JP2014031360A - Anhydrous aripiprazole crystal and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a novel anhydrous aripiprazole crystal, and to provide the anhydrous aripiprazole crystal.SOLUTION: The method comprises producing a novel anhydrous aripiprazole crystal, and more specifically, an anhydrous aripiprazole crystal having a powder X-ray diffraction spectrum having peaks at 2θ(±0.2°) of 7.6°, 8.0°, 13.4°, 13.8°, 20.4°, 22.1°, 22.5° and 24.1°. The anhydrous aripiprazole crystal obtained does not exhibit changes in crystal form by maintaining an inherent melting point (melting point of 148-149°C) which is unchanged even under accelerated conditions. The anhydrous aripiprazole crystal can efficiently be made into a preparation, because the hygroscopic properties are very low and the light stability is outstanding.

Description

  The present invention relates to a novel anhydrous aripiprazole crystal and a method for producing the same.

Aripiprazole has the chemical name 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] -butoxy} -3,4-dihydrocarbostyril, or 7- {4- [4- ( 2,3-dichlorophenyl) -1-piperazinyl] -butoxy} -3,4-dihydro-2 (1H) -quinolinone, which has the structure of Chemical Formula 1 below. Aripiprazole is an antipsychotic drug that exhibits strong affinity for dopamine D2 and D3, serotonin 5-HT1A receptor and serotonin 5-HT2A receptor, and mild affinity for the serotonin reabsorption site.

  Patent document 1 is disclosing the aripiprazole and its manufacturing method. According to Patent Document 1, aripiprazole is finally obtained by recrystallization from ethanol.

  Non-Patent Document 1 discloses that aripiprazole anhydride crystals exist as type I crystals and type II crystals. Aripiprazole anhydrous Form I crystals are prepared by recrystallization from an aripiprazole ethanol solution or by heating aripiprazole hydrate at 80 ° C. An aripiprazole anhydride type II crystal is prepared by heating an aripiprazole anhydride type I crystal at 130 ° C. to 140 ° C. for 15 hours. Patent Document 2 discloses crystal types A, B, C, D, E, F, and G, and methods for producing them. The crystal form A disclosed in Patent Document 2 is a hydrate form, but the hydrate form has a disadvantage that it is inferior in bioavailability and degradability to the anhydrous form. In addition, Patent Document 3 discloses various crystal forms such as crystal forms J and L, and Patent Document 4 discloses aripiprazole alcohol (ethanol, methanol, etc.) hemihydrate. .

  Various crystal forms of aripiprazole and methods for producing the same have been reported. However, interconversion occurs between crystal forms during long-term storage, resulting in high hygroscopicity, making it difficult to make an efficient formulation.

US Pat. No. 5,006,528 International Patent Publication No. WO03 / 26659 Pamphlet International Patent Publication No. WO2007 / 004061 Pamphlet International Patent Publication No. WO2006 / 079548 Pamphlet

"The Fourth Japan-Korea symposium on separation technology" bulletin, October 6-8, 1996

  The present inventors have conducted various studies to produce a new anhydrous crystal form that does not cause a change in crystal form even when stored for a long period of time and has a low hygroscopic property and enables efficient formulation. went.

  As a result, it was discovered that when a mono-ethanol solvate of aripiprazole was slurried from a specific ether solvent and subjected to the steps of stirring, filtration and drying, a new anhydrous crystalline form of aripiprazole was obtained. Further, the obtained anhydrous aripiprazole crystal does not show a change in crystal form by maintaining its inherent melting point (melting point of 148 ° C. to 149 ° C.) under accelerated conditions (stability test), and also absorbs moisture. It has been discovered that efficient formulation is possible due to its extremely low stability and excellent light stability.

  Accordingly, an object of the present invention is to provide a method for producing novel anhydrous aripiprazole crystals. Another object of the present invention is to provide the anhydrous aripiprazole crystals.

According to one aspect of the present invention, the following steps are included: 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1. A method for producing anhydrous aripiprazole crystals having a powder X-ray diffraction spectrum having a peak at 2 ° (± 0.2 °) of ° is provided:
(A) slurrying the mono-ethanol solvate of aripiprazole in a solvent selected from the group consisting of diethyl ether, dipropyl ether, diisopropyl ether and methyl tert-butyl ether;
(B) a step of filtering the slurry obtained from step (a) after stirring at 0 ° C. to 30 ° C. for 1 to 6 hours; and (c) a step of drying the solid obtained from step (b). .

  In the production process according to the invention, the products, ie 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1. An anhydrous aripiprazole crystal having a powder X-ray diffraction spectrum having a peak at 2θ of ± (± 0.2 °) can have the powder X-ray diffraction spectrum of FIG. 1 and has a melting point of 148 ° C. to 149 ° C. be able to.

  In the production method of the present invention, the aripiprazole mono-ethanol solvate used in step (a) can be obtained by recrystallizing a hydrous crystal of aripiprazole from absolute ethanol. It can have two powder X-ray diffraction spectra.

  In the production method of the present invention, step (b) is performed by stirring the slurry obtained from step (a) at 18 ° C. to 25 ° C. for 1 to 6 hours and then filtering. In addition, the drying in the step (c) is performed at a temperature of 50 ° C. to 85 ° C. for 40 hours to 80 hours, preferably at a temperature of 78 ° C. to 85 ° C. for 50 hours to 60 hours.

  According to another aspect of the present invention, 2θ (7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1 °) Anhydrous aripiprazole crystals having a powder X-ray diffraction spectrum having a peak at ± 0.2 ° are provided.

  The anhydrous aripiprazole crystals may have the powder X-ray diffraction spectrum of FIG. 1 and may have a melting point of 148 ° C. to 149 ° C.

  According to the present invention, when a mono-ethanol solvate of aripiprazole is slurried using a specific solvent and agitation, filtration and drying steps are performed, a new anhydrous crystalline form of aripiprazole is obtained. It was. The novel anhydrous aripiprazole crystals obtained by the production method of the present invention show no change in crystal form by maintaining the inherent melting point (melting point of 148 ° C. to 149 ° C.) as it is even under accelerated conditions. In addition, since the hygroscopic property is very low and the light stability is excellent, an efficient formulation can be achieved.

1 is an X-ray diffraction (hereinafter, also referred to as XRD) pattern of anhydrous aripiprazole crystals produced according to the present invention. 1 is an XRD pattern of aripiprazole mono-ethanol solvate used as a starting material in the present invention.

The present invention includes the following steps: 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 °, and 24.1 ° 2θ. A method for producing anhydrous aripiprazole crystals having a powder X-ray diffraction spectrum with a peak at (± 0.2 °) is provided:
(A) slurrying the mono-ethanol solvate of aripiprazole in a solvent selected from the group consisting of diethyl ether, dipropyl ether, diisopropyl ether and methyl tert-butyl ether;
(B) a step of filtering the slurry obtained from step (a) after stirring at 0 ° C. to 30 ° C. for 1 to 6 hours; and (c) a step of drying the solid obtained from step (b). .

  In the production process according to the invention, the products, ie 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1. An anhydrous aripiprazole crystal having a powder X-ray diffraction spectrum having a peak at 2 ° of ± 2 ° (± 0.2 °) has the powder X-ray diffraction spectrum of FIG. 1 and has a melting point of 148 ° C. to 149 ° C. it can. Anhydrous aripiprazole crystals obtained by the production method of the present invention are crystal forms reported in conventional literature, for example, crystal forms A, B, C, D, E disclosed in International Patent Publication No. WO 03/26659. , F and G are different crystal forms.

  The production method of the present invention includes a step of slurrying a mono-ethanol solvate of aripiprazole in a specific ether solvent [ie, step (a)]. The aripiprazole mono-ethanol solvate used as a starting material in the production method of the present invention has an ethanol content of 8 wt% to 10 wt%, preferably about 9.3 wt%. The mono-ethanol solvate of aripiprazole is obtained from hydrated crystals of aripiprazole. For example, the hydrous crystal of aripiprazole disclosed in "The Fourth Japan-Korea symposium on separation technology", October 6-8, 1996. ) Can be recrystallized using absolute ethanol to obtain the mono-ethanol solvate of aripiprazole. Therefore, as the mono-ethanol solvate of aripiprazole used in the production method according to the present invention, a product obtained by recrystallizing hydrated crystals of aripiprazole from absolute ethanol can be desirably used. The obtained aripiprazole mono-ethanol solvate has the powder X-ray diffraction spectrum of FIG. The mono-ethanol solvate of aripiprazole obtained through the recrystallization is used as a starting material in the production method according to the present invention without a separate drying step.

  The amount of the specific ether solvent used in the production method of the present invention, that is, the solvent selected from the group consisting of diethyl ether, dipropyl ether, diisopropyl ether and methyl tert-butyl ether is not greatly limited. It may be used in an amount sufficient to obtain a solution. For example, the solvent is used in the range of 2 to 10 parts by weight based on 1 part by weight of anhydrous aripiprazole crystal form I.

  The production method of the present invention includes a step of stirring the slurry obtained from step (a) at 0 ° C. to 30 ° C. for 1 to 6 hours and then filtering [ie, step (b)], preferably , By stirring the slurry obtained from step (a) at 18 ° C. to 25 ° C. for 1 hour to 6 hours, more preferably 2 hours to 3 hours, followed by filtration.

  The production method of the present invention includes a step of drying the solid obtained from step (b) [ie, step (c)]. The drying is performed at a temperature of 50 ° C. to 85 ° C. for 40 hours to 80 hours, preferably at a temperature of 78 ° C. to 85 ° C. for 50 hours to 60 hours.

  The present invention also provides 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1 ° 2θ (± 0.2 An anhydrous aripiprazole crystal having a powder X-ray diffraction spectrum having a peak at ゜). The anhydrous aripiprazole crystals may have the powder X-ray diffraction spectrum of FIG. 1 and may have a melting point of 148 ° C. to 149 ° C.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

  The mono-ethanol solvate of aripiprazole used in the following examples is “The Fourth Japan-Korea symposium on separation technology”, October 1996, 6- After 8 days, a hydrous crystal of aripiprazole was prepared, which was then recrystallized using absolute ethanol. That is, 14 g of aripiprazole was added to 200 mL of an aqueous ethanol solution containing 20% (v / v) water, and dissolved while stirring under reflux. The resulting solution was allowed to cool to about 15 ° C., stirred at this temperature for 2 hours and then filtered. The obtained solid, that is, hydrated crystals, was added to 100 mL of absolute ethanol, and dissolved while stirring under reflux, followed by filtration to remove crystal nuclei. The obtained filtrate was cooled to about 15 ° C., stirred at this temperature for 2 hours, and then filtered to obtain a solid. The resulting solid, ie the mono-ethanol solvate of aripiprazole, was used in the examples below without drying. The powder X-ray diffraction spectrum of the undried aripiprazole mono-ethanol solvate used in the following examples is as shown in FIG.

Example 1
To 12 g of aripiprazole mono-ethanol solvate, 20 mL of diisopropyl ether was added. The resulting slurry was stirred at about 23 ° C. for about 2 hours and then filtered. The obtained solid was dried in a circulating hot air dryer at about 80 ° C. for 55 hours to obtain 9.6 g of anhydrous aripiprazole crystals. The X-ray diffraction spectrum of the obtained anhydrous aripiprazole crystal is as shown in FIG. Further, the melting point of the obtained anhydrous aripiprazole crystal was measured using a melting point measuring machine and found to be 148 ° C. to 149 ° C.

(Example 2)
To 12 g of aripiprazole mono-ethanol solvate, 20 mL of diethyl ether was added. The resulting slurry was stirred at about 23 ° C. for about 2 hours and then filtered. The obtained solid was dried in a circulating hot air dryer at about 80 ° C. for 55 hours to obtain 9.3 g of anhydrous aripiprazole crystals. As a result of measuring the X-ray diffraction spectrum of the obtained anhydrous aripiprazole crystal, it was the same as FIG. 1, and the melting point was measured by the same method as in Example 1. As a result, it was 148 ° C. to 149 ° C.

(Example 3)
To 12 g of aripiprazole mono-ethanol solvate, 20 mL of methyl tert-butyl ether was added. The resulting slurry was stirred at about 23 ° C. for about 2 hours and then filtered. The obtained solid was dried in a circulating hot air dryer at about 80 ° C. for 55 hours to obtain 9.2 g of anhydrous aripiprazole crystals. As a result of measuring the X-ray diffraction spectrum of the obtained anhydrous aripiprazole crystal, it was the same as FIG. 1, and the melting point was measured by the same method as in Example 1. As a result, it was 148 ° C. to 149 ° C.

Example 4
To 12 g of aripiprazole mono-ethanol solvate, 20 mL of dipropyl ether was added. The resulting slurry was stirred at about 23 ° C. for about 2 hours and then filtered. The obtained solid was dried in a circulating hot air dryer at about 80 ° C. for 55 hours to obtain 8.9 g of anhydrous aripiprazole crystals. As a result of measuring the X-ray diffraction spectrum of the obtained anhydrous aripiprazole crystal, it was the same as FIG. 1, and the melting point was measured by the same method as in Example 1. As a result, it was 148 ° C. to 149 ° C.

(Test Example 1) Stability test (acceleration test)
While the anhydrous aripiprazole crystals obtained in Example 1 were stored for 4 weeks under the conditions of 75% RH (relative humidity) and 40 ° C. (acceleration conditions), the properties, content, melting point and water content were measured. The results are shown in Table 1 below. In Table 1, the content (%) is a value calculated by setting the initial weight as 100%, and the water content indicates the content (% by weight) of water contained in the sample.

(Test Example 2) Light Stability Test After placing 1 g of anhydrous aripiprazole crystals obtained in Example 1 on a petri dish so as to spread widely, the lid was opened and the condition was 4500 Lx for 10 days. The properties, content, melting point and water content were measured while being stored. The results are as shown in Table 2 below. In Table 2, the content (%) is a value calculated by setting the initial weight as 100%, and the water content indicates the content (% by weight) of water contained in the sample.

  As can be seen from the results of Tables 1 and 2, the anhydrous aripiprazole crystals obtained according to the present invention maintain their inherent melting point (melting point of 148 ° C. to 149 ° C.) as they are even under accelerated conditions. Showed no change. Moreover, it turns out that an efficient formulation is possible by very low hygroscopicity and being excellent in light stability.

Claims (11)

7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1 ° 2θ (± 0. Method for producing anhydrous aripiprazole crystals having a powder X-ray diffraction spectrum having a peak at 2 °:
(A) slurrying the mono-ethanol solvate of aripiprazole in a solvent selected from the group consisting of diethyl ether, dipropyl ether, diisopropyl ether and methyl tert-butyl ether;
(B) a step of filtering the slurry obtained from step (a) after stirring at 0 ° C. to 30 ° C. for 1 to 6 hours; and (c) a step of drying the solid obtained from step (b). .   At 2θ (± 0.2 °) of 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1 °. The production method according to claim 1, wherein the anhydrous aripiprazole crystal having a powder X-ray diffraction spectrum having a peak has the powder X-ray diffraction spectrum of FIG.   At 2θ (± 0.2 °) of 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1 °. The method according to claim 2, wherein the anhydrous aripiprazole crystal having a powder X-ray diffraction spectrum having a peak has a melting point of 148 ° C to 149 ° C.   The mono-ethanol solvate of aripiprazole used in step (a) is obtained by recrystallizing hydrated crystals of aripiprazole from absolute ethanol. Of these, the production method according to any one of the above.   The production method according to claim 4, wherein the mono-ethanol solvate of aripiprazole used in step (a) has the powder X-ray diffraction spectrum of Fig. 2.   The step (b) is carried out by stirring the slurry obtained from step (a) at 18 ° C to 25 ° C for 1 to 6 hours and then filtering. 3. The production method according to any one of 3 above.   The method according to any one of claims 1 to 3, wherein the drying in the step (c) is performed at a temperature of 50 ° C to 85 ° C for 40 hours to 80 hours. .   The method according to claim 7, wherein the drying in the step (c) is performed at a temperature of 78 ° C to 85 ° C for 50 hours to 60 hours.   Peaks at 2θ (± 0.2 °) of 7.6 °, 8.0 °, 13.4 °, 13.8 °, 20.4 °, 22.1 °, 22.5 ° and 24.1 ° Anhydrous aripiprazole crystals having a powder X-ray diffraction spectrum.   The anhydrous aripiprazole crystal according to claim 9, which has the powder X-ray diffraction spectrum of FIG. 1.   The anhydrous aripiprazole crystal according to claim 10, which has a melting point of 148 ° C to 149 ° C.