, i.e. cross-linked sodium carboxymethyl cellulose), crosslinked polyvinylpyrrolidone polyvinylpyrrolidone polyivonidone may also be present. microcrystalline cellulose, sodium carboxymethyl cellulose, Amberlite®, alginic acid, sodium alginate, guar gum, gelan gum, xanthan gum, calcium silicate, magnesium silicate, magnesium trisilicate, aluminum magnesium metasilicate (as in. Preferably, the excipients include at least one disintegrant or disintegrant selected from croscarmellose, crospovidone and microcrystalline cellulose. Further, lubricants such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, macrogols may be present as excipients. Preferably, the excipients include at least one lubricant selected from magnesium stearate, sodium stearyl fumarate or hydrogenated vegetable oil.

In the pharmaceutical form of the invention, gliders can also be added. They may be selected from the group consisting of talc, silica of various types (such as colloidal or precipitated silica), etc.

Excipients may have several functions, i.e. one excipient may be a diluent and an additional binder, binder and disintegrant, etc.

Optionally, surfactants may be included in the solid pharmaceutical formulation. Surfactants may be selected from the group of non-ionic or ionic surfactants or mixtures thereof. Suitable nonionic surfactants are selected from the group of alkylglucosides, alkilmaltozidov, alkiltioglukozidov, lauryl macrogolglycerides, polyoxyethylene alkylphenols, polyoxyethylene alkiletrov, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyglyceryl fatty acid esters, polyoxyethylene glycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, sterols and mixtures thereof. Preferred non-ionic surfactants are polyoxyethylene sorbitan fatty acid esters sold under the trade names Polysorbate or Tween.

Suitable ionic surfactants are selected from the group of fatty acid salts, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates, sulfonates and mixtures thereof. A preferred ionic surfactant is sodium lauryl sulfate.

Further, the present invention may comprise sweeteners. Examples of sweeteners include aspartame, acesulfame K, saccharin sodium, dicalium glycyl lysinate, stevia and taumatine.

Flavoring agents may be natural or synthetic materials such as e.g. vanilla aroma.

Any suitable process can be used to prepare the pharmaceutical forms, e.g. direct compression, wet (water or alcohol) but dry granulation, etc.

The pharmaceutical form of aripiprazole hemifumarate can be processed and packaged under a modified atmosphere. An atmosphere with a modified oxygen content or a reduced partial pressure of oxygen can be obtained using a reduced pressure atmosphere, e.g. by creating a partial vacuum by means of a suitable pump, or by partial freezing or liquefaction of the atmosphere, or by using an inert gas such as nitrogen or argon, or by using oxygen absorbers, although despite the high efficiency of such absorbers leading to very low oxygen levels, this is not usually necessary.

The pharmaceutical form is present in the package, preferably in a blister or glass container. This creates a packaged pharmaceutical form. The packaging may be equipped with means of trapping and removing free oxygen. The pharmaceutical form may be enclosed in a material substantially impermeable to gas exchange, as a package having an atmosphere with the required reduced oxygen content. Preferably, the gas-tight packaging is preferably selected from the group consisting of Al / Al blister, Al-polychloro-3-fluoroethylene homopolymer / PVC laminate blister or glass container.

¹ C

The pharmaceutical formulation of the invention has such a dissolution profile that at least 80% of aripiprazole is released in 0.1 M HCl after 30 minutes or at least 80% of aripiprazole is released at pH 4.5 after 30 minutes.

The results of the test for the uniformity of the content and the dissolution test of aripiprazole from tablets according to Example 23 are presented below. Figure 10 shows the dissolution profiles of aripiprazole in 900 ml of 0, 1M HCl and 900 ml of acetate buffer with pH 4.5. Both profiles show that sieving has a positive effect on dissolution, since dissolution of sown aripiprazole hemifumarate in 0, 1M HC1 was faster by 17-19% and in acetate buffer pH 4.5 by 12-22%.

Further details of the present invention can be found in the following examples, without limiting the scope of protection for years.

EXAMPLES

L SYNTHESIS

Example 1: Preparation of aripiprazole hemifumarate

4.8 g of 7- (4- (4- (2,3-dichlorophenyl) -1-piperazinyl) -3,4-dihydrocarbostyril, obtained as described in EP 367141 BI, Example 1, was dissolved in 72 mL of ethanol. 0.6 g of fumic acid was added to this solution, the suspension was maintained at reflux for 15 minutes and allowed to cool to room temperature for three hours. The precipitate was collected by filtration and dried at 50 ° C below 5.33 kPa to give aripiprazole. hemifumarate in 94.8% yield.

Melting range: 187-192 ° C.

1 H NMR (DMSO) δ 1.60-1.72 (4H, m), 2.38-2.47 (4H, m), 2.59 (4H, bm), 2.99 (4H, bm). 3.92 (2H, t), 6.43-6.44 (1H, d), 6.45-6.50 (1H, dd), 6.60 (1H, s), 7.02-7. 05 (IH,

d) 7.12-7.15 (1H, m), 7.29-7.31 (2H, m) and 9.98 (1H, s).

Example 2: Preparation of aripiprazole hemifumarate from tetrahydrofuran

1.2 g of 7- (4- (4- (2,3-dichlorophenyl) -1-piperazinyl) -3,4-dihydrocarbostyril are dissolved in 25 mL of tetrahydrofuran. 0.127 g of fumic acid are added to this solution. The suspension is maintained at 20- 25 ° C for 12 hours The precipitate was collected by filtration and dried at 50 ° C below 5.33 kPa to give aripiprazole hemifumarate in 62.7% yield.

Example 3: Preparation of aripiprazole hemifumarate from acetonitrile

1.2 g of 7- (4- (4- (2,3-dichlorophenyl) -1-piperazinyl) -3,4-dihydrocarbostyril are suspended in 25 mL of acetonitrile. 0.127 g of fumaric acid are added to this suspension. The suspension is maintained at 20- 25 ° C for 12 hours The precipitate was collected by filtration and dried at 50 ° C below 5.33 kPa to give aripiprazole hemifumarate in 89% yield.

Example 4: Preparation of aripiprazole hemifumarate from methylene chloride

1.2 g of 7- (4- (4- (2,3-dichlorophenyl) -1-piperazinyl) -3,4-dihydrocarbostyril are dissolved in 25 mL of methylene chloride. 0.127 g of fimamic acid is added to this solution. The suspension is maintained at 20 -25 ° C for 12 h. The precipitate was collected by filtration and dried at 50 ° C below 5.33 kPa to give aripiprazole hemifumarate in 76.8% yield.

Example 5: Preparation of aripiprazole

To 4.65 g of 1- (2,3-dichlorophenyl) -piperazine hydrochloride was added 50 mL of CH ₂ C1 ₂ (or isopropyl acetate) stirred for 10 minutes and then a solution of sodium hydroxide (0.71 g of NaOH in 20 ml of water) was added, the pH should be be between 7 and 8. The two-phase system is stirred vigorously for 30 minutes at room temperature. The layers are separated and the aqueous layer is washed once with CH ₂ C1 ₂ (broken plastic security element). Evaporate the volatile components to an oily residue (4.0g) in the organic phase. To a solution of 4.0g of 1- (2,3-dichlorophenyl) piperazine in acetonitrile (20ml) was added water (30ml). With vigorous stirring at room temperature, 4.7g 7- (4bromobutoxy) -3,4-dihydrocarbostyryl, Nal (0.2g) and triethylamine (2.6ml) were added in a row, and the suspension was heated to reflux (T = 78 ° C) for 3 hours . After three hours, cool the white suspension to room temperature and macerate for another hour at room temperature. The precipitate was filtered off and washed with water (lOml).

Example 6: Preparation of aripiprazole hemifumarate from ethanol

To a solution of aripiprazole (2g) in ethanol (35ml) was added at reflux temperature a hot solution of filaric acid (0.26g) in ethanol (5ml, 50 ° C). The resulting suspension was refluxed for another 15 minutes and cooled to room temperature and macerated at room temperature for 2-3 hours. The precipitated product was recovered and washed with ethanol (2ml) and dried at 60 ° C (2.15g, 95%).

Example 7: Preparation of aripiprazole hemifumarate from ethanol-water mixture

To a suspension of ariprazole (1g) in ethanol (10ml), water (30ml) was added and heated to reflux and filaric acid (0.15g) was added. Macerate the suspension for another 10 minutes at reflux and cool to room temperature. Macerate for 2-3 hours at room temperature. It was filtered off and washed with water / ethanol (5ml). Dry in air overnight (1.08g, 96%).

Example 8: Preparation of aripiprazole fumarate (1: 1), type II

To a suspension of ariprazole (2g) in acetonitrile (30ml) was added water (0.4ml) and heated to reflux and added cinnamic acid (0.58g). Macerate the suspension for another 10 minutes at reflux and cool to room temperature. Macerate overnight at room temperature. It was drained and rinsed with acetonitrile (5ml). Dry in air overnight (2.47g, 98%).

II. PHARMACEUTICAL FORMULATIONS

TOOL DISPOSABLE TABLETS

A.) Dry granulation

Example 9: 5 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 5.65 * 7.53 Xylitol 39.45 52,60 Microcrystalline cellulose 10,00 13,33 Calcium silicate 11,25 15,00 Crospovidone 5,00 6.67 Amorphous silica 1.50 2.00 Aspartame 1.00 1.33 Vanilla flavor 0.40 0.54 Magnesium stearate 0.75 1.00 In total 75.00 100

* corresponds to 5 mg of aripiprazole

Aripiprazole hemifumarate is mixed in a high speed blender with all other excipients (except part of magnesium stearate), 0.25% of magnesium stearate is added, the mixture is compacted with a roller compactor, the compacts are ground and sieved, mixed with the remaining magnesium stearate. To distinguish between different strengths, a portion of the microcrystalline cellulose can be replaced by different coloring agents such as iron oxides.

B.) Wet granulation

Example 10: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Mannitol 81,90 54.60 Microcrystalline cellulose 12,00 8,00 Low substituted HPC 9,00 6,00 Aspartame 1.00 0.67 Vanilla flavor 0.80 0.53 Crospovidone 12,00 8,00 Calcium silicate 20,00 13,34 Magnesium stearate 2.00 1.33 In total 150 100 Purified water q.s. Evaporates during the process

* corresponds to 10 mg of aripiprazole q.s. means as much as necessary

Mannitol, microcrystalline cellulose, low substituted HPC, aspartame and crospovidone are mixed in a suitable mixer and granulated with purified water. The resulting granulate is dried, sieved and mixed with aripiprazole hemifumarate, vanilla aroma and calcium silicate. Finally, the magnesium stearate was mixed and the resulting mixture was compressed into tablets of <60 N. The decay times were in the range of 10 to 20 s (purified water at 37 ° C, Ph. Eur.).

Example 11: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Mannitol 17.70 11.80 Microcrystalline cellulose (Avicel PH 101) 50.00 33.33 Pregelatinized starch 7.50 5,00 Aspartame 2.00 1.33 Vanilla flavor 1.00 0.67 Crospovidone 15,00 10,00 Colloidal silica 2.00 1.33 Microcrystalline cellulose (Avicel PH 112) 35,00 23,34 Microcrystalline cellulose and guar gum (Avicel CE 15) 7,00 4.67 Sodium lauryl sulfate 0.50 0.33 Magnesium stearate 1.00 0.67 In total 150 100.00 Purified water q.s. Evaporates during the process

* corresponds to 10 mg of aripiprazole q.s. means as much as necessary

Aripiprazole hemifumarate, mannitol, microcrystalline cellulose (Avicel PH 101), pregelatinized starch and half of crospovidone are mixed in a suitable granulator and granulated with sodium lauryl sulfate solution in water. The granules are dried and sieved, all other ingredients are added, and the mixture is added with a slider to tablets at <60 N. Decay times are in the range of 10 to 20 s (purified water at 37 ° C, Ph. Eur.)

Example 12: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Xylitol 55.91 37,27 Microcrystalline cellulose 30.48 20,32 Low substituted HPC 9,00 6,00 Crospovidone 10,00 6.67 Mannitol 30,00 20,00 Vanilla flavor 0.81 0.54 Aspartame 1.00 0.67 Mg-stearate 1.50 1.00 In total 150,00 100 Purified water q.s. Evaporates during the process

* corresponds to 10 mg of aripiprazole q.s. means as needed

Xylitol, mannitol, microcrystalline cellulose, low substituted HPC, aspartame and crospovidone are mixed in a suitable mixer and granulated with purified water. The resulting granulate is dried, sieved and mixed with aripiprazole hemifumarate and vanilla flavor. Finally, the magnesium stearate is mixed and the resulting mixture is compressed into round tablets.

Example 13: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Sucrose 65.27 43.51 Povidon 4,35 2.90

Silica, colloidal, anhydrous 1.09 0.73 Sodium starch glycolate 10,00 6.67 Corn starch 53.73 35.82 Aspartame 0.69 0.46 Vanilla flavor 2.07 1.38 Magnesium stearate 1.50 1.00 In total 150,00 100 Purified water q.s. Evaporates during the process

* corresponds to 10 mg of aripiprazole q.s. means as much as necessary

Aripiprazole hemifumarate, sucrose and corn starch are mixed in a granulator. The granular fluid is prepared by dissolving povidone in purified water and dispersing it to a powder mixture. The obtained granulate is dried and sieved. Finally, the aroma of vanilla, aspartame, sodium starch glycolate, silica and magnesium stearate are mixed and the resulting mixture is compressed into tablets.

Example 14: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Xylitol 80.47 53.65 Magnesium aluminum silicate 22,50 15,00 Microcrystalline cellulose 22,50 15,00 Aspartame 3.00 2.00 Vanilla flavor 0.23 0.15 Crospovidone 9,00 6,00 Magnesium stearate 1.00 0.67

In total 150,00 100.00 Purified water q.s. Evaporates during the process

* corresponds to 10 mg of aripiprazole q.s. means as much as necessary

Aripiprazole hemifumarate, xylitol, aluminum magnesium silicate, a portion of microcrystalline cellulose, aspartame, aroma and crospovidone are mixed in a suitable mixer and granulated with purified water. The resulting granulate is dried, sieved and mixed with the rest of the microcrystalline cellulose. Finally, the magnesium stearate is mixed and the resulting mixture is compressed into tablets.

C.) Direct tableting

Example 15: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Maltodextrin (Maltrin QD) 75.90 50.60 Microcrystalline cellulose (Avicel PH 105) 10,00 6.67 Microcrystalline cellulose (Avicel PH 102) 10,00 6.67 Aspartame 1.00 0.67 Vanilla flavor 0.80 0.53 Crospovidone 10,00 6.67 Calcium silicate 30,00 20,00 Magnesium stearate 1.00 0.66 In total 150 100

* corresponds to 10 mg of aripiprazole

All ingredients except magnesium stearate are mixed in a suitable blender. Finally, magnesium stearate was added and the resulting compression mixture was compressed into tablets using round seals. Decay time is about 20 s, tablet strength is about 50 N.

Example 16: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Pharmburst ™ 133.00 88.67 Acesulfam K 0.22 0.15 Aspartame 0.23 0.15 Vanilla flavor 2.25 1.50 Magnesium stearate 1.50 1.00 Talc 1.50 1.00 In total 150,00 100

* corresponds to 10 mg of aripiprazole

All ingredients except magnesium stearate are mixed homogeneously in a suitable blender. Finally, magnesium stearate is added and the lubricated compression mixture is compressed into tablets using round seals.

Example 17: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 Pharmburst ^1M 132.85 88.57 Sucrose 0.45 0.30

Vanilla flavor 2.25 1.50 Sodium stearyl fumarate 3.15 2.10 In total 150,00 100

* corresponds to 10 mg of aripiprazole

All ingredients except magnesium stearate are mixed homogeneously in a suitable blender. Finally, magnesium stearate is added and the lubricated compression mixture is compressed into tablets using round seals.

Example 18: 10 mg orodispersible tablets

Amount / mg Quantity /% (wt.) Aripiprazole hemifumarate 11.30 * 7.53 4) Jc F-MELT 137.20 91.47 Sodium stearyl fumarate 1.50 1.00 In total 150 100

* corresponds to 10 mg of aripiprazole * * (S) ·

F-MELT C contains mannitol, xylitol, microcrystalline cellulose crospovidone and anhydrous calcium hydrogen phosphate or F-MELT®M contains mannitol, xylitol, microcrystalline cellulose crospovidone and aluminum magnesium trisilicate.

In the appropriate mixer, mix aripiprazole hemifumarate and F-MELT. Finally, a slider is added, sodium stearyl fumarate and the resulting tabletting mixture is compressed into tablets.

D.) Molding

Example 19: 10 mg orodispersible tablets

Amount / mg

Quantity /% (wt.) Χ «ζ ·

Aripiprazole hemifumarate 11.30 * 7.53 Xylitol 84,10 56.07 Sodium starch glycolate 4,50 3.00 Starch 1500 LM 48.58 32.39 Aspartame 0.25 0.17 Vanilla flavor 1,27 0.84 In total 150,00 100

corresponds to 10 mg of aripiprazole

All ingredients are homogeneously mixed and wetted with purified water and kneaded. The compression mixture is formed with a round seal to form tablets. Dry the obtained tablets.

QUICK RELEASE TABLES:

A.) Direct compression:

The tablets of Examples 20 and 21 are prepared by direct compression.

The ferric oxide dye (red) is mixed with a small amount of celactose and added to aripiprazole hemifumarate, the rest of the celactose and all other excipients in a suitable mixer. All ingredients are homogeneously mixed and compressed into tablets using round seals.

Example 20: 30 mg quick release tablets

Amount [mg] Quantity in wt. % Aripiprazole hemifumarate 33,88 * 7.5 Celactose 306.30 68.1

Microcrystalline cellulose 90,00 20,0 Croscarmellose sodium 15,00 3.3 Magnesium stearate 4,50 1.0 Iron oxide 0.32 0.07 In total 450,00 100

* corresponds to 30 mg of aripiprazole

Example 21: 30 mg fast-release tablets

Amount [mg] Quantity in wt. % Aripiprazole hemifumarate 33,88 * 7.5 Celactose 356,00 79.11 Pregelatinized starch 40,30 8.96 Corn starch 15 3,33 Magnesium stearate 4,50 1.00 Iron oxide 0.32 0.07 In total 450,00 100

* corresponds to 30 mg of aripiprazole

B.) Wet granulation:

Tablets of Examples 22 and 23 are prepared by the wet granulation process.

A mixture of aripiprazole hemifumarate, lactose monohydrate, maize starch, hydroxypropyl cellulose and iron oxide was wetted with purified water and kneaded. The granules are dried and sieved. Finally, microcrystalline cellulose and magnesium stearate were added to the dry granulate and the resulting mixture was compressed into tablets using round seals.

Example 22: 30 mg quick release tablets

Amount [mg] Quantity in wt. % Aripiprazole hemifumarate 33,88 * 7.5 Lactose monohydrate 207.06 46.0 Corn starch 51.77 11.5 Microcrystalline cellulose 132.80 29.5 Hydroxypropyl cellulose 19,67 4.4 Magnesium stearate 4,50 1.0 Iron oxide 0.32 0.07 In total 450,00 100

* corresponds to 30 mg of aripiprazole

Example 23: 30 mg quick release tablets

The mixture of aripiprazole hemifumarate and all other ingredients except magnesium stearate is wetted with purified water and kneaded. The wet granules are dried and sieved. Finally, magnesium stearate is added to the dry granulate and the resulting compression mixture is compressed into tablets using 11 mm round seals.

Quantity [mg] Quantity in wt. % Aripiprazole hemifumarate 33,88 * 7.5 Lactose monohydrate 296,76 65,9 Corn starch 52.06 11.6 Microcrystalline cellulose 52.06 11.6 Hydroxypropyl cellulose 10,41 2.3 Magnesium stearate 4,50 1.0 Iron oxide 0.32 0.07 In total 450,00 100

* corresponds to 30 mg of aripiprazole

Example 24: Test results for the uniformity of aripiprazole content in the tablets of Example 23

Table 1: The uniformity of aripiprazole content in tablets made by sieving the active substance with a portion of the filler prior to the granulation process and without sieving before the granulation process.

aripiprazole content (%) without sowing with sowing 1 104,7 100,1 2 103,1 100,4 3 107,3 103,4 4 100,5 104,8 5 103,5 100,9 6 107,5 101,5 7 101,2 101,8 8 104,1 101,8 9 102,0 101,9 10 103,3 103,5 average 103,7 102,0 std% 2,31 1.5 RSD 2.23 1.5 AV 7.74 4,1

It can be seen that the content of aripiprazole in tablets made by pre-sowing aripiprazole hemifumarate with a portion of the filler is more evenly distributed than in tablets where the active ingredient was not screened prior to the granulation process.

Claims (23)

PATENT APPLICATIONS Aripiprazole hemifumarate, characterized in that the ratio of aripiprazole to fumarate is 2: 1. Crystalline aripiprazole hemifumarate according to claim 1, characterized by an x-ray powder diffraction pattern having peaks at about 12.1, 15.8, 17.9, 19.7, 21.8 ± 0.2 degrees two-theta. The crystalline form of aripiprazole hemifumarate according to claim 2, further characterized by having peaks at about 6.7, 8.9, 11.1, 12.1, 15.8, 17.9, 19.7, 21.8, 24.6 ± 0.2 degrees two-theta. Crystalline aripiprazole hemifumarate according to claim 1, characterized in that the DSC has an endothermic peak at about 187-192 ° C. Aripiprazole hemifumarate according to claim 1, characterized by an X-ray powder diffraction pattern as essentially shown in Figure 1. Aripiprazole hemifumarate according to claim 1, characterized by a DSC thermogram pattern as shown essentially in Figure 2. 7. Amorphous aripiprazole hemifumate. 8. Amorphous aripiprazole hemifumarate characterized by an X-ray powder diffractogram, as shown essentially in Figure 6. 9. A process for the preparation of aripiprazole hemifumarate, characterized in that it comprises: a. dissolving aripiprazole in the solvent at a temperature between 15 ° C and the reflux temperature of the solvent used; b. adding fumaric acid in a molar ratio of 0.5-0.7 with respect to aripiprazole and heating the mixture to a temperature between 15 ° C and the reflux temperature of the solvent used; c. optional solution cooling and d. filtering precipitated solids. A process for the preparation of aripiprazole hemifumarate as described in claim 9, characterized in that the order of addition of aripiprazole and fumaric acid can be reversed and aripiprazole added to fumaric acid. The process of claim 9, wherein the organic solvent is selected from hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones and alcohols or a combination of these solvents. The process of claim 11, wherein the organic solvent is ethanol, THF, acetonitrile and / or methylene chloride. Aripiprazole hemifumarate according to claim 1, with an average particle size below 70 micrometers. Aripiprazole hemifumarate according to claim 13, with an average particle size below 50 micrometers. Aripiprazole hemifumarate according to claim 14, with an average particle size below 30 micrometers. Aripiprazole hemifumarate according to claim 15, with an average particle size of less than 20 micrometers. A pharmaceutical formulation comprising aripiprazole hemifumarate as defined in any preceding claim and pharmaceutically acceptable excipients. The pharmaceutical formulation according to claim 17, wherein the aripiprazole hemifumarate agglomerates are broken down before formulation. The pharmaceutical form of claim 17, wherein the aripiprazole hemifumarate is screened prior to formulation. A pharmaceutical formulation according to claim 17 having such a dissolution profile that at least 80% of aripiprazole is released in 0.1 M HCl after 30 minutes. 21. A pharmaceutical formulation according to claim 17 having such a dissolution profile that at pH 4.5 releases at least 80% of aripiprazole after 30 minutes. Use of aripiprazole hemifumate for the preparation of a pharmaceutical form. Use of aripiprazole hemifumarate as described in claim 22, characterized in that the aripiprazole used is in the form described in claims 1 to 16.