SK50092006A3 - Aripiprazole salts and a method for preparation thereof - Google Patents

Abstract

The present invention relates to a process for preparing aripiprazole tartrate, having purity 99.5 percent and higher according to HPLC, with particular impurities content lower than 0.1 percent in crystalline form A, characterized by reflection at diffraction angle 21.86 degree, found out using X-ray diffraction of CuK{alpha} radiation ({lambda} = 1.5402 A), applying with 0.2 degree accuracy, wherein the preparation process comprises the following steps: a) dissolution of aripiprazole tartrate using suitable solvent; b) reflux for a period of 10 to 30 minutes; c) cooling down to laboratory temperature; d) filtration of separated salt; wherein the suitable solvent is selected from the group consisting of methanol and ethanol.

Description

Technical field

The invention relates to novel salts of aripiprazole, i. 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one with tartaric acid, including method for their preparation and physicochemical properties. Said salts may serve for the preparation of a medicament for the treatment of schizophrenia and bipolar disorders.

Fry and the state of the art

Aripiprazole, chemically 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one of formula I, is a known antipsychotic that was first described in EP 367141 (1989) by Otsuka Pharmaceutical. Aripiprazole is currently used in free base form. In the basic patent EP 367141 several aripiprazole salts are described, both with mineral acids (hydrochloride, sulphate) and with organic acids (fumarate, maleate). Information on the polymorphism of aripiprazole salts has not been published.

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The solution described by us comprises novel salts of aripiprazole I with tartaric acid, which exhibit a number of advantageous properties not previously observed in the previously described salts.

SUMMARY OF THE INVENTION

The invention relates to novel salts of aripiprazole, i. 7- {4- [4- (2,3-Dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one, with tartaric acid and methods for their preparation. These processes make it possible to obtain aripiprazole I salts of tartaric acid which have not been described so far in a high yield and in the quality required for pharmaceutical substances.

For example, aripiprazole base obtained by the known process of EP 367141 has a purity of 98.38%. The tartrate produced according to Example 1 of the present invention had a purity of 99.83%. In addition, aripiprazole tartrate is not hygroscopic, as shown in some crystalline forms of aripiprazole base (WO 03/026659).

From a chemical point of view, our products are salts containing the component described by formula I and tartaric acid in a 1: 1 ratio. The chemical structure of the salts we obtain can be described by the formula ΠΙ. The salts obtained can be expected to be effective in the treatment of schizophrenia and bipolar disorders as well as the aripiprazole free base. An economical process for the preparation of these salts has also been found which can also be used on a production scale.

The process of the invention is characterized by reacting 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one I with an ethanolic or aqueous acid solution. tartaric acid. The production of salts ΙΠ can advantageously be carried out at a temperature close to the boiling point of the solvent used, ensuring good solubility of the starting component I. The process for preparing salts ΠΙ is described in the equation in Scheme 1.

Scheme 1

The choice of solvent depends on the solubility of the starting material and the product. As the solvent, C1-C4 alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, butanols), C1-C3 carboxylic acid esters of C1-C3 alcohols (e.g. ethyl acetate), ethers (e.g. dioxane, tetrahydrofuran), ketones (e.g. acetone), acetonitrile, any mixtures thereof and mixtures with water. If a pre-prepared acid solution is used, it is a solution in ethanol or water.

A particular advantage of the preparation of the novel aripiprazole salts is their ease of isolation, water solubility in the case of tartrate, and excellent salt-cleaning performance. With a simple operation it is thus possible to achieve a chemical purity of at least 99.5% and higher, with individual impurities below 0.1%, i.e. a chemical purity that is easy to achieve. purity API substance.

The preferred salt form III is the crystalline form, which is chemically stable, chemically highly pure (HPLC above 99.5%), water soluble, which can be prepared in high yields in defined crystalline modifications. These conditions are met by the crystalline salt form soliΠ prepared by us.

The crystalline structure of the salts of formula III was unambiguously characterized by the results of the following analytical methods: X-ray powder diffraction (XRPD), melting point, differential scanning calorimetry (DSC), ¹³ C CP-MAS NMR. The results of the analyzes are presented in examples and annexes.

It is particularly advantageous to prepare the crystalline salt form ΠΙ of the invention when ethanol or a mixture thereof with water is used as the solvent. The reason is the good reproducibility of the process for both small and large batches, the process further leads exclusively to the defined crystalline modification (DSC and XRPD) and moreover, the process is characterized by high yields that are reproducible. The aforementioned properties of crystalline salt III are very advantageous for its production and pharmaceutical use.

The invention also relates to two preferred crystalline salt forms III obtainable by the method outlined above.

It is a form designated A, which, when measured by CuKa X-ray diffraction (λ = 1.5402 Å), exhibits a reflection at a diffraction angle of 21.86 °, determined to within 0.2 °.

In a preferred embodiment, Form A is characterized by further reflections at diffraction angles of 17.80; 21.17 and 25.07 ⁰ under the same conditions.

The second crystalline form B is unambiguously characterized by a reflection at a diffraction angle of 15.88 °, measured under the same conditions as for Form A, preferably a further reflection at an angle of 23.53, particularly preferably at 15.42; 16.96; 17.74; 18.67 and 21.89 °.

The above process repeatedly yields crystalline tartaric acid salt of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinoline-2 in yields of 90-95%. -one I described by formula III.

Crystallizations of aripiprazole tartrate prepared according to Example 1 produced 2 polymorphic salt forms of ΙΠ, see Examples 3, 4 and 5.

By spray drying, aripiprazole tartrate was prepared in amorphous form with a water content of 2 to 2.5%, see Examples 6 and 7.

The obtained tartaric acid salt of the 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one I described in formula III is possible in practice, for the preparation of pharmaceutically useful compositions, in particular medicaments having an antipsychotic effect.

The novel aripiprazole III salts obtained can advantageously be used in practice for the purification of aripiprazole.

The following examples illustrate the invention in more detail, but do not affect the width of the invention as defined in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an XRPD pattern of crystalline form A of aripiprazole tartrate III salt prepared according to Example 3.

Fig. 2 shows an XRPD diffractogram of crystalline form B of aripiprazole tartrate III salt prepared according to Example 4 or 5.

Fig. 3 is an XRPD pattern of the amorphous form of aripiprazole tartrate III salt prepared according to Example 6 or 7.

Fig. 4 shows the DSC curve of crystalline form A of aripiprazole tartrate prepared according to Example 3.

Fig. 5 shows the DSC curve of crystalline form B of aripiprazole tartrate prepared according to Example 4 or 5.

Fig. 6 shows the DSC curve of the amorphous form of aripiprazole tartrate III prepared according to Example 6 or 7.

Fig. 7 shows a ¹³ C CP-MAS NMR spectrum of crystalline form A of aripiprazole tartrate III prepared according to Example 3.

Fig. 8 shows a ¹³ C CP-MAS NMR spectrum of crystalline form B of aripiprazole tartrate III prepared according to Example 4 or 5.

Fig. 9 shows a ¹³ C CP-MAS NMR spectrum of the amorphous form of aripiprazole tartrate III prepared according to Example 6 or 7.

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLE 1 - Preparation of tartrate in ethanol

To a solution of 16.4 g of aripiprazole in 200 ml of ethanol at 60 ° C was added 5.5 g of cold (L) (+) tartaric acid dissolved in 200 ml of ethanol. Upon cooling to room temperature, a solid precipitated. The product was filtered off and dried at 60 ° C. Melting point 186 -191 ° C. The purity of the product was 99.83% by HPLC.

EXAMPLE 2 - Preparation of Tartrate in Acetonitrile

To a solution of 8.2 g of aripiprazole in 200 ml of acetonitrile at 75 ° C was added 2.8 g of cold (L) (+) tartaric acid dissolved in 3 ml of water. After cooling to room temperature, a solid precipitated. The product was filtered off and dried at 60 ° C. Melting point 188-192 ° C.

EXAMPLE 3 - Preparation of Tartrate - Crystalline Form A

2.5 g of aripiprazole tartrate prepared according to Example 1 were dissolved in 150 ml of methanol at reflux. The solution was cooled slowly to room temperature. The precipitated product was filtered off and dried at 80 ° C. Melting point 196.8 - 198.0 ° C.

EXAMPLE 4 - Preparation of Tartrate - Crystalline Form B

2.5 g of aripiprazole tartrate prepared according to Example 1 were dissolved in 175 ml of water at 80 ° C. The solution was cooled slowly to room temperature. The precipitated product was filtered off and dried at 80 ° C. Melting point not sharp, 184-193 ° C.

EXAMPLE 5 - Preparation of Tartrate - Crystalline Form B

2.5 g of aripiprazole tartrate prepared according to Example 1 were dissolved in 60 ml of a 4/1 ethanol / water mixture at 70 ° C. The solution was cooled slowly to room temperature. The precipitated product was filtered off and dried at 80 ° C. Melting point not sharp, 183 193 ° C.

EXAMPLE 6 - Preparation of an amorphous form of tartrate

Aripiprazole tartrate solution in a mixture of 60% ethanol and 40% water at a concentration of 1 * 25 g ¹ and the temperature of 25 DEG C. was continuously fed into a spray drier with a co-current stream of nitrogen. The feed temperature was 120 ° C and the cyclone outlet temperature was 70 ° C. The amorphous aripiprazole tartrate thus prepared contained 2.5 wt. water.

EXAMPLE 7 - Preparation of an amorphous form of tartrate

A solution of aripiprazole tartrate in a mixture of 60% ethanol and 40% water at a concentration of 25 g * l 'and a temperature of 25 ° C was fed continuously to a spray dryer with a continuous stream of nitrogen. The feed temperature was 150 ° C and the cyclone outlet temperature was 95 ° C. The amorphous aripiprazole tartrate thus prepared contained 2.0 wt. water.

ANALYTICAL DATA (A - G): The following analytical data unambiguously characterizes the crystalline salt of aripiprazole tartrate ΠΙ.

A X-ray powder diffraction (XRPD)

XRPD diffraction patterns of crystalline forms A and B of aripiprazole tartrate ΠΙ prepared according to Examples 3, 4 and 5 are shown in Figs. 1 and 2.

The XRPD pattern of the amorphous salt of aripiprazole tartrate III prepared according to Examples 6 and 7 is shown in FIG. Third

The characteristic diffraction angles of crystalline forms A and B of aripiprazole tartrate III are given in Tables 1 and 2.

Diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer under the following experimental conditions:

Radiation: CuKa (λ = 1,5402 Å)

Monochromator: graphite

Excitation voltage: 45 kV

Anode current: 40 mA

Measured range: 4 - 40 ° 20

Step size: 0.004 2Θ

Flat sample with flat / thickness 10 / 0.5 mm

Table 1

Values of characteristic 2Θ diffraction angles and inter-plane distances d of form A of crystalline aripiprazole tartrate III

20 [°] will give] Irel 10,888 8,126 37,12 14,532 6,096 18.53 15,303 5,790 36.06 16,220 5,465 25.45 16,644 5,326 20.68 17,119 5,180 30.85 17,590 5,042 33.95 17,795 4,984 77,31 18,189 4,878 68.31 18,627 4,764 42.58 19,588 4,532 55.25 20,662 4,299 16.95 21,168 4,197 76.62 21,543 4,125 55,86 21,860 4,066 100.00 22,654 3,925 14.17 23,124 3,847 32.56 23,508 3,784 12.01 24,189 3,679 18,15 24,453 3,640 13.44 24,794 3,591 54.56 25,071 3,552 97.97 25,875 3,443 37.44 26,068 3,418 14.99 26,458 3,369 12.97 29,292 3,049 16,11 29,855 2,993 14.33 30,099 2,969 19.38

Table 2

Values of characteristic diffraction angles of 2Θ and inter-plane distances d of crystalline aripiprazole tartrate salt III form B

20 [°] will give] Irel 11,031 8,021 13.32 11,527 7,677 23,04 15,140 5,852 10.42 15,417 5,747 44.63 15,877 5,582 100.00 16,416 5,400 27.57 16,964 5,227 49.94 17,739 5,000 46.38 18,671 4,753 42.22 20,528 4,327 16.28 21,893 4,060 47,66 22,216 4,001 24.90 23,218 3,831 18.93 23,531 3,781 82,80 24,172 3,682 14.57 24,754 3,597 32,61 25,116 3,546 41.94 25,436 3,502 12.76 25,730 3,462 10.94 25,977 3,430 18.96 26,571 3,355 12.65 27,125 3,288 13.01 28,333 3,150 16.93 35,713 2,514 10.29

B Melting point

Melting points of crystalline aripiprazole tartrate salts ΙΠ were measured on a Kofler block with a sample heating rate of 10 ° C (up to 150 ° C) and 4 ° C (above 150 ° C) per minute. The measured melting point values are within a temperature range of 180 to 200 ° C. Typical melting point values are given in Examples 1 to 5.

C Differential Scanning Calorimetry (DSC)

DSC records were measured on a Perkin Elmer PYRIS 1. The measurements were made for samples weighing 3-6 mg of the substance. The samples were heated in a temperature range of 20-210 ° C with a heating rate of 10 ° C per minute. Examples of measured DSC curves are shown in FIG. 4, 5 and 6.

The crystalline salt of aripiprazole tartrate III form A shows a maximum at 195.8 ° C. The crystalline salt of aripiprazole tartrate III form B shows a maximum at 194.8 ° C.

D Solid State Carbon NMR ( ¹³ C CP-MAS NMR)

NMR spectra of crystalline forms A, B and amorphate of aripiprazole tartrate ΙΠ for the isotope carbon ^I3 C were measured on an Avance 500 Bruker spectrometer with a measuring frequency of 125.77 MHz using CP / MAS technique with a sample rotation of 15 kHz. The spectra obtained are shown in FIG. 7, 8 and

Claims (30)

l. The tartaric acid salt of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one of formula III including tautomers and solvates thereof. A salt according to claim 1 having an HPLC purity of 99.5% and above, with individual impurity contents below 0.1%. A process for preparing a tartaric acid salt of 7- {4- [4- (2,3-dichlorophenyl) -1-piperaziyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one of the formula ΠΙ according to claim 1, characterized in that 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one of formula I is reacted with tartaric acid, wherein the reaction is carried out in an organic solvent. TO HOOC.aOH hooc-V _oh SOLVENT, Cl HOOCyOH N in CH 2 Cl 2 HOOC% H III A process according to claim 3, characterized in that a solvent selected from the group consisting of C1-C4 alcohols, C1-C3 carboxylic acid esters of C1-C3 alcohols, ethers, ketones, acetonitrile, mixtures thereof and mixtures with water in any of these is used. ratios. Process according to claim 4, characterized in that ethanol or a mixture thereof with water is used as the solvent. The tartaric acid salt of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one according to claim 2 in crystalline form A, characterized by reflection at a diffraction angle of 21.86 °, ascertained by X-ray diffraction of CuKα radiation (λ = 1.5402 Å), which is accurate to 0.2 °. Crystalline form A of aripiprazole tartrate according to claim 6, characterized by further reflections at diffraction angles of 17.80; 21.17 and 25.07 °, as determined by the method of claim 15, with the same accuracy. The salt of claim 6 having a melting point in the range of 196.8 to 198.0 ° C. The salt of claim 6, having a DCS with a maximum near about 196 ° C. The salt of claim 6, characterized by the ¹³ C CP-MAS NMR spectrum shown in FIG. 7th A process for preparing aripiprazole tartrate in crystalline form A according to any one of claims 6 to 10, characterized in that it comprises the following steps: (a) dissolving aripiprazole tartrate in a suitable solvent; b) reflux for 10 to 30 min; (c) cooling to room temperature; d) filtering out the precipitated salt; wherein a suitable solvent is methanol, ethanol. Process according to claim 11, characterized in that methanol is used as the solvent. The tartaric acid salt of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one according to claim 2 in crystalline form B, characterized by reflection at a diffraction angle of 15.88 °, measured by the X-ray diffraction method of CuKα radiation (λ = 1.5402 Å), accurate to 0.2 °. Crystalline form B of aripiprazole tartrate according to claim 13, characterized by further reflection at an angle of 23.53 ° as measured by the same method. Crystalline form B of aripiprazole tartrate according to claim 14, characterized by further reflections at angles of 15.42; 16.96; 17.74; 18.67 and 21.890, as determined by the method of claim 13, with equal accuracy. The salt of claim 14, having a melting point in the range of 183-193 ° C. The salt of claim 14, having a DCS with a maximum near about 195 ° C. The salt of claim 14, characterized by the ¹³ C CP-MAS NMR of Figs. 8th Process for preparing aripiprazole tartrate in crystalline form B according to any one of claims 13 to 18, characterized in that it comprises the following steps: (a) dissolving aripiprazole tartrate in a suitable solvent; b) reflux for 10 to 30 min; (c) cooling to room temperature; d) filtering out the precipitated salt; wherein as a suitable solvent is meant a solvent selected from the group consisting of water or an aqueous C1-C4 alcoholic mixture. The process according to claim 19, characterized in that water is used as the solvent. Process according to claim 19, characterized in that the solvent used is a 4/1 ethanol / water mixture. The tartaric acid salt of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one according to claim 2 in amorphous form. The amorphous form of aripiprazole tartrate according to claim 22, characterized by the X-ray diffractogram shown in FIG. Third The amorphous salt form of claim 22 having the DSC shown in FIG. 6th I Ί The amorphous salt form of claim 22, characterized by the C CP-MAS NMR of FIG. 11th A process for preparing an amorphous form according to any one of claims 22 to 25, characterized by spray drying from a mixture of organic solvent and water. A process according to claim 26, characterized in that an alcohol from the group of methanol, ethanol, 1-propanol, 2-propanol is used in admixture with water. 28. The process of claim 26 wherein ethanol is used in a 3: 2 mixture with water. Use of salts according to any one of claims 1, 2, 6 to 10, 13 to 18 and 22 to 25 for the preparation of pharmaceutically useful compositions. Use of salts according to any one of claims 1, 2, 6 to 10, 13 to 18 and 22 to 25 for the preparation of a medicament having an antipsychotic effect.