RU2259366C2 - Low hygroscopicity arypyprazole medicinal agent and methods for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to arypyprazole anhydrous crystals B showing characteristic peaks in powdered roentgen rays diffraction at 2θ = 11.0^°, 16.6^°, 19.3^°, 20.3^° and 22.1^°, specific infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm^-1 in IR-spectrum, endothermic peak at 141.5^° in thermogravimetric/differential thermic analysis and endothermic peak at 140.7^° C in differential scanning calorimetry, arypyprazole A hydrate, to methods for their preparing, pharmaceutical compositions comprising arypyprazole crystals B and methods for their preparing. Invention provides reduced hygroscopicity of arypyprazole crystals B.

EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

Description

Field of Invention

The present invention relates to an improved form of aripiprazole having reduced hygroscopicity, and methods for producing this improved form.

BACKGROUND OF THE INVENTION

Aripiprazole, 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 is an atypical antipsychotic agent useful in treating schizophrenia (US Pat. No. 4,734,416 and US Pat. No. 5,005,528). Schizophrenia is a common type of psychosis characterized by delirium, hallucinations and a pronounced avoidance of communication with other people. The onset of schizophrenia usually occurs between the ages of 16 and 25, and schizophrenia usually affects 1 out of 100 individuals worldwide. It is more common than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and muscle dystrophy. Early diagnosis and treatment can lead to recovery with a significantly improved condition and outcome. In addition, early therapeutic intervention can prevent expensive hospitalization.

According to Example 1 of Japanese Patent Laid-Open No. 191256/1990, an aripiprazole anhydride crystals is obtained, for example, by reacting 7- (4-bromobutoxy) -3,4-dihydrocarbostyril with 1- (2,3-dichlorophenylpiperazine) and recrystallizing the resulting crude anhydrous aripiprazole with ethanol. In addition, in accordance with the proceedings of the 4th Japanese-Korean symposium on separation technology (October 6-8, 1996), anhydrous aripiprazole crystals are obtained by heating aripiprazole hydrate at 80 ° C. However, the crystals of anhydrous aripiprazole obtained by the above methods have the disadvantage of significant hygroscopicity.

The hygroscopicity of these crystals makes it difficult to work with them, since expensive and burdensome measurements must be taken to ensure that they are not exposed to moisture during the preparation and preparation of the finished formulation from them. Exposed to moisture, the anhydrous form can absorb water and turn into an aqueous form. This creates several difficulties. Firstly, aqueous forms of aripiprazole have the disadvantage of lower bioavailability and lower solubility than the anhydrous forms of aripiprazole. Secondly, a change in the amount of aripiprazole aqueous compared to an aripiprazole anhydrous drug from batch to batch may not satisfy the specifications established by drug regulatory organizations. Thirdly, milling can cause the sticking of a drug substance, ordinary aripiprazole anhydrous, to production equipment, which can further lead to a slowdown of the process, more frequent involvement of the operator in the process, increased cost, increased service and lower product yield. Fourth, in addition to the problems caused by the introduction of moisture during the processing of these hygroscopic anhydrous forms, the possibility of moisture absorption during storage and handling of these forms may adversely affect the solubility of the aripiprazole drug substance. Thus, the shelf life of the product can be significantly reduced and / or the cost of packaging can be significantly increased. It would be highly desirable to find a form of aripiprazole that has low hygroscopicity, thereby facilitating the pharmaceutical processing and preparation of the finished formulation required to produce unit dosage forms of an aripiprazole drug product having an extended shelf life, suitable solubility and suitable bioavailability.

In addition, the proceedings of the 4th Japanese-Korean symposium on separation technology (October 6–8, 1996) indicate that anripiprazole anhydride crystals exist as type I crystals and type II crystals; Type I crystals of aripiprazole anhydride can be obtained by recrystallization of aripiprazole from a solution in ethanol or by heating aripiprazole hydrate at 80 ° C; and type II crystals of aripiprazole anhydride can be obtained by heating type I crystals of aripiprazole anhydride at a temperature of from 130 to 140 ° C for 15 hours.

By the above methods, crystals of type II anhydrous aripiprazole having high purity cannot be easily obtained on an industrial scale with good reproducibility.

SUMMARY OF THE INVENTION

Thus, in accordance with the present invention, a form of aripiprazole is provided which has reduced hygroscopicity and which is readily susceptible to pharmaceutical processing and preparation of a finished formulation from it. It was found that this form of aripiprazole with reduced hygroscopicity is a crystalline substance, defined here as crystals of anhydrous aripiprazole B. A specific process for the preparation of this anhydrous crystalline substance has also been discovered; it constitutes yet another aspect of the present invention. In particular, as part of the present invention, it was found that to obtain crystals of anhydrous aripiprazole B, which has the required pharmaceutical properties and for which the most effective method is used, hydrate A can be used as an intermediate, as defined above. It has also been found that a particular process sequence must be carried out so that hydrate A is formed. It has been found that the preparation of hydrate A, which requires grinding, is defined here as the preparation of a conventional hydrate. Hydrate A can then be converted to anripiprazole anhydride crystals B by suitable heating, as defined herein. Oddly enough, if a conventional hydrate is first heated and then ground, this leads to severe agglomeration, making the process commercially unsuitable.

The aim of the present invention is the provision of new crystals of anhydrous aripiprazole.

In addition, it is another object of the present invention to provide anhydrous aripiprazole crystals that do not readily convert to hydrates, do not substantially reduce the initial solubility, even when a pharmaceutical composition comprising an aripiprazole anhydride is stored for an extended period of time.

The next objective of the present invention is the provision of methods for producing crystals of anhydrous aripiprazole having high purity on an industrial scale with good reproducibility.

Research has been carried out to achieve the above objectives. In the course of the studies, it was found that the required crystals of anhydrous aripiprazole can be obtained when the well-known anhydrous aripiprazole is heated at a certain temperature. In addition, it was found that the desired crystals of anhydrous aripiprazole can be obtained by recrystallization of the well-known anhydrous aripiprazole using certain solvents. In addition, it was found that the desired crystals of anhydrous aripiprazole can be obtained by suspending the well-known anhydrous aripiprazole in a specific solvent and heating the suspension thus obtained.

The present invention is thus created based on these discoveries and knowledge.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a thermogravimetric / differential thermogram of aripiprazole hydrate A obtained in Example 1.

Figure 2 shows a ¹ H NMR spectrum (DMSO-d ₆ , TMC) of aripiprazole hydrate A obtained in Example 1.

Figure 3 shows a powder X-ray diffraction diagram of aripiprazole hydrate A obtained in Example 1.

Figure 4 shows a ¹ H NMR spectrum (DMSO-d ₆ , TMC) of anhydrous aripiprazole crystals B obtained in Example 2.

The figure 5 shows a diagram of powder x-ray diffraction of crystals In anhydrous aripiprazole obtained in example 2.

Figure 6 is a thermogravimetric / differential thermogram of aripiprazole hydrate obtained in Reference Example 3.

The figure 7 shows a diagram of powder x-ray diffraction of aripiprazole hydrate obtained in reference example 3.

The figure 8 shows the endothermic curve of thermogravimetric / differential thermal analysis of type C crystals of anhydrous aripiprazole obtained in example 11.

Figure 9 shows the ¹ H NMR spectrum (DMSO-d ₆ , TMC) of type C crystals of aripiprazole anhydride obtained in Example 11.

The figure 10 shows the spectrum of powder x-ray diffraction of crystals of type C anhydrous aripiprazole obtained in example 11.

The figure 11 shows the IR spectrum of type C crystals of anhydrous aripiprazole obtained in example 11.

Figure 12 shows the ¹³ C NMR spectrum of type C crystals of aripiprazole anhydride (aripiprazole spectrum was taken in the solid state) obtained in Example 11.

The figure 13 shows the endothermic curve of thermogravimetric / differential thermal analysis of crystals of type D of anhydrous aripiprazole obtained in example 12 or example 13.

Figure 14 shows a ¹ H NMR spectrum (DMSO-d ₆ , TMC) of type D crystals of aripiprazole anhydride obtained in Example 12 or Example 13.

The figure 15 shows the spectrum of powder x-ray diffraction of crystals of type D of anhydrous aripiprazole obtained in example 12 or example 13.

Figure 16 shows the IR spectrum of type D crystals of aripiprazole anhydride obtained in Example 12 or Example 13.

Figure 17 shows the ¹³ C NMR spectrum of type D crystals of aripiprazole anhydride (aripiprazole spectra were taken in the solid state) obtained in Example 12 or Example 13.

Figure 18 shows the endothermic curve of a thermogravimetric / differential thermal analysis of type E crystals of aripiprazole anhydride obtained in Example 14.

Figure 19 shows the ¹ H NMR spectrum (DMSO-d ₆ , TMC) of type E crystals of aripiprazole anhydride obtained in Example 14.

The figure 20 shows the spectrum of powder x-ray diffraction of crystals of type E anhydrous aripiprazole obtained in example 14.

Figure 21 shows the IR spectrum of type E crystals of aripiprazole anhydride obtained in Example 14.

The figure 22 shows the endothermic curve of thermogravimetric / differential thermal analysis of type F crystals of anhydrous aripiprazole obtained in example 15.

Figure 23 shows the ¹ H NMR spectrum (DMSO-d ₆ , TMS) of type F crystals of anhydrous aripiprazole obtained in Example 15.

24 shows a powder X-ray diffraction spectrum of type F crystals of aripiprazole anhydride obtained in Example 15.

The figure 25 shows the IR spectrum of type F crystals of anhydrous aripiprazole obtained in example 15.

Figure 26 shows the endothermic curve of a thermogravimetric / differential thermal analysis of type G crystals of aripiprazole anhydride obtained in Example 16-b).

Figure 27 shows a ¹ H NMR spectrum (DMSO-d ₆ , TMS) of type G crystals of aripiprazole anhydride obtained in Example 16-b).

Figure 28 shows the X-ray powder diffraction spectrum of type G crystals of aripiprazole anhydride obtained in Example 16-b).

Figure 29 shows the IR spectrum of type G crystals of aripiprazole anhydride obtained in Example 16-b).

The figure 30 shows the endothermic curve of thermogravimetric / differential thermal analysis of the vitreous form of anhydrous aripiprazole obtained in example 16-a).

The figure 31 shows the spectrum of powder x-ray diffraction of the vitreous anhydrous aripiprazole obtained in example 16-a).

DETAILED DESCRIPTION OF THE INVENTION

According to a first embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has a powder X-ray diffraction spectrum that is substantially the same as the powder X-ray diffraction spectrum shown in FIG. 3.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has characteristic X-ray powder diffraction peaks at 2θ = 12.6 °, 15.4 °, 17.3 °, 18.0 °, 18, 6 °, 22.5 ° and 24.8 °.

In accordance with another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has characteristic infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm ^-1 in the IR spectrum (KBr )

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has a ¹ H NMR spectrum that is substantially the same as the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 2 .

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has a ¹ H NMR spectrum (DMSO-d ₆ , TMS) having characteristic peaks at 1.55-1.63 ppm. (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an endothermic curve that is substantially the same as the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate of 5 ° C./min) shown in FIG. 1 .

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size of 50 μm or less.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size of 40 microns or less.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size of 35 μm or less.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size of 30 microns or less.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size of 25 microns or less.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size of 20 microns or less.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size in the range of 40 to 10 microns.

According to another embodiment of the first aspect of the present invention, an aripiprazole hydrate A is provided, wherein said hydrate has an average particle size in the range of 36 to 14 microns.

In accordance with a second aspect of the present invention, there is provided a process for producing hydrate A, wherein said process comprises the steps of milling a conventional hydrate.

According to a first embodiment of the second aspect of the present invention, there is provided a method for producing hydrate A, comprising the steps of grinding a conventional hydrate, wherein said grinding is carried out by a grinding machine.

In accordance with another embodiment of the second aspect of the present invention, there is provided a method for producing hydrate A, comprising the steps of milling a conventional hydrate, wherein said milling machine is a fine grinding apparatus (aerosol apparatus) a spindle mill, a jet mill or a ball mill.

In accordance with another embodiment of the second aspect of the present invention, there is provided a method for producing hydrate A, comprising the steps of grinding a conventional hydrate, wherein said grinding machine is a fine grinding apparatus.

In accordance with another embodiment of the second aspect of the present invention, there is provided a method for producing hydrate A, comprising the steps of grinding a conventional hydrate, wherein said grinding machine is a fine grinding apparatus using a rotation speed of 5000-15000 rpm for the main axis, rotation of the starting material 10-30 rpm and a sieve opening size of 1-5 mm.

In accordance with various embodiments of a third aspect of the present invention, there is provided a hydrate A defined in accordance with one or more of the embodiments described herein, wherein said hydrate is prepared by the method described herein.

In accordance with a fourth aspect of the present invention, an aripiprazole drug substance with low hygroscopicity is provided.

According to a first embodiment of the fourth aspect of the present invention, there is provided a low hygroscopic aripiprazole drug substance, wherein said low hygroscopicity is a moisture content of 0.5% or less after placing the drug substance for 24 hours in a desiccator, which is held at a temperature of 60 ° C. and humidity level of 100%.

According to a first embodiment of the fourth aspect of the present invention, there is provided an aripiprazole drug substance with low hygroscopicity, wherein said low hygroscopicity is a moisture content of 0.4% or less after placing said drug substance for 24 hours in a desiccator, which is held at a temperature of 60 ° C. and humidity level of 100%.

According to another embodiment of the fourth aspect of the present invention, an aripiprazole drug substance with low hygroscopicity is provided, wherein said low hygroscopicity is a moisture content of 0.25% or less after the said drug substance has been placed for 24 hours in a desiccator, which is held at a temperature of 60 ° C. and humidity level of 100%.

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug substance with low hygroscopicity is provided, wherein said low hygroscopicity is a moisture content of 0.15% or less after placing said drug substance for 24 hours in a desiccator, which is held at a temperature of 60 ° C. and humidity level of 100%.

In accordance with another embodiment of the fourth aspect of the present invention, there is provided an aripiprazole drug substance with low hygroscopicity, wherein said low hygroscopicity is a moisture content of 0.10% or less after placing said drug substance for 24 hours in a desiccator, which is held at a temperature of 60 ° C. and humidity level of 100%.

According to another embodiment of the fourth aspect of the present invention, an aripiprazole drug substance with low hygroscopicity is provided, wherein said low hygroscopicity is a moisture content of 0.05% or less after placing said drug substance for 24 hours in a desiccator, which is held at a temperature of 60 ° C. and humidity level of 100%.

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug substance with low hygroscopicity is provided, wherein said low hygroscopicity is a moisture content of 0.04% or less after placing said drug substance for 24 hours in a desiccator, which is held at a temperature of 60 ° C. and humidity level of 100%.

According to another embodiment of the fourth aspect of the present invention, there is provided a low hygroscopic aripiprazole drug substance, wherein said drug substance are aripiprazole anhydride crystals B as defined herein.

According to another embodiment of the fourth aspect of the present invention, there is provided a low hygroscopic aripiprazole drug substance, wherein said drug substance has an X-ray powder diffraction spectrum that is substantially the same as the X-ray powder diffraction spectrum shown in FIG. 5.

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance has characteristic X-ray powder diffraction peaks at 2θ = 11.0 °, 16.6 °, 19.3 °, 20.3 ° and 22.1 °.

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug has characteristic infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm ^-1 on IR spectrum (KBr).

According to another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug has a ¹ H NMR spectrum that is substantially the same as a ¹ H NMR spectrum (DMSO-d ₆ , TMS), shown in figure 4.

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug has a ¹ H NMR spectrum (DMSO-d ₆ , TMS) having characteristic peaks at 1.55-1.63 m. d. (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance has an endothermic peak of about 141.5 ° C in a thermogravimetric / differential thermal analysis (heating rate of 5 ° C / min).

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance has an endothermic peak of about 140.7 ° C in differential scanning calorimetry (heating rate of 5 ° C / min).

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance is anripiprazole anhydride crystals B and does not substantially convert to an aripiprazole aqueous form when properly maintained even for an extended period. For example, these crystals of anhydrous aripiprazole can be stored at a relative humidity (RH) of 60% and at a temperature of 25 ° C, even for a period of not less than 1 year.

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance is anripiprazole anhydride crystals B and does not substantially convert to an aripiprazole aqueous form when properly maintained even for an extended period. For example, these crystals of anhydrous aripiprazole can be stored at a relative humidity (RH) of 60% and at a temperature of 25 ° C, even for a period of not less than 4 years.

According to another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance is anripiprazole anhydride crystals B and does not substantially convert to an aripiprazole aqueous form when properly maintained even for a period of not less than 0.5 years, at a relative humidity (RH) of 75% and at a temperature of 40 ° C.

According to another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance has an average particle size of 50 μm or less when for a formulation, such as a tablet or other solid dosage formulations, including including, for example, fast-melting finished formulations, small particles are required.

In accordance with another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance has an average particle size of 40 microns or less if for a formulation, such as a tablet or other solid dosage formulations, including including, for example, fast-melting finished formulations, small particles are required.

According to another embodiment of the fourth aspect of the present invention, an aripiprazole drug with low hygroscopicity is provided, wherein said drug substance has an average particle size of 30 μm or less if for a formulation, such as a tablet or other solid dosage formulations, including including, for example, fast-melting finished formulations, small particles are required.

In accordance with a fifth aspect of the present invention, there is provided a process for the preparation of anripiprazole anhydride crystals B.

According to a first embodiment of the fifth aspect of the present invention, there is provided a method for producing anripiprazole anhydride crystals B, wherein said method comprises heating aripiprazole hydrate A.

In accordance with a first embodiment of the fifth aspect of the present invention, there is provided a process for the preparation of aripiprazole anhydride crystals B, wherein said process comprises heating aripiprazole hydrate A at 90-125 ° C. for about 3-50 hours.

In accordance with another embodiment of the fifth aspect of the present invention, there is provided a process for the preparation of aripiprazole anhydride crystals B, wherein said process comprises heating aripiprazole hydrate A at 100 ° C. for about 18 hours.

In accordance with another embodiment of the fifth aspect of the present invention, there is provided a process for the preparation of aripiprazole anhydride crystals B, wherein said process comprises heating aripiprazole hydrate A at 100 ° C. for about 24 hours.

According to another embodiment of the fifth aspect of the present invention, there is provided a process for the preparation of aripiprazole anhydride crystals B, wherein said process comprises heating aripiprazole hydrate A at 120 ° C. for about 3 hours.

In accordance with another embodiment of the fifth aspect of the present invention, there is provided a process for the preparation of aripiprazole anhydride crystals B, wherein said process comprises heating aripiprazole hydrate A for approximately 18 hours at 100 ° C followed by further heating for about 3 hours at 120 ° C.

In accordance with a sixth aspect of the present invention, there are provided anhydrous aripiprazole crystals B determined in accordance with one or more of the embodiments described herein and obtained by the method provided herein.

In accordance with a seventh aspect of the present invention, there are provided anripiprazole anhydride crystals B made with one or more pharmaceutically acceptable carriers.

Other embodiments of the present invention may include suitable combinations of two or more of the embodiments and / or aspects described herein.

Other embodiments and aspects of the invention will be apparent from the description below.

Another aspect of the present invention includes the discovery that when aripiprazole hydrate (conventional hydrate, as defined here) is milled, it is converted to aripiprazole hydrate (hydrate A, as defined here) with a different powder X-ray diffraction spectrum due to other peak intensities. In addition, it was found that hydrate A loses a sharp endothermic dehydration peak of 123.5 ° C, which characterizes the unmilled conventional hydrate during thermogravimetric / differential thermal analysis. Thus, the ordinary hydrate is converted to hydrate A after grinding the ordinary hydrate and has an unsharp endothermic dehydration peak between about 60 ° C and 120 ° C with a weak peak at about 71 ° C.

Another aspect of the invention includes the discovery that when heated to a certain temperature of 90-125 ° C for 3-50 hours, this new aripiprazole hydrate is gradually dehydrated without the aggregation phenomenon, which is believed to be caused in ordinary aripiprazole hydrate by rapid dehydration, and that the crystals anhydrous aripiprazole, obtained by heating a new aripiprazole hydrate to a certain temperature, are crystals of anhydrous aripiprazole with the desired properties.

Characterization of hydrate A

The particles of "hydrate A" used here have the physicochemical properties given below in (1) - (5):

(1) They have an endothermic curve, which is essentially the same as the endothermic curve in thermogravimetric / differential thermal analysis (heating rate of 5 ° C / min) shown in figure 1. Specifically, it is characterized by the appearance of a small peak at approximately 71 ° C and unsharp endothermic peak in the range from about 60 ° C to 120 ° C.

(2) They have a ¹ H NMR spectrum that is substantially the same as the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in FIG. 2. Specifically, it has characteristic peaks at 1.55-1, 63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

(3) They have a powder X-ray diffraction spectrum that is substantially the same as the powder X-ray diffraction spectrum shown in FIG. 3. Specifically, it has characteristic peaks at 2θ = 12.6 °, 15.4 °, 17, 3 °, 18.0 °, 18.6 °, 22.5 ° and 24.8 °.

(4) They have clear infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963, and 784 cm ⁻¹ in the IR spectrum (KBr).

(5) They have an average particle size of 50 μm or less.

A method of manufacturing a hydrate A

Hydrate A is produced by grinding a conventional hydrate. Conventional grinding methods may be used to grind conventional hydrate. For example, conventional hydrate can be milled in a milling machine. You can use a widely used grinding machine, such as a finer grinding machine, spindle mill, jet mill or ball mill. Of these, a fine grinding apparatus is preferred.

With regard to certain grinding conditions, when using the installation for fine grinding for the main axis, you can use a rotation speed of 5000-15000 rpm./min, for example, with a rotation of the source material 10-30 rpm./min and the size of the holes of the sieve 1-5 mm

The average particle size of the aripiprazole hydrate A obtained by milling should usually be 50 μm or less, preferably 30 μm or less. The average particle size can be set as described below for measuring particle size.

Characterization of Anripiprazole Anhydride Crystals B

The “aripiprazole anhydride crystals B” of the present invention used here have the physicochemical properties described below in (6) to (12).

(6) They have a ¹ H NMR spectrum that is substantially the same as the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 4. Specifically, they have characteristic peaks at 1.55-1, 63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

(7) They have a powder X-ray diffraction spectrum that is substantially the same as the powder X-ray diffraction spectrum shown in Figure 5. Specifically, they have characteristic peaks at 2θ = 11.0 °, 16.6 °, 19, 3 °, 20.3 ° and 22.1 °.

(8) They have clear infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm ⁻¹ in the IR spectrum (KBr).

(9) They have an endothermic peak of approximately about 141.5 ° C in thermogravimetric / differential thermal analysis (heating rate of 5 ° C / min).

(10) They have an endothermic peak of about 140.7 ° C in differential scanning calorimetry (heating rate of 5 ° C / min).

(11) Crystals B of anhydrous aripiprazole of the present invention have low hygroscopicity. For example, the aripiprazole anhydride crystals B of the present invention retain a water content of 0.4% or less after 24 hours of aging inside an desiccator in which a temperature of 60 ° C. and a humidity of 100% are set. Well-known methods for measuring water content may be used since they are methods commonly used for measuring water content of crystals. For example, you can use a method such as the Karl Fischer method.

(12) When a small formulation is required for a finished formulation, such as a tablet and other solid dosage formulations, including, for example, fast melting formulation, the average particle size is preferably 50 μm or less.

The method of preparation of anhydrous B

In the case of the finished formulation, which requires small particles (less than 50 microns), grinding is required to obtain. However, when a large amount of conventional aripiprazole anhydrous or aripiprazole anhydride crystals B having large particle sizes are milled, the milled materials adhere to each other in the milling machine. Accordingly, a disadvantage arises in that on an industrial scale it is difficult to obtain anripiprazole anhydride crystals B having a small particle size.

Under such circumstances, it was found that a conventional hydrate can be easily milled and crystals of anhydrous aripiprazole B can be obtained having a small particle size, high yield and good suitability by heating the milled hydrate A thus obtained.

Anhydrous aripiprazole crystals B of the present invention are prepared, for example, by heating the above aripiprazole hydrate A at 90-125 ° C. The heating time is usually 3-50 hours, but it cannot be indicated exactly, since it varies with the heating temperature. The heating time and heating temperature are inversely proportional, so that, for example, the heating time will be longer, the lower the heating temperature, and the shorter the higher the heating temperature. In particular, if the heating temperature of aripiprazole hydrate A is 100 ° C, the heating time should usually be 18 hours or more, or, preferably, about 24 hours. On the other hand, if the heating temperature of aripiprazole hydrate A is 120 ° C., the heating time can be about 3 hours. Anhydrous aripiprazole crystals B of the present invention can be obtained with confidence by heating aripiprazole hydrate A for 18 hours at 100 ° C and then heating it for about 3 hours at 120 ° C. Anhydrous aripiprazole crystals of the present invention can also be obtained if the heating time is continued even further, but this may be uneconomical.

When a small particle is not required for the formulation, for example, when the formulation for the formulation is prepared as injectable or oral solutions, anripiprazole anhydride crystals B can also be prepared in the following manner.

It was found that crystals of anhydrous aripiprazole can be obtained by heating conventional aripiprazole hydrate or crystals of ordinary anhydrous aripiprazole to a certain temperature, but this method does not allow to obtain crystals of anhydrous aripiprazole B as an crystalline substance suitable for commercial use in solid oral dosage formulations.

In addition, crystals of anhydrous aripiprazole B of the present invention are obtained, for example, by heating crystals of ordinary anhydrous aripiprazole at 90-125 ° C. The heating time is usually 3-50 hours, but it cannot be indicated exactly, since it varies with the heating temperature. The heating time and heating temperature are inversely proportional, so that, for example, the heating time will be longer, the lower the heating temperature, and the shorter the higher the heating temperature.

In particular, if the heating temperature of the crystals of anhydrous aripiprazole is 100 ° C, the heating time can be about 4 hours and, if the heating temperature is 120 ° C, the heating time can be about 3 hours.

In addition to the aripiprazole hydrate A and the aripiprazole anhydride crystals B indicated above, the present invention provides the following C to G aripiprazole anhydride crystals.

1. The present invention relates to crystals of anhydrous aripiprazole (hereinafter referred to as "type C crystals of anhydrous aripiprazole") having the following physicochemical properties from (1) to (5):

(1) an endothermic curve that is substantially identical to the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 8;

(2) ¹ H NMR spectrum that is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in FIG. 9;

(3) a powder x-ray diffraction spectrum that is substantially identical to the powder x-ray diffraction spectrum shown in FIG. 10;

(4) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 11, and

(5) ¹³ C NMR spectrum (spectrum of a substance in the solid state), which is essentially identical to the ¹³ C NMR spectrum (spectrum of a substance in the solid state) shown in figure 12.

2. The present invention relates to crystals of anhydrous aripiprazole (hereinafter referred to as "type D crystals of anhydrous aripiprazole") having the following physicochemical properties from (6) to (10):

(6) an endothermic curve that is substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 13;

(7) ¹ H NMR spectrum, which is essentially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in figure 14;

(8) a powder x-ray diffraction spectrum that is substantially identical to the powder x-ray diffraction spectrum shown in FIG. 15;

(9) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 16; and

(10) ¹³ C NMR spectrum (spectrum of a solid state), which is substantially identical to the ¹³ C NMR spectrum shown in FIG. 17.

3. The present invention relates to crystals of anhydrous aripiprazole (hereinafter referred to as “type E crystals of anhydrous aripiprazole”) having the following physicochemical properties from (11) to (14):

(11) an endothermic curve that is substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 18;

(12) ¹ H NMR spectrum that is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in FIG. 19;

(13) a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in FIG. 20; and

(14) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 21.

4. The present invention relates to anripiprazole anhydrous crystals (hereinafter referred to as “an aripiprazole anhydride type F crystals”) having the following physicochemical properties from (15) to (18):

(15) an endothermic curve that is substantially identical to the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate: 5 ° C./min) shown in FIG. 22;

(16) ¹ H NMR spectrum, which is essentially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in FIG. 23;

(17) a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in FIG. 24; and

(18) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 25.

5. The present invention relates to a method for producing anripiprazole anhydride crystals as defined in the above paragraph 1, characterized by heating an aripiprazole anhydride crystals at a temperature higher than 140 ° C and lower than 150 ° C.

6. The present invention relates to a method for producing anripiprazole anhydride crystals as defined in paragraph 2 above, characterized by recrystallization from toluene.

7. The present invention relates to a method for producing anripiprazole anhydride crystals as defined in the above paragraph 3, characterized by heating and dissolving an aripiprazole anhydride crystals in acetonitrile and cooling the solution.

8. The present invention relates to a method for producing anripiprazole anhydride crystals as defined in paragraph 4 above, characterized by heating a suspension of aripiprazole anhydride crystals in acetone.

9. The present invention relates to a pharmaceutical composition comprising at least one of the types of aripiprazole anhydride crystals selected from the group consisting of aripiprazole anhydride crystals as defined in paragraph 1 above, an aripiprazole anhydride crystals as defined in paragraph 2 above, anhydrous crystals aripiprazole, as defined in paragraph 3 above, anripiprazole anhydride crystals, as defined in paragraph 4 above, and aripiprazole anhydride crystals, as defined s in paragraph 10 below, together with pharmaceutically acceptable carriers.

10. The present invention relates to crystals of anhydrous aripiprazole (hereinafter referred to as “type A crystals of aripiprazole anhydride”) having the following physicochemical properties from (19) to (22):

(19) an endothermic curve that is substantially identical to the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 26;

(20) ¹ H NMR spectrum that is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in FIG. 27;

(21) a powder x-ray diffraction spectrum that is substantially identical to the powder x-ray diffraction spectrum shown in FIG. 28; and

(22) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 29.

11. The present invention relates to a method for producing crystals of anhydrous aripiprazole, as defined in paragraph 10 above, characterized in placing the aripiprazole anhydrous in a vitreous state in a sealed vessel and keeping it at room temperature for at least 2 weeks.

12. The present invention relates to a method for producing granules, characterized by wet granulation of crystals of ordinary anhydrous aripiprazole or crystals B, C, D, E, F or G anhydrous aripiprazole, drying the obtained granules at a temperature of from 70 to 100 ° C and sieving them, then again drying sieved granules at a temperature of from 70 to 100 ° C.

13. The present invention relates to a method for producing a pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation, comprising crystals of ordinary aripiprazole anhydride or crystals of B, C, D, E, F or G of an aripiprazole and one or more pharmaceutically acceptable carriers, at a temperature from 70 to 100 ° C.

14. The present invention relates to a pharmaceutical solid oral preparation comprising crystals of B, C, D, E, F or G of an aripiprazole anhydride and one or more pharmaceutically acceptable carriers, wherein said pharmaceutical solid oral preparation has at least one dissolution rate, selected from the group consisting of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes.

15. The present invention relates to a pharmaceutical solid oral preparation having at least one dissolution rate selected from the group consisting of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4, 5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes.

16. The present invention relates to a pharmaceutical solid oral preparation obtained by wet granulation of crystals of conventional anhydrous aripiprazole, drying the obtained granules at a temperature of from 70 to 100 ° C and sieving them, then again drying the sieved granules at a temperature of from 70 to 100 ° C, where the pharmaceutical the solid oral preparation has at least one dissolution rate selected from the group consisting of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or b longer at pH 5.0 after 60 minutes.

17. The present invention relates to a pharmaceutical solid oral preparation obtained by drying a pharmaceutical solid oral preparation comprising crystals of the usual anhydrous aripiprazole and one or more pharmaceutically acceptable carriers, at a temperature of from 70 to 100 ° C, where the pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes.

18. The present invention relates to a method for producing granules, characterized by wet granulation of crystals of ordinary aripiprazole hydrate, drying the obtained granules at a temperature of from 70 to 100 ° C and sieving them and then again drying the sieved granules at a temperature of from 70 to 100 ° C.

19. The present invention relates to a method for producing a pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation, comprising crystals of the usual aripiprazole hydrate and one or more pharmaceutically acceptable carriers, at a temperature of from 70 to 100 ° C.

20. The present invention relates to a pharmaceutical solid oral preparation obtained by wet granulation of crystals of conventional aripiprazole hydrate, drying the obtained granules at a temperature of from 70 to 100 ° C and sieving them, then again drying the sieved granules at a temperature of from 70 to 100 ° C, where the pharmaceutical the solid oral preparation has at least one dissolution rate selected from the group consisting of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or pain further at pH 5.0 after 60 minutes.

21. The present invention relates to a pharmaceutical solid oral preparation obtained by drying a pharmaceutical solid oral preparation comprising crystals of the usual aripiprazole hydrate and one or more pharmaceutically acceptable carriers, at a temperature of from 70 to 100 ° C, where the pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more he longer at pH 5.0 after 60 minutes.

Crystals of type C to F of anhydrous aripiprazole of the present invention correspond to crystals of type III to VI of an aripiprazole anhydride described in JP-2001-348276.

Type A crystals of aripiprazole anhydride

The type C crystals of anhydrous aripiprazole of the present invention have the following physicochemical properties from (1) to (5):

(1) an endothermic curve that is substantially identical to the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 8; more specifically, it has an endothermic peak of about 150.2 ° C;

(2) ¹ H NMR spectrum, which is essentially identical to the 1H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 9. In particular, it has characteristic peaks at 1.55-1.63 ppm. (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H);

(3) a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in Figure 10. In particular, it has characteristic peaks at 2θ = 12.6 °, 13.7 °, 15.4 °, 18 , 1 °, 19.0 °, 20.6 °, 23.5 ° and 26.4 °;

(4) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 11. In particular, it has clear infrared absorption bands at 2939, 2804, 1680, 1375, and 780 cm ⁻¹ ; and

(5) ¹³ C NMR spectrum (spectrum of a substance in the solid state), which is essentially identical to the ¹³ C NMR spectrum (spectrum of a substance in the solid state) shown in figure 12, in particular, it has characteristic peaks at 32.8 m ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm

The method of obtaining crystals of type C anhydrous aripiprazole

Type C crystals of anhydrous aripiprazole of the present invention are obtained, for example, by heating anhydrous aripiprazole at a temperature higher than 140 ° C and lower than 150 ° C.

The aripiprazole anhydride used as the starting material may be crystals of ordinary aripiprazole anhydride, for example, type I aripiprazole anhydride crystals, type II aripiprazole anhydride crystals and the like, and these anhydrous crystals can be either purified products or raw materials. Alternatively, type B anripiprazole anhydride crystals, type A anipiprazole anhydride crystals, aripiprazole anhydride type E crystals, aripiprazole anhydride a type crystals or type A anipiprazole anhydride crystals obtained in the present invention can be used as a starting material of anhydrous aripiprazoles. These anhydrous aripiprazoles can be used individually or as a combination of at least 2 types thereof.

The heating temperature is usually higher than 140 ° C and lower than 150 ° C, preferably 142-148 ° C and the heating time is usually from 15 minutes to 3 hours, preferably from 30 minutes to 1 hour.

When an aripiprazole anhydride is heated at the above temperature, type C crystals of an aripiprazole anhydride are formed.

Thus obtained type C crystals of anhydrous aripiprazole can be isolated and purified by well-known methods. For example, after heating an aripiprazole anhydride at the above temperature and cooling to room temperature, type C crystals of an aripiprazole anhydride having a purity of 100% can be obtained.

Type D crystals of aripiprazole anhydride

The type D crystals of anhydrous aripiprazole of the present invention have the following physicochemical properties from (6) to (10):

(6) an endothermic curve that is substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 13; more specifically, it has an endothermic peak of about 136.8 ° C and 141.6 ° C;

(7) ¹ H NMR spectrum, which is essentially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 14. In particular, it has characteristic peaks at 1.55-1.63 ppm . (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H);

(8) a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in Figure 15. In particular, it has characteristic peaks at 2θ = 8.7 °, 11.6 °, 16.3 °, 17 7 °, 18.6 °, 20.3 °, 23.4 ° and 25.0 °;

(9) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in Figure 16. In particular, it has clear infrared absorption bands at 2946, 1681, 1375, 1273, 1175, and 862 cm ^-1 ; and

(10) ¹³ C NMR spectrum (spectrum of a substance in the solid state), which is essentially identical to the ¹³ C NMR spectrum (spectrum of a substance in the solid state) shown in figure 17, in particular, it has characteristic peaks at 32.1 m ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.4 ppm and 174.1 ppm

The method of obtaining crystals of type D anhydrous aripiprazole

Type D crystals of an aripiprazole anhydride of the present invention are obtained, for example, by recrystallization of an aripiprazole anhydride from toluene. In particular, anhydrous aripiprazole is added to toluene, then heated and dissolved, then the solution thus obtained is cooled. By such procedures, type D crystals of anhydrous aripiprazole of the present invention are separated as crystals in toluene.

Anhydrous aripiprazole, which is used as starting materials, can be ordinary anhydrous aripiprazole, for example, type I crystals of anhydrous aripiprazole, type II crystals of anhydrous aripiprazole and the like, these anhydrous aripiprazoles can be either purified products or raw materials. Alternatively, type B crystals of aripiprazole anhydride, type C crystals of aripiprazole anhydride, type E crystals of aripiprazole anhydride, type F crystals of aripiprazole anhydride or type G crystals of aripiprazole anhydrous aripiprazole which are obtained in the present invention can be used as starting material for anhydrous aripiprazoles. These anhydrous aripiprazoles can be used individually or as a combination of at least 2 types thereof.

When the solution obtained by heating and dissolving is cooled, type D crystals of aripiprazole anhydride are added as seed crystals to said solution. In addition, seed crystals can be obtained by gradually cooling said solution, which is obtained by heating and dissolving. In the presence of seed crystals, type D crystals of anhydrous aripiprazole can be separated.

Thus, the separated type D crystals of aripiprazole anhydride can be isolated and purified according to well-known methods. By such procedures, type D crystals of aripiprazole anhydride having a purity of 100% can be obtained.

Type E crystals of aripiprazole anhydride

The type E crystals of anhydrous aripiprazole of the present invention have the following physicochemical properties from (11) to (14):

(11) an endothermic curve that is substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 18; more specifically, it has an endothermic peak of about 146.5 ° C;

(12) ¹ H NMR spectrum, which is essentially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 19. In particular, it has characteristic peaks at 1.55-1.63 ppm . (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H);

(13) a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in FIG. 20. In particular, it has characteristic peaks at 2θ = 8.0 °, 13.7 °, 14.6 °, 17 6 °, 22.5 ° and 24.0 °; and

(14) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in Figure 21. In particular, it has clear infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969, and 774 cm ⁻¹ .

The method of obtaining crystals of type E anhydrous aripiprazole

Type E crystals of anhydrous aripiprazole of the present invention are obtained, for example, by recrystallization of anhydrous aripiprazole from acetonitrile. In particular, by adding the well-known anhydrous aripiprazole to acetonitrile, heating and dissolving, then the solution thus obtained can be cooled. In accordance with such procedures, type E crystals of anhydrous aripiprazole of the present invention are isolated in acetonitrile.

When ordinary aripiprazole is added to acetonitrile, type I crystals of aripiprazole anhydride, type II crystals of aripiprazole anhydride and type D crystals of aripiprazole anhydride other than type A crystals of aripiprazole are separated. Ribbon crystals that are isolated from a solution in acetonitrile at 70 ° C are type I crystals, type II crystals, and type D crystals, while type E crystals are precipitated as needle crystals. When the solution in acetonitrile is again heated after separation of these crystals (for example, heated above 75 ° C), ribbon crystals (type I crystals, type II crystals, type D crystals) quickly dissolve, on the contrary, needle-shaped crystals (type E crystals) do not dissolve. In addition, when the solution in acetonitrile is cooled again, needle-shaped crystals (type E crystals) are further separated around needle-shaped crystals (type E crystals) pre-deposited as seed crystals. Thus, type E crystals of aripiprazole anhydride can be precipitated in an acetonitrile solution.

The aripiprazoles anhydrous used as starting materials can be ordinary aripiprazoles anhydrous, for example any one of type I crystals of an aripiprazole anhydride and type II crystals of an aripiprazole anhydride and the like, and these anhydrous aripiprazoles can be either purified products or raw materials.

Alternatively, type A crystals of aripiprazole anhydride, type C crystals of aripiprazole anhydride, type D crystals of aripiprazole anhydride, type F crystals of aripiprazole anhydride or type G crystals of aripiprazole anhydride can be used as starting materials for anhydrous aripiprazoles. These anhydrous aripiprazoles can be used individually or as a combination of at least 2 types thereof.

When the solution in acetonitrile obtained by heating (heating and dissolving) is cooled, type E crystals of anhydrous aripiprazole can be added to the indicated solution as a seed crystal. In addition, seed crystals can be obtained by gradually cooling said solution in acetonitrile, which is obtained by heating.

Thus, the separated type E crystals of aripiprazole anhydride can be isolated and purified in accordance with well-known methods. By such procedures, type E crystals of aripiprazole anhydride having a purity of 100% can be obtained.

Type F Crystals of Aripiprazole Anhydrous

The type F crystals of anhydrous aripiprazole of the present invention have the following physicochemical properties from (15) to (18):

(15) an endothermic curve that is substantially identical to the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate: 5 ° C./min) shown in FIG. 22; more specifically, it has endothermic peaks of about 137.5 ° C and 149.8 ° C;

(16) ¹ H NMR spectrum, which is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 23. In particular, it has characteristic peaks at 1.55-1.63 ppm. . (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H);

(17) a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in Figure 24. In particular, it has characteristic peaks at 2θ = 11.3 °, 13.3 °, 15.4 °, 22 , 8 °, 25.2 ° and 26.9 °, and

(18) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 25. In particular, it has clear infrared absorption bands at 2940, 2815, 1679, 1383, 1273, 1177, 1035, 963 and 790 cm ^-1 .

The method of obtaining crystals of type F anhydrous aripiprazole

Type F crystals of anhydrous aripiprazole of the present invention are prepared, for example, by suspending anhydrous aripiprazole in acetone and heating the suspension thus obtained in acetone.

The aripiprazoles anhydrous used as starting materials may be ordinary aripiprazole anhydride, for example, any one of type I crystals of an aripiprazole anhydride and type II crystals of an aripiprazole anhydride and the like, and these anhydrous aripiprazoles can be either purified products or raw materials. Alternatively, type B crystals of aripiprazole anhydride, type C crystals of aripiprazole anhydride, type D crystals of aripiprazole anhydride, type E crystals of aripiprazole anhydride or type G crystals of aripiprazole anhydride can be used as starting materials for anhydrous aripiprazoles. These anhydrous aripiprazoles can be used individually or as a combination of at least 2 types thereof.

The heating temperature of the suspension in acetone is usually near the boiling point of acetone and the heating time is usually from 5 to 10 hours. When the suspension in acetone is heated to approximately the boiling point of acetone, then type F crystals of anhydrous aripiprazole are formed, the crystals are isolated by heating filtration. The selection of crystals can be carried out by well-known methods. By such procedures, type F crystals of aripiprazole anhydride having a purity of 100% can be obtained.

Type A crystals of aripiprazole anhydride

The aripiprazole anhydride type G crystals of the present invention have the following physicochemical properties from (19) to (22):

(19) an endothermic curve that is substantially identical to the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in FIG. 26; more specifically, it has an endothermic peak of about 141.0 ° C and an exothermic peak of about 122.7 ° C;

(20) ¹ H NMR spectrum, which is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 27. In particular, it has characteristic peaks at 1.55-1.63 ppm. . (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H);

(21) a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in FIG. 28. In particular, it has characteristic peaks at 2θ = 10.1 °, 12.8 °, 15.2 °, 17 , 0 °, 17.5 °, 19.1 °, 20.1 °, 21.2 °, 22.4 °, 23.3 °, 24.5 ° and 25.8 °, and

(22) an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 29. In particular, it has clear infrared absorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787 cm ^{- 1} .

The method of obtaining crystals of type G anhydrous aripiprazole

Type G crystals of anhydrous aripiprazole of the present invention can be obtained, for example, by placing the aripiprazole anhydrous in the vitreous state in a sealed vessel and keeping it at room temperature for at least two weeks, preferably from two weeks to six months. Further, anhydrous aripiprazole in the vitreous state as a starting material can be obtained by heating and grinding anhydrous aripiprazole at approximately 170 ° C, then cooling it to room temperature.

The aripiprazole anhydride used as the starting material can be well-known aripiprazole anhydride crystals, for example, any one of the type I crystals of an aripiprazole anhydride and type II crystals of an aripiprazole anhydride and the like, and these anhydrous aripiprazole can be either purified products or raw materials. Alternatively, type B crystals of aripiprazole anhydride, type C crystals of aripiprazole anhydride, type D crystals of aripiprazole anhydride, type E crystals of aripiprazole anhydride or type F crystals of aripiprazole anhydrous aripiprazole which are obtained in the present invention can be used as starting material for anhydrous aripiprazoles. These anhydrous aripiprazoles can be used individually or as a combination of at least 2 types thereof.

Thus obtained crystals of type G of anhydrous aripiprazole can be isolated and purified by well-known methods. For example, when anhydrous aripiprazole in a glassy state is left to stand according to the above method, then type G crystals of an aripiprazole anhydride having a purity of 100% can be obtained.

Anhydrous aripiprazole type C crystals, an aripiprazole anhydride type D crystals, aripiprazole anhydride type E crystals, aripiprazole anhydride type F crystals and an aripiprazole anhydride type G crystals of the present invention do not readily convert to their hydrates, do not substantially reduce the initial solubility even when they are retained in over a long period of time.

The present invention provides methods for producing high purity aripiprazole anhydride crystals, which can be used on an industrial scale with good reproducibility.

The present invention provides pharmaceutical compositions comprising an aripiprazole anhydride crystals whose solubility does not decrease and whose stability can be maintained excellent even if they are stored for a long time.

Anhydrous aripiprazole crystals, which are the starting material for obtaining crystals from B to G of an aripiprazole anhydrous of the present invention, are obtained, for example, by the following method a or b.

"Method a": A method of obtaining crystals of crude aripiprazole

Crystals of conventional anhydrous aripiprazole are prepared by well-known methods, as described in Example 1 of Japanese Patent Publication No. 191256/1990.

A suspension of 47 g of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril, 35 g of sodium iodide with 600 ml of acetonitrile is refluxed for 30 minutes. To this suspension was added 40 g of 1- (2,3-dichlorophenyl) piperazine and 33 ml of triethylamine, and the whole mixture was further refluxed for 3 hours. After removal of the solvent by evaporation, the residue thus obtained was dissolved in chloroform, washed with water and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue thus obtained was recrystallized from ethanol twice, to obtain 57.1 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril.

Colorless scaly crystals with mp: 139.0-139.5 ° C.

"Method b": Method for preparing conventional aripiprazole anhydrous

Method b is described in the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (October 6-8, 1996).

In addition, crystals of anhydrous aripiprazole B of the present invention are obtained, for example, by heating a conventional hydrate of ordinary aripiprazole at 90-125 ° C. The heating time is usually about 3-50 hours, but it cannot be indicated exactly, since it varies with the heating temperature. The heating time and heating temperature are inversely proportional, so that, for example, the heating time will be longer, the lower the heating temperature, and the shorter the higher the heating temperature. In particular, if the heating temperature of aripiprazole hydrate is 100 ° C, the heating time can be approximately 24 hours, while if the heating temperature is 120 ° C, the heating time can be approximately 3 hours.

Aripiprazole hydrate, which is the starting material for the preparation of anhydrous aripiprazole crystals B of the present invention, is prepared, for example, by the following method c.

"Method C": Method for preparing a conventional hydrate

Aripiprazole hydrate is readily prepared by dissolving the crystals of anhydrous aripiprazole obtained by the above method a in an aqueous solvent and heating and then cooling the resulting solution. Using this method, aripiprazole hydrate precipitates as crystals in an aqueous solvent.

As the aqueous solvent, an organic solvent containing water is usually used. The organic solvent should be a solvent which is miscible with water, such as, for example, an alcohol, such as methanol, ethanol, propanol or isopropanol, a ketone, such as acetone, an ether, such as tetrahydrofuran, dimethylformamide or mixtures thereof, particularly preferred is ethanol. The amount of water in the aqueous solvent may be 10-25 vol.% Solvent or preferably close to 20 vol.%.

Drug composition

The drug composition of the present invention will contain crystals of B, C, D, E, F and G of an aripiprazole anhydride in a pharmaceutically acceptable carrier or combination of carriers.

Carriers that are pharmaceutically acceptable include diluents and excipients commonly used in pharmaceutical preparations, such as fillers, dry diluents, binders, moisturizers, disintegrants, surfactants and lubricants.

The pharmaceutical composition of the present invention can be prepared in the form of a conventional drug, for example, in the form of tablets, fast-melting tablets, pills, powder, liquid, suspension, emulsion, granules, capsules, suppositories, or as an injection (liquid, suspension, etc. )

When a tablet formulation is used, a wide variety of carriers that are known in the art can be used. Examples thereof include lactose, sucrose, sodium chloride, glucose, xylitol, mannitol, erythritol, sorbitol, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients; water, ethanol, propanol, regular syrup, liquid glucose, liquid starch, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and other disintegrants; sucrose, stearin, cocoa butter, hydrogenated oil and other disintegration inhibitors; quaternary ammonium salts, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other means of retaining moisture; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents and purified talc, stearate, boric acid powder, polyethylene glycol and other lubricants and the like. Tablets can also be made, if necessary, in the form of tablets with conventional coatings, such as sugar coated tablets, gelatin coated tablets, enteric coated tablets and film coated tablets, as well as double tablets and multilayer tablets.

When a formulation in the form of a pill is used, a wide variety of carriers that are known in the art can be used. Examples thereof include glucose, lactose, starch, cocoa butter, cured vegetable oil, kaolin, talc and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol and other binders; and laminarine, agar and other disintegrants and the like.

When a formulation in the form of a suppository is used, a wide variety of carriers that are known in the art can be used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic glyceride and the like.

Capsules are prepared in accordance with generally accepted methods by mixing crystals of anhydrous aripiprazole with various carriers described above and filling mixtures of hard gelatin capsules, soft capsules, hydroxypropyl methylcellulose capsules (HPMC capsules) and the like.

In addition, dyes, preservatives, perfumes, flavoring agents, sweeteners, and the like, as well as other drugs, can be included in the drug composition.

In the case of obtaining a pharmaceutical solid oral preparation in the form of granules, it can be obtained by wet granulation of a mixed powder of granular ingredients, including crystals of anhydrous aripiprazole (crystals of ordinary anhydrous aripiprazole or crystals of anhydrous aripiprazole selected from the group consisting of crystals of type B, C, D, E , F and G of aripiprazole anhydrous) and various carriers that are still well known in the art, such as excipients, disintegrants, disintegration inhibitors, moisturize see, absorption accelerators, adsorbents, lubricants, colorants and the like (examples of these agents may be mentioned agents previously mentioned) with the addition of liquid (usually water or an aqueous solution containing binding agents). With regard to wet granulation, there are various methods that include, for example, fluidized bed granulation, kneading granulation, extrusion granulation, rotational granulation and the like. Among these methods, in the case of granulation in a fluidized bed, granular ingredients containing various carriers are mixed with the intake air, and then, with continuous fluidization of the granular ingredients, granulation liquid is sprayed. In the case of granulation by mixing, the granular ingredients containing various carriers are mixed by stirring, then, while the granulating ingredients are continuously mixed, the granulation is carried out by adding liquid. After granulation, if necessary, the granules obtained are sieved to obtain granules of the desired size from them using a suitable sieve or mill having a suitable sieve size. Thus, the granules obtained by this method are dried again in addition to the conventional drying which is carried out upon receipt of the granules. As for the drying methods, various methods can be applied, for example, methods using a fluidized bed dryer, a fan dryer, a vacuum dryer and the like can be indicated. Drying methods are usually carried out under generally accepted conditions, for example, in the case of using a fluidized bed dryer, the drying procedure is carried out with an air flow from 0.5 m ³ / min to 50 m ³ / min, inlet air temperature from 70 to 100 ° C for 10 minutes to 1 hour. After drying, the granules are sieved, then dried again. In the case of using a fluidized bed dryer or a fan dryer or the like, the drying procedure is carried out under conditions with an air flow of from 0.5 m ³ / min to 50 m ³ / min, inlet air temperature from 70 to 100 ° C for 1 to 6 o'clock. In the case of using a vacuum dryer, the drying procedure is carried out under reduced pressure of approximately 0-10 torr at a shell temperature of from 70 to 100 ° C for 1-6 hours.

The granules thus obtained can be used directly as pharmaceutical solid oral preparations or, if necessary, they can be shaped into tablets. In addition, the granules dried in the usual way are converted into tablets, which can be dried again.

Thus obtained pharmaceutical solid oral preparation, including crystals of anhydrous aripiprazole, is difficult to convert into hydrates, even if they are stored for a long period of time, therefore, it is possible to provide a pharmaceutical solid oral preparation, the dissolution rate of which is almost not reduced (dissolution rate to maintain maximum drug concentration (Cmax): a dissolution rate of 60% or higher obtained after 30 minutes at pH 4.5, a dissolution rate of 70% or you further obtained after 60 minutes at pH 4.5, or a dissolution rate of 55% or higher, obtained after 60 minutes at pH 5.0).

Another pharmaceutical solid oral preparation can be obtained by granulation of crystals of the usual aripiprazole hydrate in a manner similar to the method described above, and dried in the usual way under similar conditions, then dried again. Alternatively, the granules dried in the usual way are converted into the form of tablets, then they are dried again, then you can offer a pharmaceutical solid oral preparation, the dissolution rate of which is not reduced (dissolution rate to maintain the maximum concentration of the drug (Cmax): dissolution rate of 60% or higher obtained after 30 minutes at pH 4.5, a dissolution rate of 70% or higher, obtained after 60 minutes at pH 4.5, or a dissolution rate of 55% or higher, obtained after 60 minutes at pH 5.0). These facts can be interpreted so that conventional aripiprazole anhydride crystals or aripiprazole hydrate crystals contained in a pharmaceutical solid oral preparation are converted to “type B crystals” of anhydrous aripiprazole by double drying.

The number of crystals B, C, D, E, F and G of an aripiprazole anhydride to be included in the pharmaceutical composition of the present invention can be selected from a wide range suitable for the indication in question. Anhydrous aripiprazole crystals B are usually present in an amount of about 1-70 wt.% Or specifically about 1-30 wt.% Based on the drug composition.

The method of administering the drug composition of the present invention can be selected to be suitable, for example, for the formulation of the drug product, age, gender and other criteria (including the severity of the condition) of the patient. In the case of tablets, pills, liquids, suspensions, emulsions, granules and capsules, the administration is, for example, oral. In the case of an injection, it is administered intravenously either separately or in a mixture with a conventional excipient such as glucose or amino acids, or, if necessary, it can be administered separately by intramuscular, intradermal, subcutaneous or intraperitoneal route. In the case of a suppository, the administration is intrarectal.

The dosage of the drug composition of the present invention is selected depending on the application, age, gender and other criteria of the patient, severity of the condition, and so on, but usually the number of crystals of anhydrous aripiprazole is approximately 0.1-10 mg per kg of body weight per day. The preparation, which is a unit dose, should contain crystals of anhydrous aripiprazole B in the range of about 1-100 mg, more specifically 1-30 mg per unit dose.

The drug composition of the present invention is very stable, essentially does not show a decrease in solubility, even when stored for extended periods of time.

The drug composition of the present invention is effective in the prevention and treatment of dysfunctions of the central nervous system, such as schizophrenia, it can also be effective in the treatment of intractable (drug-resistant, chronic) schizophrenia with decreased mental activity and intractable (drug-resistant, chronic ) schizophrenia without reducing mental activity, anxiety, including mild anxiety, mania, including acute mania with bipolar m disorder and acute mania, bipolar disorder, depression, including depression with bipolar disorder, autism, Down syndrome, disorders of the attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, panic disorder, obsessive compulsive disorder , sleep disorders, sexual dysfunction, alcohol and drug dependence, vomiting, motion sickness, obesity, migraine and decreased mental activity.

Analytical methods

(1) ¹ H NMR spectrum was measured in DMSO-d ₆ using TMS as a standard.

(2) X-ray Powder Diffraction

Using a Rigaku Denki RAD-2B diffraction meter, the X-ray powder diffraction pattern was measured at room temperature using a tube filled with Cu Ka (35 kV, 20 mA) as an X-ray source with a wide-angle goniometer, 1 ° scattering gap, 0.15 mm light-cutting gap, graphite secondary monochromator and scintillation counter. Data was collected in the 2θ continuous scanning mode at a scanning speed of 5 ° / minute in scan steps of 0.02 ° in the range from 3 ° to 40 °.

(3) The IR spectrum was measured by the KBr method.

(4) Thermogravimetric / differential thermal analysis

Thermogravimetric / differential thermal analysis was performed using a Seiko SSC 5200 control unit and a TG / DTA 220 differential thermal / thermogravimetric measurement device simultaneously. Samples of 5-10 mg were placed in open aluminum cups and heated from 20 ° C to 200 ° C in a dry nitrogen atmosphere at a heating rate of 5 ° C / minute. α-alumina was used as a standard substance.

(5) Differential Scanning Calorimetry Thermogravimetric / differential thermal analysis was performed using a Seiko SSC 5200 control device and a DSC 220C differential scanning calorimeter. Samples of 5-10 mg were placed in corrugated aluminum plates and heated from 20 ° C to 200 ° C in an atmosphere of dry nitrogen at a heating rate of 5 ° C / min. α-alumina was used as a standard substance.

(6) particle size measurement

0.1 g of the measured particles was suspended in 20 ml of a solution of 0.5 g of soya lecithin in n-hexane and the particle size was measured using a particle size distribution meter (Microtrack HRA, Microtrack Co.).

(7) Hygroscopicity Test Method

One g of the sample was accurately weighed in a weighing flask (5 cm diameter) coated with Kim wipes and left alone in the environment with 60 ° C / 100% RH (water, desiccator). After 24 hours, the weighed flask was removed, transferred to ambient temperature at room temperature and approximately 30% RH (saturated aqueous solution of magnesium chloride hexahydrate / desiccator) was left at rest for 24 hours and the water content of the sample was measured by the Karl Fischer method.

(8) ¹³ C solid state NMR spectrometry

¹³ C NMR spectra of substances in the solid state were measured under the following conditions.

Measurement equipment: SMX-360 Solid State NMR spectrometer (manufactured by Chemagnetic Inc.)

Computer: SPARC Station 2 (manufactured by SUN Microsystem, Inc.)

OS, Software: Solalis I.I.I Rev. In (Registered trademark: UNIX), Spinsight Ver. 2.5.

Name of the measured pulse: TOSS method (TOSS is the name of the instrument program) within the CP / MAS method.

Duration of the measured pulses: 90 ° pulses were used in SR conditions.

Tube measuring sample; a dough tube made of zirconia and having an outer diameter of 7.5 mm and an inner capacity of 0.8 ml.

Frequency: 4250 Hz (Frequency per second contact time: 1 ms.

Waiting time: 20 sec.

Integrated time: 512 times.

Measurement temperature: the temperature outside the test tube is approximately 25 ° C).

External standard: methyl group (δ 17.3) of hexamethylbenzene was used as the external standard.

The present invention is explained in more detail below using reference examples, examples, sample preparations, and formulation examples.

Reference Example 1

7- (4-Chlorobutoxy) -3,4-dihydrocarbostyril in an amount of 19.4 g and 16.2 g of 1- (2,3-dichlorophenyl) piperidine hydrochloride 1 are added to 8.39 g of potassium carbonate dissolved in 140 ml of water and the mixture is circulated with stirring for 3 hours. After completion of the reaction, the mixture was cooled and the precipitated crystals were filtered off. These crystals were dissolved in 350 ml of ethyl acetate, and approximately 210 ml of a water / ethyl acetate mixture was removed by azeotropic distillation under reflux. The remaining solution was cooled and the precipitated crystals were filtered off. The resulting crystals are dried for 14 hours at 60 ° C, while obtaining 20.4 g (74.2%) of the crude aripiprazole.

The crude aripipraeol in an amount of 30 g obtained above was recrystallized from 450 ml of ethanol in accordance with the methods described in Japanese Patent Layout No. 191256/1990, and the resulting crystals were dried for 40 hours at 80 ° C., thereby obtaining crystals of anhydrous aripiprazole. The yield is 29.4 g (98.0%).

The melting point (mp.) Of these aripiprazole anhydride crystals was 140 ° C, which corresponds to the melting point of an aripiprazole anhydride crystals described in Japanese Patent Layout No. 191256/1990.

When these crystals were left for 24 hours in a desiccator in which a humidity of 100% and a temperature of 60 ° C were set, they had a hygroscopicity of 3.28% (see table 1 below).

Reference Example 2

6930 g of crude aripiprazole obtained in Reference Example 1 were dissolved by heating in 138 liters of aqueous ethanol (water content 20%) according to the method presented at the 4th Japanese-Korean symposium on separation technology, gradually (2-3 hours) ) cooled to room temperature and then cooled to approximately 0 ° C. The precipitated crystals are filtered off, thereby obtaining approximately 7200 g of aripiprazole hydrate (in a moist state).

The aripiprazole hydrate crystals in the wet state obtained above are dried for 30 hours at 80 ° C. to obtain 6480 g (93.5%) of crystals of the usual anhydrous aripiprazole. The melting point (mp.) Of these crystals was 139.5 ° C. By the method of Karl Fischer, it was confirmed that these crystals are anhydrous, with a moisture value of 0.03%.

When these crystals were incubated for 24 hours in a desiccator, which maintained a humidity of 100% and a temperature of 60 ° C, they had a hygroscopicity of 1.78% (see table 1 below).

Reference Example 3

The wetted aripiprazole intermediate hydrate in an amount of 820 g obtained in Reference Example 2 was dried for 2 hours at 50 ° C., thereby obtaining 780 g of aripiprazole hydrate crystals. These crystals have a moisture value of 3.82% according to the method of Karl Fischer. As shown in figure 6, thermogravimetric / differential thermal analysis detects endothermic peaks at 75.0, 123.5 and 140.5 ° C. Since dehydration begins at about 70 ° C, there was no apparent melting point (mp.).

As shown in FIG. 7, the X-ray powder diffraction spectrum of aripiprazole hydrate obtained by this method has characteristic peaks at 2θ = 12.6 °, 15.1 °, 17.4 °, 18.2 °, 18.7 °, 24 , 8 ° and 27.5 °.

The powder X-ray diffraction spectrum of this aripiprazole hydrate was identical to the powder X-ray diffraction spectrum of this aripiprazole hydrate presented at the 4th Japanese-Korean symposium on separation technology.

Reference Example 4

Obtaining 15 mg of tablets containing crystals of type I anhydrous aripiprazole obtained in reference example 2.

Type I crystals of aripiprazole anhydride (525 g), lactose (1.995 g), corn starch (350 g) and crystalline cellulose (350 g) are loaded into a fluid bed granulation dryer (Flow Coater FLO-5, manufactured by FREUND INDUSTRIAL CO., LTD .) and these granulation ingredients are mixed by fluidization for approximately 3 minutes with an air temperature at the inlet of 70 ° C and an air flow rate of 3 m ³ / min. Next, the granulation ingredients are kept under continuous fluidization under the same conditions and sprayed approximately 1400 g of an aqueous solution to obtain wet granules. The wet granules are dried at an air temperature of about 80 ° C. for about 15 minutes. The resulting dried granules contain 4.3% water (99% yield). The dried granules are sorted by passing through a 710 μm sieve.

About 1% by weight of magnesium stearate is added and mixed with the sieved granules, then the granules are fed to a tabletting machine (Rotary single tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHO CO., LTD), and tablets are obtained, each weighing 95 mg.

The water content of the tablets is measured by the volumetric titration method (Karl Fischer method) described in the method of measuring the water content in the Japanese Pharmacopoeia, or by the method of electric quantitative titration.

Method for measuring water content:

A sample (0.1 to 0.5 g) (in the case of tablets, 1 tablet is used) is accurately weighed and the water content is measured by using water content measuring equipment.

Volumetric titration:

Automated equipment for measuring water content

Model: KF-06 (manufactured by MITSUBISHI CHEMICAL CORP.)

Method of electrical quantitative titration:

Automated equipment for measuring micro-content of water

Model: AQ-7F (manufactured by HIRANUMA SANGYO CO., LTD.)

Automated model of water evaporation equipment:

LE-20S (manufactured by HIRANUMA SANGYO CO., LTD.)

Heating temperature: 165 ± 10 ° C

Nitrogen gas flow rate: about 150 ml / min.

Reference Example 5

Obtaining 15 mg tablets containing crystals of type B anhydrous aripiprazole

Type B crystals of aripiprazole anhydride (4500 g), lactose (17100 g), corn starch (3000 g) and crystalline cellulose (3000 g) are loaded into a granulating fluidized bed dryer (NEW-MARUMERIZER Model: NQ-500, manufactured by FUJI PAUDAL CO ., LTD.) And these granulation ingredients are mixed by fluidization for approximately 3 minutes with an air temperature at the inlet of 70 ° C, at an air flow rate of 10 to 15 m ³ / min. The granulation ingredients are then kept under continuous fluidization under the same conditions and sprayed with approximately 12000 g of a 5% aqueous hydroxypropyl cellulose solution to obtain wet granules. The wet granules are dried at an air temperature of 85 ° C inlet for approximately 28 minutes. The dried granules thus obtained contain 3.8% water (measured by the method of Reference Example 4). (Yield: 96%). The dried granules are sorted by passing through a 850 micron sieve.

Approximately 1 wt.% Of magnesium stearate is added to the sieved granules and mixed with them, then the granules are fed to a tablet machine (Rotary single tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHO CO., LTD), resulting in tablets, each weighing 95 mg) .

Example 1

The crystals of aripiprazole hydrate in an amount of 500.3 g obtained in Reference Example 3 are milled using a sample mill (small unit for finest grinding). The rotation speed of the main axis is set to 12000 rpm and the rotation speed of the raw material to 17 rpm and a 1.0 mm herringbone sieve is used. Milling is completed in 3 minutes, giving 474.6 g (94.9%) of aripiprazole hydrate A powder.

Aripiprazole hydrate A (powder) obtained in this way has an average particle size of 20-25 microns. The melting point (mp.) Is uncertain, since dehydration is observed starting at about 70 ° C.

The aripiprazole hydrate A obtained above (powder) has a ¹ H NMR spectrum (DMSO-d ₆ , TMS), which is essentially the same as the ¹ H NMR spectrum shown in Figure 2. In particular, they have characteristic peaks at 1 55-1.63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

Aripiprazole hydrate A (powder) obtained above has an X-ray powder diffraction spectrum that is substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3. In particular, it has characteristic peaks at 2θ = 12.6 °, 15.4 °, 17.3 °, 18.0 °, 18.6 °, 22.5 ° and 24.8 °. This diffraction pattern is different from the powder X-ray spectrum of the unrefined aripiprazole hydrate shown in Figure 7.

Aripiprazole hydrate A (powder) obtained above has infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963, and 784 cm ⁻¹ in the IR spectrum (KBr).

As shown in FIG. 1, aripiprazole hydrate A (powder) obtained above has a weak peak at 71.3 ° in thermogravimetric / differential thermal analysis and a wide endothermic peak (observed weight loss corresponding to one water molecule) between 60-120 ° C , which clearly differs from the endothermic curve of unrefined aripiprazole hydrate (see figure 6).

Example 2

Aripiprazole hydrate A (powder) in an amount of 450 g obtained in Example 1 was dried for 24 hours at 100 ° C. using a hot air dryer to obtain 427 g (yield 98.7%) of anhydrous aripiprazole crystals B.

These crystals of anhydrous aripiprazole have a melting point (mp.) Of 139.7 ° C.

Anhydrous aripiprazole crystals B obtained above have a ¹ H NMR spectrum (DMSO-d ₆ , TMS), which is essentially the same as the ¹ H NMR spectrum shown in Figure 4. In particular, they have characteristic peaks at 1 55-1.63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

The aripiprazole anhydride crystals B obtained above have a powder X-ray diffraction spectrum that is substantially the same as the powder X-ray diffraction spectrum shown in Figure 5. In particular, it has characteristic peaks at 2θ = 11.0 °, 16, 6 °, 19.3 °, 20.3 ° and 22.1 °.

The aripiprazole anhydride crystals B obtained above have noticeable infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm ⁻¹ in the IR spectrum (KBr).

Anhydrous aripiprazole crystals B obtained above have an endothermic peak of approximately about 141.5 ° C. by thermogravimetric / differential thermal analysis.

Anhydrous aripiprazole crystals B obtained above have an endothermic peak of about 140.7 ° C. with differential scanning calorimetry.

Even when the crystals of anhydrous aripiprazole obtained above were kept for 24 hours in a desiccator, in which the humidity was set to 100%, a temperature of 60 ° C, they did not show hygroscopicity in excess of 0.4% (see table 1 below).

Example 3

Aripiprazole hydrate A (powder) obtained in Example 1 in an amount of 44.29 kg is heated for drying for 18 hours in a hot air dryer at 100 ° C and then heated for 3 hours at 120 ° C, thereby obtaining 42 , 46 kg (yield 99.3%) of crystals of anhydrous aripiprazole.

The physicochemical properties of the resulting B crystals of anhydrous aripiprazole were the same as the physicochemical properties of the crystals of Anhydrous aripiprazole B obtained in Example 2.

Anhydrous aripiprazole crystals B obtained in this way do not exhibit hygroscopicity higher than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

Example 4

Aripiprazole hydrate A (powder) obtained in Example 1 in an amount of 40.67 kg is heated for drying for 18 hours in a hot air dryer at 100 ° C and then heated for 3 hours at 120 ° C, thereby obtaining 38 95 kg (99.6% yield) of B crystals of aripiprazole anhydride.

The physicochemical properties of the resulting B crystals of anhydrous aripiprazole were the same as the physicochemical properties of the crystals of Anhydrous aripiprazole B obtained in Example 2.

Anhydrous aripiprazole crystals B obtained in this way do not exhibit hygroscopicity higher than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

The products of examples 5-10 are suitable for the preparation of injectable or oral formulations in the form of solutions, since they are prepared by heating conventional anhydrous crystals or a conventional hydrate instead of hydrate A.

Example 5

The hygroscopic crystals of anhydrous aripiprazole obtained in Reference Example 1 are heated for 50 hours at 100 ° C. using the same methods as in Example 2. The physicochemical properties of the resulting crystals of anhydrous aripiprazole were the same as the physicochemical properties of the crystals In anhydrous aripiprazole obtained in example 2.

Anhydrous aripiprazole crystals B obtained in this way do not exhibit hygroscopicity higher than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

Example 6

The hygroscopic crystals of anhydrous aripiprazole obtained in Reference Example 1 are heated for 3 hours at 120 ° C. using the same methods as in Example 2. The physicochemical properties of the resulting crystals of anhydrous aripiprazole were the same as the physicochemical properties of the crystals In anhydrous aripiprazole obtained in example 2.

Anhydrous aripiprazole crystals B obtained in this way do not exhibit hygroscopicity higher than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

Example 7

The hygroscopic crystals of anhydrous aripiprazole obtained in Reference Example 2 are heated for 50 hours at 100 ° C. using the same methods as in Example 2. The physicochemical properties of the resulting crystals of anhydrous aripiprazole were the same as the physicochemical properties of the crystals In anhydrous aripiprazole obtained in example 2.

Anhydrous aripiprazole crystals B obtained in this way do not exhibit hygroscopicity higher than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

Example 8

Hygroscopic crystals of anhydrous aripiprazole obtained in Reference Example 2 were heated for 3 hours at 120 ° C. using the same methods as in Example 2.

The physicochemical properties of the resulting B crystals of anhydrous aripiprazole were the same as the physicochemical properties of the crystals of Anhydrous aripiprazole B obtained in Example 2.

Anhydrous aripiprazole crystals B obtained in this way do not exhibit hygroscopicity higher than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

Example 9

The aripiprazole hydrate crystals obtained in Reference Example 3 are heated for 50 hours at 100 ° C. using the same methods as in Example 2. The physicochemical properties of the resulting B crystals of aripiprazole anhydride were the same as the physicochemical properties of B crystals anhydrous aripiprazole obtained in example 2.

Anhydrous aripiprazole crystals B obtained in this way do not exhibit hygroscopicity higher than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

Example 10

The aripiprazole hydrate crystals obtained in Reference Example 3 are heated for 3 hours at 120 ° C. using the same methods as in Example 2. The physicochemical properties of the resulting B crystals of aripiprazole anhydride were the same as the physicochemical properties of B crystals anhydrous aripiprazole obtained in example 2.

Anhydrous aripiprazole crystals B obtained in this way have a hygroscopicity of not more than 0.4%, even when they are incubated for 24 hours in a desiccator in which humidity of 100% is maintained at a temperature of 60 ° C (see table 1 below).

Example 11 (Preparation of Type C Crystals of Aripiprazole Anhydride)

The type I crystals of aripiprazole anhydride obtained in Reference Example 2, in an amount of 100 milligrams, are heated at approximately 145 ° C (± 3 ° C). In this case, there is such a phenomenon that the crystals melt once and crystallize again. After this, 100 mg (yield: 100%) of type C crystals of anhydrous aripiprazole are obtained. The melting point of the crystals is 150 ° C. The crystals are in the form of colorless prisms.

The type C crystals of anhydrous aripiprazole obtained above have an endothermic curve, which is essentially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in figure 8. In particular, it has an endothermic curve of about 150, 2 ° C.

Anhydrous aripiprazole type C crystals thus obtained have a ¹ H NMR spectrum (DMSO-d ₆ , TMS), which is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 9. In particular It has characteristic peaks at 1.55-1.63 ppm. (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

The type C crystals of anhydrous aripiprazole obtained above have a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in FIG. 10. In particular, it has characteristic peaks at 2θ = 12.6 °, 13.7 ° , 15.4 °, 18.1 °, 19.0 °, 20.6 °, 23.5 ° and 26.4 °.

The type C crystals of aripiprazole anhydride obtained above have an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in Figure 11. In particular, it has characteristic infrared absorption bands at 2939, 2804, 1680, 1375 and 780 cm ^-1 .

The type C crystals of aripiprazole anhydride obtained above have a ¹³ C NMR spectrum (solid state spectrum), which is essentially identical to the ¹³ C NMR spectrum (solid state spectrum) shown in Figure 12. In particular, it has characteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm, 104.9 ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm

In accordance with the above data on the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) and powder X-ray diffraction spectrum, the formation of type C crystals of aripiprazole anhydride is confirmed.

When the type C crystals of anhydrous aripiprazole obtained above were kept for 24 hours in a desiccator in which there was a humidity of 100% and a temperature of 60 ° C, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Example 12 (Preparation of Type D Crystals of Aripiprazole Anhydride)

The type I crystals of aripiprazole anhydride obtained in Reference Example 2 were added to 200 ml of toluene and dissolved by heating at 74 ° C. After confirming that they are completely dissolved, the toluene solution is cooled to 7 ° C. and the precipitated crystals are collected by filtration. The crystals as such were dried in air, thereby obtaining 17.9 g (yield: 89.5%) of type D crystals of anhydrous aripiprazole.

The type D crystals of aripiprazole anhydride obtained above have an endothermic curve substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C./min) shown in FIG. 13. In particular, it has endothermic peaks of about 136.8 ° C and about 141.6 ° C.

The type D crystals of aripiprazole anhydride obtained above have a ¹ H NMR spectrum (DMSO-d ₆ , TMS), which is essentially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 14. In particular, they have characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

The type D crystals of aripiprazole anhydride obtained above have a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in Figure 15. In particular, it has characteristic peaks at 2θ = 8.7 °, 11.6 ° , 16.3 °, 17.7 °, 18.6 °, 20.3 °, 23.4 ° and 25.0 °.

The type D crystals of aripiprazole anhydride obtained above have an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in Figure 16. In particular, it has characteristic infrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm ^-1 .

The type D crystals of aripiprazole anhydride obtained above have a ¹³ C NMR spectrum (solid state spectrum), which is substantially identical to the ¹³ C NMR spectrum (solid state spectrum) shown in Figure 17. In particular, it has characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm

According to the above data on the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) and the powder X-ray diffraction spectrum, the formation of type D crystals of anhydrous aripiprazole is confirmed.

When the type D crystals of aripiprazole anhydride obtained above were kept for 24 hours in a desiccator in which there was a humidity of 100% and a temperature of 60 ° C, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Example 13 (Preparation of Type D Crystals of Aripiprazole Anhydride)

The type I crystals of aripiprazole anhydride obtained in Reference Example 2, in an amount of 1200 g, were dissolved in 18 liters of toluene with heating. This solution in toluene is cooled to 40 ° C. and 36 g of the type D crystals of aripiprazole anhydride obtained in Example 12 are added as seed crystals, then the solution is cooled to 10 ° C. and left to stand as it is. The precipitated crystals are collected by filtration, dried at 60 ° C for 18 hours, while obtaining 1,073 g (yield: 86.8%) of type D crystals of anhydrous aripiprazole (purity: 100%). The crystals are in the form of colorless plates.

Type D crystals of aripiprazole anhydride have an endothermic curve substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in Figure 13. In particular, it has endothermic peaks of about 136.8 ° C and about 141.6 ° C.

The type D crystals of aripiprazole anhydride obtained above have a ¹ H NMR spectrum (DMSO-d ₆ , TMS), which is essentially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 14. In particular, it has characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

The type D crystals of aripiprazole anhydride obtained above have a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in Figure 15. In particular, it has characteristic peaks at 2θ = 8.7 °, 11.6 ° , 16.3 °, 17.7 °, 18.6 °, 20.3 °, 23.4 ° and 25.0 °.

The type D crystals of aripiprazole anhydride obtained above have an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in Figure 16. In particular, it has characteristic infrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm ^-1 .

The type D crystals of aripiprazole anhydride obtained above have a ¹³ C NMR spectrum (solid state spectrum), which is substantially identical to the ¹³ C NMR spectrum (solid state spectrum) shown in Figure 17. In particular, it has characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm

According to the above data on the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) and the powder X-ray diffraction spectrum, the formation of type D crystals of aripiprazole anhydride is confirmed.

When the type D crystals of aripiprazole anhydride obtained above were kept for 24 hours in a desiccator in which there was a humidity of 100% and a temperature of 60 ° C, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Example 14 (Preparation of Type E Crystals of Aripiprazole Anhydride)

Type I crystals of anhydrous aripiprazole obtained in Reference Example 2, in an amount of 40 grams, were dissolved in 1000 ml of acetonitrile with heating at 80 ° C. This solution in acetonitrile is cooled to approximately 70 ° C by keeping it for approximately 10 minutes and kept at this temperature for approximately 30 minutes to precipitate seed crystals. Then the temperature of the specified solution is slowly raised to 75 ° C and crystals are grown by maintaining this temperature for 1 hour. The solution was then cooled to 10 ° C and held for approximately 4 hours and the precipitated crystals were collected by filtration. The crystals thus obtained were dried in air overnight to obtain 37.28 g (yield: 93.2%) of type E crystals of anhydrous aripiprazole (purity: 100%). The melting point of these crystals is 145 ° C; the crystals are in the form of colorless needles.

Type E crystals of aripiprazole anhydride have an endothermic curve substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in Figure 18. In particular, it has an endothermic peak of about 146.5 ° C.

The type E crystals of aripiprazole anhydride obtained above have an ^l H NMR spectrum (DMSO-d ₆ , TMS), which is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 19. In particular, they have characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

The type E crystals of aripiprazole anhydride obtained above have a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in Figure 20. In particular, it has characteristic peaks at 2θ = 8.0 °, 13.7 ° , 14.6 °, 17.6 °, 22.5 ° and 24.0 °.

The type E crystals of aripiprazole anhydride obtained above have an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in Figure 21. In particular, it has characteristic infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969 and 774 cm ^-1 .

In accordance with the above data on the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) and powder X-ray diffraction spectrum, the formation of type E crystals of anhydrous aripiprazole is confirmed.

When the type E crystals of aripiprazole anhydride obtained above were kept for 24 hours in a desiccator in which there was a humidity of 100% and a temperature of 60 ° C, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Example 15 (Preparation of Type F Crystals of Aripiprazole Anhydrous)

The type I crystals of aripiprazole anhydride obtained in Reference Example 2, in the amount of 140 grams, were suspended in 980 ml of acetone and continued to boil under reflux for 7.5 hours with stirring. The suspension was then filtered under hot conditions and the separated crystals were dried in air for 16 hours at room temperature to obtain 86.19 g (yield: 61.6%) of type F crystals of aripiprazole anhydride (purity: 100%). The crystals are in the form of colorless prisms.

Type F crystals of aripiprazole anhydride have an endothermic curve substantially identical to the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) shown in Figure 22. In particular, it has exothermic peaks of about 137.5 ° C and about 149.8 ° C.

The type F crystals of aripiprazole anhydride obtained above have a ¹ H NMR spectrum (DMSO-d ₆ TMS), which is essentially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in Figure 23. In particular, has characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

The type F crystals of aripiprazole anhydride obtained above have a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in FIG. 24. In particular, it has characteristic peaks at 2θ = 11.3 °, 13.3 ° , 15.4 °, 22.8 °, 25.2 ° and 26.9 °.

The type F crystals of aripiprazole anhydride obtained above have an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in FIG. 25. In particular, it has characteristic infrared absorption bands at 2940, 2815, 1679, 1383, 1273, 1177, 1035, 963 and 790 cm ^-1 .

According to the data on the endothermic curve of thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min) and the powder X-ray diffraction spectrum, the formation of type F crystals of aripiprazole anhydride is confirmed.

When the type F crystals of aripiprazole anhydride obtained above were kept for 24 hours in a desiccator in which there was a humidity of 100% and a temperature of 60 ° C, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Table 1 Sample The initial moisture content (%) Moisture content after 24 hours (%) Reference Example 1 0.04 3.28 Reference Example 2 0.04 1.78 Example 2 0.04 0.04 Example 3 0.02 0.02 Example 4 0.02 0.02 Example 5 0.04 0.04 Example 6 0.04 0.04 Example 7 0.04 0,03 Example 8 0.04 0,03 Example 9 0,03 0.01 Example 10 0.05 0.05 Example 11 0,03 0,03 Example 12 0.04 0,03 Example 13 0.04 0,03 Example 14 0.06 0.09 Example 15 0.04 0.04

Example 16

a) Type I crystals of aripiprazole anhydride (10 g) obtained in Reference Example 2 are loaded into a stainless steel round tray (diameter: 80 mm) and heated to approximately 170 ° C. to completely melt them. When this molten material is cooled, it solidifies with the formation of a pale brown transparent substance, the solid is separated from the round stainless steel tray to obtain 9.8 g (yield: 98%) anhydrous aripiprazole in a glassy state. The resulting product in the vitreous state is characterized by the absence of a significant peak observed in the powder spectrum of x-rays (cf. figure 31).

According to thermogravimetric / differential thermal analysis (heating rate: 5 ° C./min), as shown in FIG. 30, an exothermic peak of type B crystals of anhydrous aripiprazole was observed at about 86.5 ° C. While the endothermic peak of type B crystals of anhydrous aripiprazole due to melting was observed at about 140.1 ° C.

b) When the glassy aripiprazole anhydride obtained in Example 16-a) was loaded into a sealed vessel and kept at room temperature for approximately 6 months, Type G crystals of an aripiprazole anhydride were obtained having a white color instead of the original pale brown (25 g, yield: 100%). Melting point: from 138 to 139 ° C.

Type A crystals of aripiprazole anhydride have an endothermic curve substantially identical to the endothermic curve of a thermogravimetric / differential thermal analysis (heating rate: 5 ° C./min) shown in FIG. 26, more specifically, it has an endothermic peak of about 141.0 ° C. and an exothermic peak is about 122.7 ° C.

The type G crystals of aripiprazole anhydride obtained as described above have a ¹ H NMR spectrum that is substantially identical to the ¹ H NMR spectrum (DMSO-d ₆ , TMS) shown in FIG. 27. In particular, it has characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm. (m, 2H), 2.35-2.46 ppm. (m, 4H), 2.48-2.56 ppm. (m, 4H + DMSO), 2.78 ppm. (t, J = 7.4 Hz, 2H), 2.97 ppm. (br t, J = 4.6 Hz, 4H), 3.92 ppm. (t, J = 6.3 Hz, 2H), 6.43 ppm. (d, J = 2.4 Hz, 1H), 6.49 ppm. (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.04 ppm. (d, J = 8.1 Hz, 1H), 7.11-7.17 ppm. (m, 1H), 7.28-7.32 ppm. (m, 2H) and 10.00 ppm. (s, 1H).

The type G crystals of aripiprazole anhydride obtained as described above have a powder X-ray diffraction spectrum that is substantially identical to the powder X-ray diffraction spectrum shown in FIG. 28. In particular, it has characteristic peaks at 2θ = 10.1 °, 12 , 8 °, 15.2 °, 17.0 °, 17.5 °, 19.1 °, 20.1 °, 21.2 °, 22.4 °, 23.3 °, 24.5 ° and 25 , 8 °.

The type G crystals of aripiprazole anhydride obtained above have an IR spectrum that is substantially identical to the IR spectrum (KBr) shown in Figure 29. In particular, it has characteristic infrared absorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787 cm ^-1 .

Example 17

a) Obtaining granules of 30 mg tablets containing type B crystals of anhydrous aripiprazole for additional drying

Type B crystals of aripiprazole anhydride (1500 g), lactose (5700 g), corn starch (1000 g) and crystalline cellulose (1000 g) are loaded into a fluidized bed granulating dryer (Flow Coater Model FLO-5M; manufactured by FROINT SANGYO KABUSHIKI KAISHA) and these granulation ingredients are mixed by fluidization for approximately 3 minutes with an air temperature of 60 ° C inlet and a flow rate of 3-4 m ³ / min. Next, the granulation ingredients are subjected to continuous fluidization under the same conditions and approximately 4000 g of a 5% aqueous solution of hydroxypropyl cellulose are sprayed onto them to obtain wet granules. The wet granules are dried at an air temperature of 85 ° C inlet for about 20 minutes. The resulting dried granules contain 3.8% water (measured by the method of Reference Example 4).

b) The dried granules (4 kg) obtained in Example 17-a) are sorted by size using a mill (FIORE F-0: manufactured by TOKUJU CORPORATION).

Sifted granules (3 kg) are loaded into a granular fluidized bed dryer (Flow Coater Model FLO-5M, manufactured by FREUND INDUSTRIAL CO., LTD.) And these granulated ingredients are dried at an air temperature of 85 ° C inlet and an air velocity of 2 m ³ / min for 2 hours. The resulting dried granules contain 3.6% water (measured by the method of Reference Example 4).

Approximately 1 wt.% Of magnesium stearate is added to the sieved granules and mixed, then the granules are fed into a tablet machine (Rotary single tablet press, model VIGRO: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), While receiving tablets, each having a weight of 190 mg .

c) The dried granules (3 kg) obtained in example 17-a) are loaded into a vacuum dryer (vacuum granulating dryer model; VG-50: manufactured by KIKUSUI SEISAKUSHO CO., LTD.) and dried at a jacket temperature of 70 ° C, at reduced pressure 5 torr degree of vacuum for 1 hour. The dried granules thus obtained contain 3.1% water (measured by the method of Reference Example 4). The dried granules are sieved by passing to a sieve of 850 microns.

About 1 wt.% Of magnesium stearate is added to the sieved granules and mixed with them, then the granules are fed into a tablet machine (Rotary single tablet press, model VIGRO: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), While receiving tablets, each having a mass 190 mg

Example 18

a) Obtaining 30 mg of tablets containing type B crystals of anhydrous aripiprazole

Anhydrous aripiprazole (type B crystals) (4500 g), lactose (17100 g), corn starch (3000 g) and crystalline cellulose (3000 g) are loaded into a granulating fluidized bed dryer (NEW-MARUMERIZER Model: NQ-500, manufactured by FUJI PAWDAL CO., LTD.) And these granular ingredients are mixed by fluidization for approximately 3 minutes at an inlet air temperature of 70 ° C. and an air flow rate of 10-15 m ³ / min. The granular ingredients are then continued to fluidize under the same conditions and approximately 12,000 g of a 5% aqueous hydroxypropyl cellulose solution are sprayed onto them to produce wet granules. The wet granules are dried at an air temperature of 85 ° C inlet for approximately 30 minutes. The resulting dried granules contain 3.6% water (measured by the method of Reference Example 4). (Yield: 96%). The dried granules are sized by passing to a mill (FIOLE F-0: manufactured by TOKUJU CORPORATION).

About 1 wt.% Of magnesium stearate is added to the sieved granules and mixed with them, then the granules are fed into a tablet machine (a Rotary single tablet press, VIGRO: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), While receiving tablets, each having a mass 190 mg

b) The tablets (5 kg) obtained in Example 18-a) are loaded into a fan dryer (AQUA COATER AQT-48T manufactured by FREUND INDUSTRIAL CO., LTD.) and dried at an inlet air temperature of 90 ° C., air flow rate 2 m ³ / min for 6 hours. The obtained dried granules contain 3.3% water (measured by the method in accordance with reference example 4).

c) The dried tablets (3 kg) obtained in Example 18-a) are loaded into a vacuum granulating dryer; VG-50: manufactured by KIKUSUI SEISAKUSHO CO., LTD.) and dried at a jacket temperature of 80 ° C, at a reduced a pressure of 5 torr degrees of vacuum for 4 hours. The resulting dried tablets contain 2.7% water (measured by the method in accordance with reference example 4).

Example 19

a) By procedures similar to those of Example 18-a), tablets (containing Type I crystals of aripiprazole anhydride obtained in Reference Example 2) are prepared here, each having a weight of 190 mg.

b) The tablets are dried by procedures similar to those of Example 18-b), except that the air temperature at the input is 100 ° C and dried for 1 hour.

c) The tablets are dried by procedures similar to those of Example 18-b), except that the air temperature at the inlet is 100 ° C and dried for 3 hours.

Example 20

By procedures similar to those of Example 18-a), tablets are prepared here, each having a mass of 190 mg containing type C crystals of an aripiprazole anhydride.

Example 21

By procedures similar to those of Example 18-a), tablets are prepared here, each having a mass of 190 mg containing type D crystals of aripiprazole anhydride.

Example 22

a) Aripiprazole hydrate crystals (156 g) obtained in Reference Example 3, lactose (570 g), corn starch (100 g) and crystalline cellulose (100 g) are loaded into a granular fluidized bed dryer (NEW-MARUMERIZER, NQ-160 : manufactured by FUJI POWDAL CO., LTD.) and these granular ingredients are mixed by fluidization for approximately 3 minutes with an air temperature at the inlet of 60 ° C, an air flow rate of from 1.0 to 1.5 m ³ / min and rotating disks with rotation speed 400 rpm The granular ingredients are then continued to fluidize under the same conditions and approximately 500 g of a 4% aqueous hydroxypropyl cellulose solution is sprayed onto them to produce wet granules. The air temperature at the input is raised to 85 ° C and the product is dried until the product temperature reaches 46 ° C. The resulting dried granules are sieved by passing to a sieve of 850 microns. The dried granules contain 4.37% water (measured by the method corresponding to Reference Example 4).

d) The dried granules (200 g) obtained in Example 22-a) are loaded into a fluidized bed dryer (multiplex, MP-01: manufactured by POWREX CORPORATION) and dried at an air temperature of 85 ° C inlet, air flow rate 0, 5 m ³ / min for 2 hours. The dried granules contain 3.50% water (measured by the method corresponding to Reference Example 4).

c) The dried granules (100 g) obtained in Example 22-a) are loaded into a vacuum dryer (vacuum granulating dryer LCV-232: manufactured by TAVAI CO., LTD.) and dried at a tray temperature of 80 ° C, a vacuum of 760 mm Hg within 2 hours. The dried granules are further dried under similar conditions for 6 hours. The dried granules contain 3.17% water (product that was dried for 2 hours: the measurement was carried out by the method corresponding to reference example 4). Additionally, the dried granules contain 2.88% water (product that was dried for 6 hours: the measurement was carried out by the method corresponding to reference example 4).

d) About 1 wt.% of magnesium stearate is added to the sieved granules obtained in Example 22-b) and mixed with them, then the mixed granules are fed into a tablet machine (Single type Tablet machine No. 2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.) And tabletted with a stamp to obtain tablets, each of which has a mass of 191 mg.

e) About 1 wt.% of magnesium stearate is added to the sieved granules obtained in Example 22-c) and mixed with them, then the mixed granules are fed into a tabletting machine (Single type Tablet machine No. 2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.) And tabletted with a stamp to obtain tablets, each of which has a mass of 191 mg.

Example 23

a) Using procedures similar to those of Example 17-a), dried granules are obtained containing Type I crystals of aripiprazole anhydride, such as those obtained in Reference Example 2.

b) The resulting granules are sized by sieving and dried by procedures similar to those of Example 17-b).

c) The granules thus obtained are dried by procedures similar to those of Example 17-c).

Example 24

a) By procedures similar to those of Example 18-a), tablets containing aripiprazole hydrate obtained in Reference Example 3 are prepared, each having a weight of 190 mg.

b) The tablets are dried by procedures similar to those of Example 18-b), except that the inlet air temperature is 100 ° C and dried for 1 hour.

c) The tablets are dried by procedures similar to those of Example 18-b), except that the inlet air temperature is 100 ° C and dried for 3 hours.

Dissolution Test

Each of the tablets of pharmaceutical solid oral preparations obtained previously was kept respectively in open space at 25 ° C / 60% RH for 6 months and at 40 ° C / 75% RH for 1 week, then their dissolution rates were measured by the following methods. Dissolution rates obtained after 60 minutes of dissolution are shown in Tables 2 and 3. Dissolution rates after 60 minutes using tablets kept in open space at 40 ° C / 75% RH for 2 weeks are shown in Tables 4 and 5. Rates dissolution after 60 minutes using tablets kept in open space at 40 ° C / 75% RH for 1 week are shown in Table 6.

Solubility Test Equipment: USP Model: NTR-6100 (manufactured by TOYAMA SANGYO CO., LTD) Model: DT-610 (manufactured by JASCO CORPORATION)

a) Test method for solubility of 15 mg tablets

One tablet (containing 15 mg of each of aripiprazole anhydride or aripiprazole hydrate) was tested using 900 ml of acetic acid buffer solution (pH 5.0) (Note: 1) as a test solution and by rotating a paddle stirrer at 100 rpm according to the method of USP (United States Pharmacopeia) (Note: 2).

Test solutions obtained respectively after 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes after the start of the test were designated as T10, T20, T30, T45 and T60.

On the other hand, approximately 0.05 g of a standard sample of aripiprazole was accurately weighed, dissolved in ethanol (95%) to obtain exactly 50 ml of a solution in ethanol. Precisely twenty (20) ml of this solution in ethanol was taken and 0.01 mol / liter of hydrochloric acid reagent solution was added to obtain exactly 1000 ml of standard solution (Note: 3).

The test solutions and the standard solution were subjected to filtration, respectively, using a filter having micropores from 10 to 20 μm in diameter, then each of the filtrates was introduced into a spectrophotometer installed with a flow-type cell (cell length: 10 mm) to measure absorption at a wavelength of 249 nm and absorbances at a wavelength of 325 nm and determined the difference between the absorbances, designated as At10, At20, At30, At45, At60 and As, respectively.

After measurements, the test solutions T10, T20, T30 and T45 were placed back into the test vessels, respectively. Further, similar procedures were performed for the other 5 samples of test solutions.

The dissolution rate (%) related to the specified

amount of aripiprazole = amount of standard sample

aripiprazole (mg) × At × As × 9/5 × 20 / C

where At: At10, At20, At30, At45 or At60

As: standard solution

C: indicated amount of aripiprazole (mg)

(Note: 1) Water is added to 1.97 g of acetic acid (100) and 9.15 g of sodium acetate trihydrate to obtain 1000 ml of a solution (0.1 mol / L).

(Note: 2) Way of paddle mixer

(Note: 3) Water is added to 100 ml of 0.1 mol / L hydrochloric acid (Note: 4) to obtain 1000 ml of a solution.

(Note: 4) Water is added to 0.9 ml of hydrochloric acid to obtain 1000 ml of solution.

b) Method for solubility test of 30 mg tablets

One tablet of each of the pharmaceutical solid oral preparations (containing 30 mg of each of aripiprazole anhydride or aripiprazole hydrate) was tested using 900 ml of acetic acid buffer solution (pH 4.5) (note: 5) as a test solution and the test was carried out by mixing paddle a mixer at 75 rpm according to the method of USP (United States Pharmacopeia) (note: 6).

Test solutions obtained respectively after 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes after the start of the test were designated T10, T20, T30, T45 and T60.

On the other hand, approximately 0.05 g of a standard sample of aripiprazole was weighed and dissolved in ethanol (95%) to obtain exactly 50 ml of a solution in ethanol. Exactly twenty (20) ml of this solution in ethanol was taken and exactly 1000 ml of the standard solution was obtained by adding 0.01 mol / liter of hydrochloric acid reagent solution (Note: 7).

The test solutions and the standard solution were subjected to filtration, respectively, using a filter having micropores from 10 to 20 μm in diameter, then each of the filtrates was introduced into a spectrophotometer installed with a flow-type cell (cell length: 10 mm) and absorbance was measured at a wavelength of 249 nm and absorbance at a wavelength of 325 nm, and the difference between the absorbances designated as At10, At20, At30, At45, At60 and As, respectively, was determined.

After measurements, the test solutions T10, T20, T30 and T45 were placed back into the test vessels, respectively. Further, similar procedures were performed for the other 5 samples of test solutions.

Dissolution rate (%) related to the indicated amount of aripiprazole = amount of the standard sample of aripiprazole (mg) x At × As × 9/5 × 20 / С

where At: At10, At20, At30, At45 or At60

As: standard solution

C: indicated amount of aripiprazole (mg)

(Note: 5) Water was added to 1.91 g of acetic acid (100) and 2.99 g of sodium acetate trihydrate to obtain 1000 ml of a solution (0.05 mol / L).

(Note: 6) Way of paddle mixer

(Note: 7) Water is added to 100 ml of 0.1 mol / L hydrochloric acid (Note: 8) to obtain 1000 ml of a solution.

(Note: 8) Water is added to 0.9 ml of hydrochloric acid to obtain 1000 ml of solution.

table 2 Samples Used Open space at 25 ° C / 60% RH Open space at 40 ° C / 75% RH Initial In 6 months Initial After 1 week Tablet (15 mg) of Reference Example 4 83.4% 44.3% 83.4% 44.1% Tablet (15 mg) of Reference Example 5 90.1% 61.9% 90.1% 65.2% Table 3 Samples Used Open space at 25 ° C / 60% RH Open space at 40 ° C / 75% RH Initial In 6 months Initial After 1 week Tablet (30 mg) of Example 18-a) 96.7% 77.1% 96.7% 75.9% Tablet (30 mg) of Example 17-b) 96.5% 93.6% 95.0% 92.2% Tablet (30 mg) of Example 17-c) 97.0% 96.3% 94.7% 94.8% Tablet (30 mg) of Reference Example 18-b) 97.2% 95.3% 97.2% 97.8% Tablet (30 mg) of Reference Example 18-c) 97.8% 96.3% 97.8% 96.9%

Table 4 Used samples Initial In 2 weeks Samples using the tablet (30 mg) of example 19-a) 89.8% 66.9% Tablet (30 mg) of Example 19-b) - 79.8% Tablet (30 mg) of example 19-c) - 85.9% Table 5 Used samples Initial In 2 weeks Tablet (30 mg) of Example 18-a) 94.8% 94.7% Tablet (30 mg) of Example 20 93.7% 93.1% Tablet (30 mg) of Example 21 94.8% 90.9%

Note: The solubility tests shown in Table 5 were carried out similarly to the procedures in the above “b) solubility test method of a 30 mg tablet, except that 900 ml of acetic acid buffer solution (pH 4.0) was used as the test solution and stirring was carried out with a paddle stirrer at 50 rpm.

As can be clearly seen from the data shown in table 2, compared with a 15 mg tablet containing crystals of ordinary anhydrous aripiprazole (reference example 4), a 15 mg tablet containing type B crystals of anhydrous aripiprazole (reference example 5) had a dissolution rate that maintains the maximum concentration of the drug (Cmax) at pH 5.0 after 60 minutes, even if such a tablet was kept in open space at 25 ° C / 60% RH for 6 months and in open space at 40 ° C / 75% RH in within 1 week.

As can be clearly seen from the data shown in table 3, even if 30 mg tablets (examples 17-b) and 17-c)) obtained from twice-dried granules of type B crystals of anhydrous aripiprazole, and 30 mg tablets (examples 18-b) and 18-c)), obtained from an additionally dried pharmaceutical solid oral preparation containing type B crystals of aripiprazole anhydride, was kept in open space at 25 ° C / 60% RH for 6 months or 40 ° C / 75% RH for 1 weeks, the dissolution rate of these tablets obtained 60 minutes after the start of the test at p H 4.5 did not significantly decrease.

As can be clearly seen from the data shown in table 4, when 30 mg tablets (examples 19-a), 19-b) and 19-c)) containing crystals of ordinary anhydrous aripiprazole were further dried and kept in open space at 40 ° C / 75% RH for 2 weeks, then the dissolution rates of the tablets obtained 60 minutes after the test at pH 4.5 were dissolution rates that maintained the maximum drug concentration (Cmax).

As can be clearly seen from the data shown in table 5, when a 30 mg tablet (example 18-a)) containing type B crystals of an aripiprazole anhydride, 30 mg tablet (example 20) containing type C crystals of an aripiprazole anhydride, and 30 mg tablet ( Example 21) containing type D crystals of aripiprazole anhydride was kept at 40 ° C / 75% RH for 2 weeks, then the dissolution rates of the tablets obtained 60 minutes after the test at pH 4.0 did not significantly decrease.

As can be clearly seen from the data shown in table 6, when a 30 mg tablet (examples 22-d and 22-e)) obtained from granules of the usual aripiprazole hydrate was dried twice and kept at 40 ° C / 75% RH for 1 week , then the dissolution rates of the tablets obtained 60 minutes after the test at pH 4.5 were dissolution rates that maintained the maximum drug concentration (Cmax).

1 sample preparation Aripiprazole Anhydride Crystals B 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200 mg

Tablets containing the above ingredients in each tablet were prepared by methods for preparing a finished formulation known to one skilled in the art of making a pharmaceutical formulation.

2 sample preparation Aripiprazole Anhydride Crystals C 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200 mg

In accordance with the generally accepted method, a tablet preparation was obtained containing the above ingredients per 1 tablet.

3 sample preparation D crystals of aripiprazole anhydrous 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200 mg

In accordance with the generally accepted method, a tablet preparation was obtained containing the above ingredients per 1 tablet.

4 sample preparation Anhydrous Aripiprazole E Crystals 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200 mg

In accordance with the generally accepted method, a tablet preparation was obtained containing the above ingredients per 1 tablet.

5 sample preparation Anhydrous aripiprazole crystals F 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200 mg

In accordance with the generally accepted method, a tablet preparation was obtained containing the above ingredients per 1 tablet.

6 sample preparation G crystals of anhydrous aripiprazole 5 mg Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200 mg

In accordance with the generally accepted method, a tablet preparation was obtained containing the above ingredients per 1 tablet.

Formulation Example

In the following examples, an aripiprazole drug was used, first obtained by grinding or pulverizing the usual aripiprazole hydrate and then heating it to form an anhydrous form (anripiprazole anhydride crystals B).

Formulation Example 1

Fast melting tablets were prepared as follows:

Intragranulation:

Ingredient Percentage, wt./wt. mg per tablet Xylitol (300) xylisorb 26 52 Avicel ^® PH 102 12 24 Calcium silicate 43.35 86.7 Crospovidone 3 6 Amorphous silicon dioxide 2 4 Aspartame 2 4 Sweet smelling fragrance 0.15 0.3 Wine acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 1,5 total weight 92.75 185.5

The ingredients, with the exception of magnesium stearate, were mixed in an industrial V-mixer in geometric proportions for 5 minutes, each, until all the ingredients were added. Then magnesium stearate was added and the mixture was stirred for an additional three minutes. The mixed composition was pressed at a pressure of 30-35 kg / cm ² in an industrial sealant equipped with such an opening so that the compacts from it were in the form of tapes. Tapes were passed through a 30 mesh (600 micron) sieve to form stable granules from about 150 to 400 microns.

Extragranulation Ingredients:

Ingredient Percentage, wt./wt. mg per tablet Intragranulation Product 92.75 185.5 Avicel ^® PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 total weight 100 200

The intragranulation product was placed in a mixer and Avicel® PH 200 and crospovidone were added to it and all was mixed for five minutes. Then magnesium stearate was added and the mixture was stirred for an additional three minutes to form the final mixture. The tablets obtained from it by compression had a breaking force of 2.3 kP (3.5 SCU) and were disintegrated in 5 ml of water in 30 seconds. The final mixture showed excellent flowability and was free from other problems such as breaking, clogging and clumping. It was found that the use of Avicela ^® PH 102 for intragranulation and Avicela ^® PH 200 as an ingredient in extra-granulation improves the quality of the resulting tablets.

Formulation Example 2

Fast melting tablets containing a combination of two types of calcium silicate were prepared as follows:

Intragranulation:

Ingredient Percentage, wt./wt. mg per tablet Xylitol (300) xylisorb 26 52 Avicel ^® PH 102 12 24 Calcium silicate (crystalline, alpha-triclinic) 33.35 66.7 Huersorb 600 NF (Amorphous Calcium Silicate) 10 twenty Crospovidone 3 6 Amorphous silicon dioxide 2 4 Aspartame 2 4 Sweet smelling fragrance 0.15 0.3 Wine acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 total weight 92.75 185.5

The ingredients, with the exception of magnesium stearate, were mixed in an industrial V-mixer in geometric proportions for 5 minutes, each, until all ingredients were added. Then magnesium stearate was added and the mixture was stirred for an additional three minutes. The mixed composition was pressed and sieved with the formation of stable granules in accordance with the procedure of example 1 of the finished formulation.

Extragranulation Ingredients:

Ingredient Percentage, wt./wt. mg per tablet Intragranulation Product 92.75 185.5 Avicel ^® PH 200 3 6 Crospovidone 4 8 Magnesium stearate 0.25 0.5 total weight 100 200

The intragranulation product was placed in a mixer, Avicel ^® PH 200 and crospovidone were added to it, and all were mixed for five minutes. Then magnesium stearate was added and the mixture was stirred for an additional three minutes to form the final mixture. The tablets obtained from it by compression had a breaking force of 2.0 kP (3.1 SCU) and were disintegrated in 10 ml of water in 10 seconds.

Formulation Example 3

Fast melting tablets containing aripiprazole, an anti-schizophrenic drug, were prepared as follows:

Intragranulation:

Ingredient Percentage, wt./wt. mg per tablet Aripiprazole fifteen thirty Xylitol (300) xylisorb 25 fifty Avicel ^® PH 102 6 12 Calcium silicate 37 74 Crospovidone 3 6 Amorphous silicon dioxide 2 4 Aspartame 2 4 Sweet smelling fragrance 0.15 0.3 Wine acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 total weight 94.4 188.8

The ingredients, with the exception of magnesium stearate, were mixed in an industrial V-mixer in geometric proportions for 5 minutes, each, until all ingredients were added. Then magnesium stearate was added and the mixture was stirred for an additional three minutes. The mixed composition was pressed and sieved with the formation of stable granules in accordance with the procedure of example 1 of the finished formulation.

Extragranulation Ingredients:

Ingredient Percentage, wt./wt. mg per tablet Intragranulation Product 94.4 188.8 Avicel ^® PH 200 1.1 2.2 Crospovidone 4 8 Magnesium stearate 1,5 1 total weight 100 200

The intragranulation product was placed in a mixer, Avicel ^® PH 200 and crospovidone were added to it, and all were mixed for five minutes. Then magnesium stearate was added and the mixture was stirred for an additional three minutes to form the final mixture. The tablets obtained from it by compression had a breaking force of 2.0 kP (3.1 SCU) and were disintegrated in 10 ml of water in 10 seconds.

Formulation Example 4

Fast melting tablets containing aripiprazole were prepared as follows:

Intragranulation:

Ingredient Percentage, wt./wt. mg per tablet Aripiprazole 0.5 1 Xylitol (300) xylisorb 27 54 Avicel ^® PH 102 12 24 Calcium silicate 42 84 Crospovidone 3 6 Amorphous silicon dioxide 2 4 Aspartame 2 4 Sweet smelling fragrance 0.15 0.3 Wine acid 2 4 Acesulfame K 2 4 Magnesium stearate 0.25 0.5 total weight 92.9 185.8

The ingredients, with the exception of magnesium stearate, were mixed in an industrial V-mixer in geometric proportions for 5 minutes, each, until all ingredients were added. Magnesium stearate was added and the mixture was stirred for an additional three minutes. The mixed composition was pressed and sieved with the formation of stable granules in accordance with the procedure of example 1 of the finished formulation.

Extragranulation Ingredients: Ingredient Percentage, wt./wt. mg per tablet Intragranulation Product 92.9 185.8 Avicel ^® PH 200 2.6 5.2 Crospovidone 4 8 Magnesium stearate 0.5 1 total weight 100 200

The intragranulation product was placed in a mixer, Avicel ^® PH 200 and crospovidone were added to it, and all were mixed for five minutes. Then magnesium stearate was added and the mixture was stirred for an additional three minutes to form the final mixture. The tablets obtained from it by compression had a breaking force of 2.3 kP (3.5 SCU) and were disintegrated in 10 ml of water in 10 seconds.

Claims (60)

1. Aripiprazole Hydrate A, wherein said hydrate has X-ray powder diffraction spectrum having characteristic peaks of X-ray powder diffraction at 2θ = 12.6 °, 15.4 °, 17.3 °, 18.0 °, 18.6 °, 22.5 ° and 24.8 ° ; characteristic infrared absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963, and 784 cm ^-1 in the IR spectrum (KBr); a weak endothermic peak at 71 ° C and a sharp endothermic peak in the range of 60-120 ° C during thermogravimetric / differential thermal analysis (heating rate of 5 ° C / min), and an average particle size of 50 μm or less. 2. Aripiprazole hydrate A according to claim 1, wherein said hydrate has a range of average particle sizes from 36 to 14 microns. 3. A method of producing aripiprazole hydrate A, wherein said method comprises milling conventional aripiprazole hydrate to an average particle size of 50 μm or less. 4. The method according to claim 3, where the specified grinding is carried out in the installation for the finest grinding using the rotation speed of the main axis 5000-15000 rpm, the rotation speed of the raw material 10-30 rpm and the size of the holes of the sieve 1-5 mm 5. Aripiprazole hydrate A obtained by the method according to claim 3, comprising milling the usual aripiprazole hydrate to an average particle size of 50 μm or less. 6. Hydrate A according to claim 5, where the specified grinding is carried out in the installation for the finest grinding using the rotation speed of the main axis 5000-15000 rpm, the rotation speed of the raw material 10-30 rpm and the size of the holes of the sieve 1-5 mm 7. Anhydrous aripiprazole crystals B that have a powder X-ray diffraction spectrum having characteristic peaks of powder X-ray diffraction at 2θ = 11.0 °, 16.6 °, 19.3 °, 20.3 ° and 22.1 °; characteristic infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960, and 779 cm ⁻¹ in the IR spectrum (KBr); endothermic peak at 141.5 ° C in thermogravimetric / differential thermal analysis (heating rate: 5 ° C / min); endothermic peak at 140.7 ° in differential scanning calorimetry (heating rate of 5 ° C / min). 8. The crystals of anhydrous aripiprazole according to claim 7, having low hygroscopicity, characterized by a moisture content of 0.40% or less after placing the drug crystals B for 24 hours in a desiccator in which a temperature of 60 ° C and a humidity level of 100% are maintained. 9. The crystals of anhydrous aripiprazole of claim 8, having low hygroscopicity, characterized by a moisture content of 0.10% or less after placing the drug crystals of B for 24 hours in a desiccator, which maintains a temperature of 60 ° C and a humidity level of 100%. 10. Crystals B of anhydrous aripiprazole according to claim 7, where these crystals have an average particle size of 50 μm or less. 11. Crystals B of anhydrous aripiprazole of claim 10, where these crystals have an average particle size of 30 μm or less. 12. Crystals B of anhydrous aripiprazole according to claim 7, wherein said crystals of B will not substantially turn into an aqueous form of aripiprazole when properly stored at a relative humidity (RH) of 60% and at a temperature of 25 ° C, even for a long period of not less than 4 years. 13. A method for producing crystals of anhydrous aripiprazole B, wherein said method comprises heating aripiprazole hydrate A according to any one of claims 1 or 2. 14. The method of obtaining crystals of anhydrous aripiprazole according to item 13, where the specified method includes heating aripiprazole hydrate A at 90-125 ° C for 3-50 hours 15. The method of obtaining crystals of anhydrous aripiprazole according to item 13, where the specified method includes heating aripiprazole hydrate A at 100 ° C for 18 hours 16. The method of obtaining crystals of anhydrous aripiprazole according to item 13, where the specified method includes heating aripiprazole hydrate A at 100 ° C for 24 hours 17. The method of obtaining crystals of anhydrous aripiprazole according to item 13, where the specified method includes heating aripiprazole hydrate A at 120 ° C for 3 hours 18. The method for producing crystals of anhydrous aripiprazole B according to claim 13, wherein said method comprises heating aripiprazole hydrate A for 18 hours at 100 ° C, followed by additional heating for 3 hours at 120 ° C. 19. Anhydrous aripiprazole crystals B according to any one of claims 7-12, obtained by a method comprising heating aripiprazole hydrate A according to any one of claim 1 or 2 for 18 hours at 100 ° C, followed by additional heating for 3 hours at 120 ° FROM. 20. A pharmaceutical composition comprising anripiprazole anhydride crystals B of any one of claims 7-12 together with one or more pharmaceutically acceptable carriers. 21. The pharmaceutical composition according to claim 20 in the form of a solid oral tablet. 22. The pharmaceutical composition according to claim 20 in the form of an oral fast-melting tablet. 23. A method for preparing a pharmaceutical solid oral preparation comprising aripiprazole anhydride crystals B as defined in claim 8 and one or more pharmaceutically acceptable carriers by wet granulating a mixture of an aripiprazole anhydride crystals powder B and carriers, wherein the method comprises heating aripiprazole hydrate A, defined in paragraph 1. 24. A method for producing a pharmaceutical solid oral preparation comprising aripiprazole anhydride crystals B as defined in claim 8 and one or more pharmaceutically acceptable carriers by wet granulation of a mixture of an aripiprazole anhydride crystals powder B and carriers, wherein the method comprises heating aripiprazole hydrate A, defined in claim 1, at 90-125 ° C for 3-50 hours 25. A method for producing a pharmaceutical solid oral preparation comprising aripiprazole anhydride crystals B as defined in claim 9 and one or more pharmaceutically acceptable carriers by wet granulating a mixture of an aripiprazole anhydride crystals powder B and carriers, wherein the method comprises heating aripiprazole hydrate A, defined in paragraph 1. 26. A method for producing a pharmaceutical solid oral preparation comprising aripiprazole anhydride crystals B as defined in claim 9 and one or more pharmaceutically acceptable carriers by wet granulating a mixture of an aripiprazole anhydride crystals powder B and carriers, wherein the method comprises heating aripiprazole hydrate A, defined in claim 1, at 90-125 ° C for 3-50 hours 27. Crystals B of anhydrous aripiprazole according to claim 7, where said crystals of B will not substantially turn into an aqueous form of aripiprazole when stored properly at a relative humidity (RH) of 60% and at a temperature of 25 ° C, even for a long period of at least than 1 year. 28. The crystals of anhydrous aripiprazole according to claim 7, where these crystals of B will not essentially turn into an aqueous form of aripiprazole when stored properly at a relative humidity (RH) of 75% and at a temperature of 40 ° C, even for a long period of at least than 0.5 years. 29. A pharmaceutical composition comprising anripiprazole anhydride crystals B of claim 27 or 28 together with one or more pharmaceutically acceptable carriers. 30. The pharmaceutical composition according to clause 29 in the form of a solid oral tablet. 31. The pharmaceutical composition according to clause 29 in the form of an oral fast-melting tablet. 32. A method of treating a violation of the central nervous system, including the introduction of crystals In anhydrous aripiprazole according to claims 7-12, 27-28. 33. A method for the treatment of schizophrenia, including the introduction of crystals In anhydrous aripiprazole according to claims 7-12, 27-28, 34. A method for the treatment of bipolar disorder, comprising the introduction of crystals of anhydrous aripiprazole according to claims 7-12, 27-28. 35. A method for the treatment of intractable (drug-resistant, chronic) schizophrenia with a decrease in mental activity or intractable (drug-resistant, chronic) schizophrenia without a decrease in mental activity, including the introduction of anhydrous aripiprazole crystals B according to claims 7-12, 27-28 . 36. A method of treating autism, Down syndrome, or attention deficit hyperactivity disorder (ADHD), comprising administering anhydrous aripiprazole crystals B as claimed in claims 7-12, 27-28. 37. A method of treating Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, including the introduction of crystals of anhydrous aripiprazole in PP.7-12, 27-28. 38. A method for the treatment of panic disorder, obsessive compulsive disorder (OCD), sleep disorders, sexual dysfunction, alcohol and drug dependence, vomiting, motion sickness, obesity, migraine or mental decline, including the introduction of anripiprazole anhydride crystals B according to claims 7-12 , 27-28. 39. A method of treating anxiety, depression, or mania, comprising administering anripiprazole anhydride crystals B according to claims 7-12, 27-28. 40. A method of treating or preventing schizophrenia or symptoms associated with schizophrenia, comprising administering anripiprazole anhydride crystals B according to claims 7-12, 27-28. 41. A medicament for treating schizophrenia or symptoms associated with schizophrenia, which comprises anhydrous aripiprazole crystals B of claims 7-12, 27-28 in an amount effective to treat schizophrenia or its symptoms, in admixture with a pharmaceutically acceptable carrier. 42. The drug according to paragraph 41, which is contained in a commercial package having instructions that the drug can be used to treat schizophrenia or its symptoms. 43. The method of producing granules of crystals of anhydrous aripiprazole B of claim 8, characterized in that it includes wet granulation of crystals of anhydrous aripiprazole defined in claim 8, drying the obtained granules at 70-100 ° C, sorting them by size and then again drying sieved granules at 70-100 ° C. 44. A method of producing granules of anhydrous aripiprazole crystals B in accordance with claim 9, characterized in that it comprises wet granulation of anhydrous aripiprazole crystals B defined in claim 9, drying the obtained granules at 70-100 ° C, sorting them by size and then again drying sieved granules at 70-100 ° C. 45. A method of obtaining a pharmaceutical solid oral preparation, characterized in that it comprises drying a pharmaceutical solid oral preparation comprising anripiprazole anhydride crystals B, as defined in claim 8, and one or more pharmaceutically acceptable carriers, at 70-100 ° C. 46. A method of obtaining a pharmaceutical solid oral preparation, characterized in that it comprises drying a pharmaceutical solid oral preparation, including anripiprazole anhydride crystals B, indicated in claim 9, and one or more pharmaceutically acceptable carriers, at 70-100 ° C. 47. A pharmaceutical solid oral preparation comprising aripiprazole anhydride crystals B as defined in claim 8 and one or more pharmaceutically acceptable carriers, wherein said pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of 60 % or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes 48. A pharmaceutical solid oral preparation comprising aripiprazole anhydride crystals B as defined in claim 9 and one or more pharmaceutically acceptable carriers, wherein said pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of 60 % or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes 49. A method of producing granules containing anripiprazole anhydride crystals B according to any one of claims 7-12, 27 and 28, characterized in that it includes wet granulation of conventional aripiprazole anhydrous crystals, drying the obtained granules at 70-100 ° C, sorting them by size and then again drying the sieved granules at 70-100 °. 50. A method of obtaining a pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole B according to any one of claims 7-12, 27 and 28, characterized in that it comprises drying a pharmaceutical solid oral preparation comprising conventional crystals of anhydrous aripiprazole and one or more pharmaceutically acceptable carriers at 70-100 ° C. 51. A pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole B according to any one of claims 7-12, 27 and 28, characterized in that it has at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes 52. A pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole B according to any one of claims 7-12, 27 and 28, characterized in that it is obtained by the method according to claim 49, wherein said pharmaceutical solid oral preparation has at least one a dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes. 53. A pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole B according to any one of claims 7-12, 27 and 28, characterized in that it is obtained by the method according to item 50, wherein said pharmaceutical solid oral preparation has at least one a dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes. 54. The method of producing granules containing crystals of anhydrous aripiprazole B according to any one of claims 7-12, 27 and 28, characterized in that it includes wet granulation of ordinary crystals of aripiprazole hydrate, drying the obtained granules at 70-100 ° C, sorting them according to size and then again drying the sieved granules at 70-100 ° C. 55. A method of obtaining a pharmaceutical solid oral preparation containing anripiprazole anhydride crystals B according to any one of claims 7-12, 27 and 28, characterized in that it comprises drying a pharmaceutical solid oral preparation comprising conventional aripiprazole hydrate crystals and one or more pharmaceutically acceptable carriers, at 70-100 ° C. 56. A pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole B according to any one of claims 7-12, 27 and 28, characterized in that it is obtained by the method according to claim 54, wherein said pharmaceutical solid oral preparation has at least one a dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes. 57. A pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole B according to any one of claims 7-12, 27 and 28, characterized in that it is obtained by the method according to claim 55, wherein said pharmaceutical solid oral preparation has at least one a dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes and 55% or more at pH 5.0 after 60 minutes. Priority on points: 09/25/2001 according to claims 1, 3-8, 13-26; 03/27/2002 according to claims 2, 9-12, 27-42; 09/25/2002 according to paragraphs 43-57.

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